Redox-dependent and independent effects of thioredoxin interacting protein

2020 ◽  
Vol 401 (11) ◽  
pp. 1215-1231 ◽  
Author(s):  
Xiankun Cao ◽  
Wenxin He ◽  
Yichuan Pang ◽  
Yu Cao ◽  
An Qin
Keyword(s):  
Glucose Metabolism ◽  
Redox Regulation ◽  
Current Knowledge ◽  
Redox System ◽  
Physiological Effects ◽  
Therapeutic Targeting ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Disease States ◽  
Independent Effects

AbstractThioredoxin interacting protein (TXNIP) is an important physiological inhibitor of the thioredoxin (TXN) redox system in cells. Regulation of TXNIP expression and/or activity not only plays an important role in redox regulation but also exerts redox-independent physiological effects that exhibit direct pathophysiological consequences including elevated inflammatory response, aberrant glucose metabolism, cellular senescence and apoptosis, cellular immunity, and tumorigenesis. This review provides a brief overview of the current knowledge concerning the redox-dependent and independent roles of TXNIP and its relevance to various disease states. The implications for the therapeutic targeting of TXNIP will also be discussed.

scholarly journals Thioredoxin-Interacting Protein Regulates Glucose Metabolism and Affects Cytoplasmic Streaming in Mouse Oocytes

PLoS ONE ◽  
2013 ◽  
Vol 8 (8) ◽  
pp. e70708 ◽  
Author(s):  
Su-Yeon Lee ◽  
Hyun-Seo Lee ◽  
Eun-Young Kim ◽  
Jung-Jae Ko ◽  
Tae Ki Yoon ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Cytoplasmic Streaming ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Mouse Oocytes

scholarly journals Long-Term Exercise Protects against Cellular Stresses in Aged Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Irina Belaya ◽  
Masataka Suwa ◽  
Tao Chen ◽  
Rashid Giniatullin ◽  
Katja M. Kanninen ◽  
...  
Keyword(s):  
Er Stress ◽  
Soleus Muscle ◽  
Redox Regulation ◽  
Wheel Running ◽  
Interacting Protein ◽  
Aged Mice ◽  
Thioredoxin Interacting Protein ◽  
Age Related ◽  
Cellular Stresses

The current study examined the effect of aging and long-term wheel-running on the expression of heat shock protein (HSP), redox regulation, and endoplasmic reticulum (ER) stress markers in tibialis anterior (T.A.) and soleus muscle of mice. Male mice were divided into young (Y, 3-month-old), old-sedentary (OS, 24-month-old), and old-exercise (OE, 24-month-old) groups. The OE group started voluntary wheel-running at 3 months and continued until 24 months of age. Aging was associated with a higher thioredoxin-interacting protein (TxNiP) level, lower thioredoxin-1 (TRX-1) to TxNiP ratio—a determinant of redox regulation and increased CHOP, an indicator of ER stress-related apoptosis signaling in both muscles. Notably, GRP78, a key indicator of ER stress, was selectively elevated in T.A. Long-term exercise decreased TxNiP in T.A. and soleus muscles and increased the TRX-1/TxNiP ratio in soleus muscle of aged mice. Inducible HSP70 and constituent HSC70 were upregulated, whereas CHOP was reduced after exercise in soleus muscle. Thus, our data demonstrated that aging induced oxidative stress and activated ER stress-related apoptosis signaling in skeletal muscle, whereas long-term wheel-running improved redox regulation, ER stress adaptation and attenuated ER stress-related apoptosis signaling. These findings suggest that life-long exercise can protect against age-related cellular stress.

scholarly journals The Complexity of Sporadic Alzheimer’s Disease Pathogenesis: The Role of RAGE as Therapeutic Target to Promote Neuroprotection by Inhibiting Neurovascular Dysfunction

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Lorena Perrone ◽  
Oualid Sbai ◽  
Peter P. Nawroth ◽  
Angelika Bierhaus
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Current Knowledge ◽  
Amyloid Peptide ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Glycation End Products ◽  
Cellular Dysfunction ◽  
Neurovascular Dysfunction

Alzheimer's disease (AD) is the most common cause of dementia. Amyloid plaques and neurofibrillary tangles are prominent pathological features of AD. Aging and age-dependent oxidative stress are the major nongenetic risk factors for AD. The beta-amyloid peptide (Aβ), the major component of plaques, and advanced glycation end products (AGEs) are key activators of plaque-associated cellular dysfunction. Aβ and AGEs bind to the receptor for AGEs (RAGE), which transmits the signal from RAGE via redox-sensitive pathways to nuclear factor kappa-B (NF-κB). RAGE-mediated signaling is an important contributor to neurodegeneration in AD. We will summarize the current knowledge and ongoing studies on RAGE function in AD. We will also present evidence for a novel pathway induced by RAGE in AD, which leads to the expression of thioredoxin interacting protein (TXNIP), providing further evidence that pharmacological inhibition of RAGE will promote neuroprotection by blocking neurovascular dysfunction in AD.

scholarly journals Thioredoxin-interacting protein: an oxidative stress-related gene is upregulated by glucose in human prostate carcinoma cells

2008 ◽  
Vol 42 (3) ◽  
pp. 205-214 ◽  
Author(s):  
See-Tong Pang ◽  
Wen-Chi Hsieh ◽  
Cheng-Keng Chuang ◽  
Chun-Hsiang Chao ◽  
Wen-Hui Weng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Glucose Metabolism ◽  
Prostate Carcinoma ◽  
Promoter Activity ◽  
Carcinoma Cells ◽  
Human Prostate ◽  
Response Element ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Human Prostate Carcinoma

Thioredoxin-interacting protein (TXNIP), also known as vitamin-D3 upregulated protein 1, interacts with reduced thioredoxin. This protein modulates the cellular redox state and plays a role in stress-induced cellular apoptosis. This study examined TXNIP gene expression in prostate cancer cells. In vitro studies by immunoblot assay have shown that elevated glucose levels (1–15 mM) upregulate TXNIP gene expression two- to fourfold in human prostate carcinoma cells (LNCaP) and hepatocellular carcinoma cells (HepG2). Transient gene expression assays reveal that the promoter activity of the TXNIP gene is upregulated by glucose, 3-O-methylglucose, and maltose, but not by mannitol. These results suggest that glucose and 3-O-methylglucose induce TXNIP expression through both glucose metabolism-dependent and -independent pathways. Cotransfection of a plasmid expression carbohydrate response element-binding protein (ChREBP) with a TXNIP reporter vector into LNCaP cells dramatically enhances reporter activity in a low glucose (1 mM) condition. The effects of glucose are apparently mediated in a region located −341 to −324 bp upstream of the translational starting point of the TXNIP gene as indicated by 5′-deletion and site-directed mutagenesis reporter assays. Mutation of the putative carbohydrate response element (ChoRE) from CACGAGGGCAGCACGAG to TTTGAGGGCAGCACGAG abolishes glucose upregulation of TXNIP promoter activity. The present study demonstrates that TXNIP is transcription induced in both LNCaP and HepG2 cells in an increased glucose metabolism-dependent or -independent response, and a putative glucose regulatory system including ChREBP and ChoRE is needed for glucose-induced TXNIP gene in human prostate carcinoma cells.

scholarly journals MondoA senses adenine nucleotides: transcriptional induction of thioredoxin-interacting protein

2013 ◽  
Vol 453 (2) ◽  
pp. 209-218 ◽  
Author(s):  
Kyoung-Sim Han ◽  
Donald E. Ayer
Keyword(s):  
Gene Expression ◽  
Feedback Inhibition ◽  
Adenine Nucleotide ◽  
Adenine Nucleotides ◽  
Interacting Protein ◽  
Kinase Activation ◽  
Thioredoxin Interacting Protein ◽  
Glucose Homoeostasis ◽  
Independent Effects ◽  
Adenine Nucleotide Pool

The MondoA–Mlx transcription complex plays a pivotal role in glucose homoeostasis by activating target gene expression in response to G6P (glucose 6-phosphate), the first reaction intermediate in glycolysis. TXNIP (thioredoxin-interacting protein) is a direct and glucose-responsive target of MondoA that triggers a negative-feedback loop by restricting glucose uptake when G6P levels increase. We show in the present study that TXNIP expression is also activated by AICAR (5-amino-4-imidazolecarboxamide ribofuranoside) and adenosine. Using pharmacological inhibitors and genetic knockdowns of purine metabolic enzymes, we establish that TXNIP induction by AICAR and adenosine requires their cellular uptake and metabolism to adenine nucleotides. AICAR induction of TXNIP depended on MondoA, but was independent of AMPK (AMP-activated protein kinase) activation and calcium. The findings of the present study have two important implications. First, in addition to activating AMPK, AICAR may have AMPK-independent effects on gene expression by regulating MondoA–Mlx activity following its flux into the adenine nucleotide pool. Secondly, MondoA–Mlx complexes sense elevated levels of G6P and adenine nucleotides to trigger a TXNIP-dependent feedback inhibition of glycolysis. We propose that this mechanism serves as a checkpoint to restore metabolic homoeostasis.

Abstract 108: Thioredoxin-interacting Protein Interacts with Glucose Transporters to Regulate Cardiac Glucose Metabolism

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Bing F Wang ◽  
Ronald B Myers ◽  
Gregory M Fomovsky ◽  
Samuel Lee ◽  
Parth Patwari ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Glucose Transporters ◽  
Cardiac Response ◽  
Diabetic Mice ◽  
Adrenergic Stimulation ◽  
Functional Reserve ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein

A change in basal glucose transport into skeletal muscle, heart, and adipose is a critical feature of insulin resistance and diabetes. Glucose transport is tightly regulated by a protein family of glucose transporters (GLUTs). Thus, defining how cardiomyocytes adapt to changes in extracellular and intracellular glucose concentrations by recruiting GLUTs is crucial to understanding cardiac metabolism under both normal and diabetic conditions. Thioredoxin-Interacting Protein (Txnip), originally characterized as a binding partner of antioxidant thioredoxin, is now known to be a member of the arrestin protein superfamily. We have previously shown that glucose uptake is robustly enhanced in Txnip-knockout hearts; however, the precise mechanism for this effect remains elusive. Here, we present a novel feedback mechanism by which Txnip controls glucose metabolism. High glucose levels induced Txnip expression in rat cardiomyocytes in vitro and in the myocardium of streptozotocin (STZ)-induced diabetic mice in vivo. Our proteomic and functional analyses found that Txnip directly interacts with GLUT1 and GLUT4 and strikingly inhibits cellular glucose uptake through direct interactions with GLUTs. Using inducible cardiac-specific deletion of Txnip (Txnip-CKO), we further demonstrated that Txnip plays a functional role in STZ-induced diabetic cardiomyopathy. While β-adrenergic challenge revealed a blunted myocardial inotropic response in wild type diabetic animals, Txnip-CKO diabetic mice retained a greater cardiac response to β-adrenergic stimulation. An ex vivo analysis of perfused hearts further demonstrated that the enhanced functional reserve afforded by deletion of Txnip was associated with myocardial glucose utilization during β-adrenergic stimulation. Thus, a high extracellular glucose concentration represses glucose uptake into the cytoplasm via Txnip-mediated inhibition of GLUTs. The metabolic alterations affected by Txnip deletion promote myocardial glucose uptake, directing cardiomyocyte towards enhanced functional reserve under diabetic conditions. These results provide a novel link between GLUTs and Txnip and highlight a fundamental regulatory mechanism of glucose homeostasis in the heart.

scholarly journals Thioredoxin-interacting protein regulates glucose metabolism and improves the intracellular redox state in bovine oocytes during in vitro maturation

2020 ◽  
Vol 318 (3) ◽  
pp. E405-E416
Author(s):  
XiaoLong Jiang ◽  
YunWei Pang ◽  
ShanJiang Zhao ◽  
HaiSheng Hao ◽  
XueMing Zhao ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Oocyte Maturation ◽  
In Vitro Maturation ◽  
Mrna Levels ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Glut1 Expression ◽  
Bovine Oocytes

The extent of glucose metabolism during oocyte maturation is closely related to oocyte developmental potential. Thioredoxin-interacting protein (TXNIP) is an α-arrestin family protein that negatively regulates glucose uptake into cells. However, little information is available regarding the function of TXNIP in bovine oocytes. Accordingly, the present study was performed to investigate the influence of TXNIP on glucose metabolism in bovine oocytes during in vitro maturation. Pharmacological inhibition of TXNIP by azaserine enhanced glucose uptake and imparted a specific metabolic effect on glycolysis and pentose phosphate pathway (PPP). RNA interference (RNAi) was adopted to further determine the biological significance of TXNIP in regulating glucose metabolism. The maturation rate and the developmental competence of TXNIP siRNA-treated oocytes were significantly improved. Knockdown of TXNIP in bovine oocytes significantly increased glycolysis by increasing the activities of phosphofructokinase (PFK), pyruvate kinase, and lactate dehydrogenase; pyruvate and lactate production; and intracellular ATP level, as well as mitochondrial activity. Furthermore, glucose metabolism through PPP was also enhanced by TXNIP depletion, as TXNIP siRNA treatment promoted glucose-6-phosphate dehydrogenase (G6PDH) activity and NADPH content, and helped maintain a high level of glutathione and a low level of reactive oxygen species within the oocytes. Further studies revealed that inhibition of TXNIP resulted increases in glucose transporter 1 (GLUT1) expression, as well as PFK1 platelet isoform ( PFKP) and G6PDH mRNA levels. These results reveal that TXNIP depletion promotes oocyte maturation by enhancing both glycolysis and the PPP. During in vitro maturation of bovine oocytes, TXNIP serves as a key regulator of glucose uptake by controlling GLUT1 expression.

scholarly journals Unique Aspects of the Developing Lung Circulation: Structural Development and Regulation of Vasomotor Tone

2016 ◽  
Vol 6 (4) ◽  
pp. 407-425 ◽  
Author(s):  
Yuangsheng Gao ◽  
David N. Cornfield ◽  
Kurt R. Stenmark ◽  
Bernard Thébaud ◽  
Steven H. Abman ◽  
...  
Keyword(s):  
Lung Development ◽  
Lung Diseases ◽  
Vascular Tone ◽  
Current Knowledge ◽  
Normal Lung ◽  
Pulmonary Vasculature ◽  
Structural Development ◽  
Vasomotor Tone ◽  
Disease States ◽  
Vasculogenesis And Angiogenesis

This review summarizes our current knowledge on lung vasculogenesis and angiogenesis during normal lung development and the regulation of fetal and postnatal pulmonary vascular tone. In comparison to that of the adult, the pulmonary circulation of the fetus and newborn displays many unique characteristics. Moreover, altered development of pulmonary vasculature plays a more prominent role in compromised pulmonary vasoreactivity than in the adult. Clinically, a better understanding of the developmental changes in pulmonary vasculature and vasomotor tone and the mechanisms that are disrupted in disease states can lead to the development of new therapies for lung diseases characterized by impaired alveolar structure and pulmonary hypertension.

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