Role of Thioredoxin-Interacting Protein in Diseases and Its Therapeutic Outlook (original) (raw)
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Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy
Diabetes mellitus (DM) is a common metabolic disorder which is characterized by a persistent increment of blood glucose. Globally, DM affects millions of people and the prevalence is increasing alarmingly. The critical step in the pathophysiology of DM is the loss of βcells of the pancreas, which are responsible for the secretion of insulin. Thioredoxin-interacting protein (TXNIP) is among the factors that control the production and loss of the pancreatic βcells. TXNIP is an α-arrestin that can bind and inhibit thioredoxin (the antioxidant protein) which is produced in the pancreatic islet after glucose intake. Numerous studies illustrated that elevated TXNIP levels were found to induce β-cell apoptosis; whereas TXNIP deficiency protects against type I and type II diabetes by promoting β-cell survival. Nowadays, TXNIP depletion is becoming a key factor in pancreatic β-cell survival enhancement. In the present review, targeting TXNIP is found to be relevant as a unique therapeutic opportunity, not only to improve insulin secretion and sensitivity, but also ameliorating the long term microvascular and macrovascular complications of the disease. Thus, TXNIP inhibitors that could reduce the expression and/or activity of TXNIP to non-diabetic levels are promising agents to halt the alarming rate of diabetes and its related complications.
Emerging potential of thioredoxin and thioredoxin interacting proteins in various disease conditions
Biochimica et Biophysica Acta (BBA) - General Subjects, 2008
Reactive oxygen species (ROS) are known to be mediators of intracellular signaling pathways. However the excessive production of ROS may be detrimental to the cell as a result of the increased oxidative stress and loss of cell function. Hence, well tuned, balanced and responsive antioxidant systems are vital for proper regulation of the redox status of the cell. The cells are normally able to defend themselves against the oxidative stress induced damage through the use of several antioxidant systems. Even though the free radical scavenging enzymes such as superoxide dismutase (SOD) and catalase can handle huge amounts of reactive oxygen species, should these systems fail some reactive molecules will evade the detoxification process and damage potential targets. In such a scenario, cells recruit certain small molecules and proteins as 'rescue specialists' in case the 'bodyguards' fail to protect potential targets from oxidative damage. The thioredoxin (Trx) system thus plays a vital role in the maintenance of a reduced intracellular redox state which is essential for the proper functioning of each individual cell. Trx alterations have been implicated in many diseases such as cataract formation, ischemic heart diseases, cancers, AIDS, complications of diabetes, hypertension etc. The interactions of Trx with many different proteins and different metabolic and signaling pathways as well as the significant species differences make it an attractive target for therapeutic intervention in many fields of medical science. In this review, we present, the critical roles that thioredoxins play in limiting oxidant stress through either its direct effect as an antioxidant or through its interactions with other key signaling proteins (thioredoxin interacting proteins) and its implications in various disease models.
Thioredoxin/Txnip: redoxisome, as a redox switch for the pathogenesis of diseases
During the past few decades, it has been widely recognized that Reduction-Oxidation (redox) responses occurring at the intra- and extra-cellular levels are one of most important biological phenomena and dysregulated redox responses are involved in the initiation and progression of multiple diseases. Thioredoxin1 (Trx1) and Thioredoxin2 (Trx2), mainly located in the cytoplasm and mitochondria, respectively, are ubiquitously expressed in variety of cells and control cellular reactive oxygen species by reducing the disulfides into thiol groups. Thioredoxin interacting protein (Txnip/thioredoxin binding protein-2/vitamin D3 upregulated protein) directly binds to Trx1 and Trx2 (Trx) and inhibit the reducing activity of Trx through their disulfide exchange. Recent studies have revealed that Trx1 and Txnip are involved in some critical redox-dependent signal pathways including NLRP-3 inflammasome activation in a redox-dependent manner. Therefore, Trx/Txnip, a redox-sensitive signaling complex is a regulator of cellular redox status and has emerged as a key component in the link between redox regulation and the pathogenesis of diseases. Here, we review the novel functional concept of the redox-related protein complex, named “Redoxisome,” consisting of Trx/Txnip, as a critical regulator for intra- and extra-cellular redox signaling, involved in the pathogenesis of various diseases such as cancer, autoimmune disease, and diabetes.
Biochemical and Biophysical Research Communications, 2009
Oxidative stress induced by hyperglycemia is a key factor in the development of cardiovascular diseases in diabetes. Thioredoxin (Trx) system, a major thiol antioxidant system, regulates the reduction of intracellular reactive oxygen species (ROS). In this study, we demonstrated that high glucose significantly increased intracellular ROS levels in human aortic endothelial cells (HAECs). Additionally, high glucose reduced the antioxidant activity of thioredoxin. To investigate the mechanisms involved, we found that glucose enhanced the expression of thioredoxin interacting protein (Txnip), a Trx inhibitory protein, through p38 mitogen-activated protein kinase (MAPK). We also showed that glucose regulated Txnip at transcription level and p38 MAPK and forkhead box O1 transcriptional factor (FOXO1) were involved in the process. Taken together, upregulation of Txnip and subsequent impairment of thioredoxin antioxidative system through p38 MAPK and FOXO1 may represent a novel mechanism for glucose-induced increase in intracellular ROS.
Thioredoxin-Interacting Protein: A Critical Link Between Glucose Toxicity and -Cell Apoptosis
Diabetes, 2008
OBJECTIVE—In diabetes, glucose toxicity affects different organ systems, including pancreatic islets where it leads to β-cell apoptosis, but the mechanisms are not fully understood. Recently, we identified thioredoxin-interacting protein (TXNIP) as a proapoptotic β-cell factor that is induced by glucose, raising the possibility that TXNIP may play a role in β-cell glucose toxicity. RESEARCH DESIGN AND METHODS—To assess the effects of glucose on TXNIP expression and apoptosis and define the role of TXNIP, we used INS-1 β-cells; primary mouse islets; obese, diabetic BTBR.ob mice; and a unique mouse model of TXNIP deficiency (HcB-19) that harbors a natural nonsense mutation in the TXNIP gene. RESULTS—Incubation of INS-1 cells at 25 mmol/l glucose for 24 h led to an 18-fold increase in TXNIP protein, as assessed by immunoblotting. This was accompanied by increased apoptosis, as demonstrated by a 12-fold induction of cleaved caspase-3. Overexpression of TXNIP revealed that TXNIP induces ...
FEBS Letters, 2006
The thioredoxin system, composed of thioredoxin and thioredoxin reductase, emerges as one of the most important thiol-based systems involved in the maintenance of the cellular redox balance. Thioredoxin-like-1 (TXL-1) is a highly conserved protein comprising an N-terminal thioredoxin domain and a C-terminal domain of unknown function. Here we show that TXL-1 is a substrate for the cytosolic selenoprotein thioredoxin reductase. In situ hybridization experiments demonstrates high expression of Txl-1 mRNA in various areas of central nervous system and also in some reproductive organs. Glucose deprivation, but not hydrogen peroxide treatment, reduced the levels of endogenous TXL-1 protein in HEK-293 cell line. Conversely, overexpression of TXL-1 protects against glucose deprivation-induced cytotoxicity. Taken together, the finding that Txl-1 mRNA is highly expressed in tissues which use glucose as a primary energy source and the modulation of TXL-1 levels upon glucose deprivation indicate that TXL-1 might be involved in the cellular response to sugar starvation stress.
Cardiovascular & Hematological Disorders-Drug Targets, 2008
The regulation of cellular reduction/oxidation (redox) balance is critically determined by several antioxidant systems such as the thioredoxin-1 (Trx-1) which reduces disulfides on targeted proteins. In addition, intracellular Trx-1 exerts most of its antioxidant properties through scavenging of reactive oxygen species. Moreover, it acts as a cofactor for several enzymes and plays an important role in the regulation of redox-sensitive transcription factors. Several studies have reported that Trx-1 activity can be modulated by the interaction with vitamin D3-upregulated protein (VDUP-1) (also called Txnip for thioredoxin interacting protein-1 or TBP-2 for Trx-binding protein-2). Trx-1 secretion has been reported to occur in conditions associated with oxidative stress and inflammation. Beneficial effects of elevated plasma Trx-1 levels on various pathologies were reported in mice. In conclusion, oxidative stress is an important actor in various pathologies including cardio-and cerebro-vascular diseases. Therefore, controlling the redox status by increasing the activity of Trx-1 seems to be a novel and an attractive approach.
Thioredoxin and related molecules-from biology to health and disease - Comprehensive Invited Review
ANTIOXIDANTS & REDOX SIGNALING, 2007
Thioredoxin and glutaredoxin systems in mammalian cells utilize thiol and selenol groups to maintain a reducing intracellular redox state acting as antioxidants and reducing agents in redox signaling with oxidizing reactive oxygen species. During the last decade, the functional roles of thioredoxin in particular have continued to expand, also including novel functions such as a secreted growth factor or a chemokine for immune cells. The role of thioredoxin and glutaredoxin in antioxidant defense and the role of thioredoxin in controlling recruitment of inflammatory cells offer potential use in clinical therapy. The fundamental differences between bacterial and mammalian thioredoxin reductases offer new principles for treatment of infections. Clinical drugs already in use target the active site selenol in thioredoxin reductases, inducing cell death in tumor cells. Thioredoxin and binding proteins (ASK1 and TBP2) appear to control apoptosis or metabolic states such as carbohydrate and lipid metabolism related to diseases such as diabetes and atherosclerosis. Antioxid. Redox Signal. 9, e.g. transcription factors, metabolic enzymes e.g. ribonucleotide reductase, Met sulfoxide reductase e.g. vaccina, HTLV, HIV thiol redox control viruses NO metabolism chemokine/ cytokine reductive enzymes TBP2 protein folding peroxiredoxins ASK1 apoptosis peroxide metabolism Trx FIG.
Redox Regulation by Thioredoxin and Thioredoxin-Binding Proteins
IUBMB Life (International Union of Biochemistry and Molecular Biology: Life), 2001
Recent works have shown the importance of reduction/oxidation (redox) regulation in various biological phenomena. Thioredoxin is a 12-kDa protein with redox-active dithiol in the active site-Cys-Gly-Pro-Cys-and constitutes a major thiol reducing system, the thioredoxin system. Thioredoxin plays multiple roles in cellular processes such as proliferation or apoptosis. It also promotes DNA binding of transcription factors such as NF-•B, AP-1, p53, and PEBP2. Overexpression of thioredoxin suppresses the degradation of I•B and the transactivation of NF-•B, whereas overexpression of nuclear-targeted thioredoxin exhibits the enhancement of NF-•B-dependent transactivation. ASK1, a MAP kinase kinase kinase mediating the TNF-® signal has been identi ed as a thioredoxin binding protein. Thioredoxin shows an inhibitory effect on the TNF-® induced activation of ASK1 and p38 MAP kinase pathway. We identi ed p40phox as the thioredoxin binding protein-1 (TBP-1) and vitamin D3 up-regulated protein 1 (VDUP1) as the thioredoxin binding protein-2 (TBP-2) by yeast two-hybrid system. TBP-2/VDUP1 negatively regulates the expression and reducing activity of thioredoxin. Thioredoxin interacting proteins may be involved in thioredoxin-mediating redox regulation.