ORCID Profile
0000-0002-1018-2798
Current Organisations
Norwegian University of Life Sciences
,
Griffith University
,
University of Adelaide
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Publisher: OAE Publishing Inc.
Date: 2021
Publisher: MDPI AG
Date: 03-03-2020
Abstract: Chronic myeloid leukaemia (CML) is currently treated with inhibitors of the CML specific oncoprotein, bcr-abl. While this strategy is initially successful, drug resistance can become a problem. Therefore, new targets need to be identified to ensure the disease can be appropriately managed. The thioredoxin (Trx) system, comprised of Trx, thioredoxin reductase (TrxR), and NADPH, is an antioxidant system previously identified as a target for therapies aimed at overcoming drug resistance in other cancers. We assessed the effectiveness of TrxR inhibitors on drug resistant CML cells and examined links between TrxR and the bcr-abl cell-signalling pathway. Two TrxR inhibitors, auranofin and [Au(d2pype)2]Cl, increased intracellular ROS levels and elicited apoptosis in both sensitive and imatinib resistant CML cells. Inhibition of TrxR activity by these pharmacological inhibitors, or by specific siRNA, also resulted in decreased bcr-abl mRNA and protein levels, and lower bcr-abl downstream signalling activity, potentially enhancing the effectiveness of TrxR inhibitors as CML therapies. In addition, imatinib resistant CML cell lines showed upregulated expression of the Trx system. Furthermore, analysis of datasets showed that CML patients who did not respond to imatinib had higher Trx mRNA levels than patients who responded to treatment. Our study demonstrates a link between the Trx system and the bcr-abl protein and highlights the therapeutic potential of targeting the Trx system to improve CML patients’ outcomes.
Publisher: Springer Science and Business Media LLC
Date: 22-11-2001
Abstract: Thioredoxin reductase (TR) is a redox active protein involved in many cellular processes as part of the thioredoxin system. Presently there are three recognised forms of mammalian thioredoxin reductase designated as TR1, TR3 and TGR, that represent the cytosolic, mitochondrial and novel forms respectively. In this study we elucidated the genomic organisation of the mouse (Txnrd1) and human thioredoxin reductase 1 genes (TXNRD1) through library screening, restriction mapping and database mining. The human TXNRD1 gene spans 100 kb of genomic DNA organised into 16 exons and the mouse Txnrd1 gene has a similar exon/intron arrangement. We also analysed the alternative splicing patterns displayed by the mouse and human thioredoxin reductase 1 genes and mapped the different mRNA isoforms with respect to genomic organisation. These isoforms differ at the 5' end and encode putative proteins of different molecular mass. Genomic DNA sequences upstream of mouse exon 1 were compared to the human promoter to identify conserved elements. The human and mouse thioredoxin reductase 1 gene organisation is highly conserved and both genes exhibit alternative splicing at the 5' end. The mouse and human promoters share some conserved sequences.
Publisher: Future Science Ltd
Date: 05-2011
DOI: 10.2144/000113666
Publisher: Oxford University Press (OUP)
Date: 1989
Abstract: The aim of this article was to use continuous glucose error-grid analysis (CG-EGA) to assess the accuracy of two time-series modeling methodologies recently developed to predict glucose levels ahead of time using continuous glucose monitoring (CGM) data. We considered subcutaneous time series of glucose concentration monitored every 3 minutes for 48 hours by the minimally invasive CGM sensor Glucoday® (Menarini Diagnostics, Florence, Italy) in 28 type 1 diabetic volunteers. Two prediction algorithms, based on first-order polynomial and autoregressive (AR) models, respectively, were considered with prediction horizons of 30 and 45 minutes and forgetting factors (ff) of 0.2, 0.5, and 0.8. CG-EGA was used on the predicted profiles to assess their point and dynamic accuracies using original CGM profiles as reference. Continuous glucose error-grid analysis showed that the accuracy of both prediction algorithms is overall very good and that their performance is similar from a clinical point of view. However, the AR model seems preferable for hypoglycemia prevention. CG-EGA also suggests that, irrespective of the time-series model, the use of ff = 0.8 yields the highest accurate readings in all glucose ranges. For the first time, CG-EGA is proposed as a tool to assess clinically relevant performance of a prediction method separately at hypoglycemia, euglycemia, and hyperglycemia. In particular, we have shown that CG-EGA can be helpful in comparing different prediction algorithms, as well as in optimizing their parameters.
Publisher: MDPI AG
Date: 13-01-2021
Abstract: Lymphoma is a blood cancer comprising various subtypes. Although effective therapies are available, some patients fail to respond to treatment and can suffer from side effects. Antioxidant systems, especially the thioredoxin (Trx) and glutathione (GSH) systems, are known to enhance cancer cell survival, with thioredoxin reductase (TrxR) recently reported as a potential anticancer target. Since the GSH system can compensate for some Trx system functions, we investigated its response in three lymphoma cell lines after inhibiting TrxR activity with [Au(d2pype)2]Cl, a known TrxR inhibitor. [Au(d2pype)2]Cl increased intracellular reactive oxygen species (ROS) levels and induced caspase-3 activity leading to cell apoptosis through inhibiting both TrxR and glutathione peroxidase (Gpx) activity. Expression of the tumour suppresser gene TXNIP increased, while GPX1 and GPX4 expression, which are related to poor prognosis of lymphoma patients, decreased. Unlike SUDHL2 and SUDHL4 cells, which exhibited a decreased GSH/GSSG ratio after treatment, in KMH2 cells the ratio remained unchanged, while glutathione reductase and glutaredoxin expression increased. Since KMH2 cells were less sensitive to treatment with [Au(d2pype)2]Cl, the GSH system may play a role in protecting cells from apoptosis after TrxR inhibition. Overall, our study demonstrates that inhibition of TrxR represents a valid therapeutic approach for lymphoma.
Publisher: MDPI AG
Date: 20-02-2023
Abstract: Diffuse large B-cell lymphoma (DLBCL) is a haematological malignancy representing the most diagnosed non-Hodgkin’s lymphoma (NHL) subtype. Despite the approved chemotherapies available in clinics, some patients still suffer from side effects and relapsed disease. Recently, studies have reported the role of the Trx system and the BCR signalling pathway in cancer development and drug resistance. In this regard, we assessed a potential link between the two systems and evaluated the effects of [Au(d2pype)2]Cl (TrxR inhibitor) and ibrutinib (BTK inhibitor) alone and in combination on the cell growth of two DLBCL lymphoma cell lines, SUDHL2 and SUDHL4. In this study, we show higher expression levels of the Trx system and BCR signalling pathway in the DLBCL patient s les compared to the healthy s les. The knockdown of TrxR using siRNA reduced BTK mRNA and protein expression. A combination treatment with [Au(d2pype)2]Cl and ibrutinib had a synergistic effect on the inhibition of lymphoma cell proliferation, the activation of apoptosis, and, depending on lymphoma cell subtype, ferroptosis. Decreased BTK expression and the cytoplasmic accumulation of p65 were observed after the combination treatment in the DLBCL cells, indicating the inhibition of the NF-κB pathway. Thus, the co-targeting of BTK and TrxR may be an effective therapeutic strategy to consider for DLBCL treatment.
Publisher: Elsevier BV
Date: 10-1994
Abstract: Cardiac troponin I (troponin Ic) expression is restricted to the heart at all stages of Xenopus development. Whole-mount in situ hybridization and Northern blot analysis indicates that troponin Ic is first expressed in tailbud embryos (stage 28) about the time of the first cytological heart differentiation and about 24 hr before beating tissue is observed. We have used this marker to examine abnormal heart morphogenesis in embryos treated with retinoic acid and lithium. When retinoic acid is administered to embryos prior to heart specification, heart tissue is reduced and often completely ablated. When embryos are treated after heart specification, but before the heart primordium migrates to the ventral midline, the migration is unaffected but smaller, abnormal hearts result. Lithium treatment of cleavage stage embryos causes an increase in heart tissue. In severely dorsalized embryos, heart tissue can be found around the entire embryo with the exception of a small gap at the most dorsal point. This gap indicates that migration of the heart to the ventral midline does not occur in these embryos. Later in development, a centrally located, beating heart is observed in dorsalized embryos. The timing of its appearance suggests that it is formed by movements normally associated with heart morphogenesis rather than migration.
Publisher: Springer Science and Business Media LLC
Date: 24-05-2006
Abstract: The Hox family of homeodomain transcription factors regulate numerous pathways during developmental and normal cellular processes. All Hox proteins recognise similar sequences in vitro yet display functional ersity in an in vivo environment. This review focuses on the transcriptional and functional specificity elicited by Hox proteins, giving an overview of homeodomain-DNA interactions and the gain of binding specificity through cooperative binding with cofactors. Furthermore, currently identified mammalian Hox target genes are presented, of which the most striking feature is that very few direct Hox targets have been identified. The direct targets participate in an array of cellular functions including organogenesis and cellular differentiation, cell adhesion and migration and cell cycle and apoptotic pathways. A further assessment of identified mammalian promoter targets and the contribution of bases outside the canonical recognition motif is given, highlighting roles they may play in either trans-activation or repression by Hox proteins.
Publisher: Future Science Ltd
Date: 12-2001
DOI: 10.2144/01316BM02
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.EJCB.2016.08.003
Abstract: As essential elements of the tumor microenvironment, the variable oxygenation state of the tumor tissue, the extracellular matrix (ECM) and different cell types are important determinants of carcinogenesis. These elements may also influence how tumor cells respond to therapeutic treatments. In the present study, we assessed the anti-cancer activity of auranofin and its effect on the thioredoxin (Trx) system under conditions that closely resemble the in vivo tumor microenvironment with respect to the oxygen levels and tissue architecture. We utilised an oxygen scheme involving growth of cancer cells under normoxia (20%) and hypoxia (0.1%). We also preconditioned cells with intermittent hypoxia (IH) prior to a prolonged hypoxic incubation. This oxygen scheme did not affect the cytotoxicity of auranofin however, IH preconditioned cells were less sensitive towards the inhibition of thioredoxin reductase (TrxR) specific activity upon treatment with auranofin. IH preconditioning also upregulated Trx protein levels in auranofin treated cells. We also compared the activity of auranofin against cancer cells cultured in 2D monolayer and 3D spheroid-based culture models. Auranofin was less potent against cells grown under a more in vivo-like 3D environment. The results presented in this paper implicate the importance of the tumor oxygen environment and tissue architecture in influencing the response of cancer cells towards auranofin.
Publisher: Informa UK Limited
Date: 16-02-2016
Publisher: InTech
Date: 23-01-2013
DOI: 10.5772/55185
Publisher: Modestum Publishing Ltd
Date: 21-06-2011
Publisher: Public Library of Science (PLoS)
Date: 28-07-2016
Publisher: Springer Singapore
Date: 2017
DOI: 10.1007/978-981-10-6583-5_6
Abstract: The DJ-1 protein was originally linked with Parkinson's disease and is now known to have antioxidant functions. The protein has three redox-sensitive cysteine residues, which are involved in its dimerisation and functional properties. A mildly oxidised form of DJ-1 is the most active form and protects cells from oxidative stress conditions. DJ-1 functions as an antioxidant through a variety of mechanisms, including a weak direct antioxidant activity by scavenging reactive oxygen species. DJ-1 also regulates a number of signalling pathways, including the inhibition of apoptosis signal-regulating kinase 1 (ASK1)-induced apoptosis under oxidative stress conditions. Other proteins regulated by DJ-1 include enzymes, chaperones, the 20S proteasome and transcription factors, including Nrf2. Once activated by oxidative stress, Nrf2 upregulates antioxidant gene expression including members of the thioredoxin and glutathione pathways, which in turn mediate an antioxidant protective function. Crosstalk between DJ-1 and both the thioredoxin and glutathione systems has also been identified. Thioredoxin reduces a cysteine residue on DJ-1 to modulate its activity, while glutaredoxin1 de-glutathionylates DJ-1, preventing degradation of DJ-1 and resulting in its accumulation. DJ-1 also regulates the activity of glutamate cysteine ligase, which is the rate-limiting step for glutathione synthesis. These antioxidant functions of DJ-1 are key to its role in protecting neurons from oxidative stress and are hypothesised to protect the brain from the development of neurodegenerative diseases such as Parkinson's disease (PD) and to protect cardiac tissues from ischaemic-reperfusion injury. However, DJ-1, as an antioxidant, also protects cancer cells from undergoing oxidative stress-induced apoptosis.
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6MD00296J
Abstract: The increasingly sophisticated array of approaches for the specific labeling and fluorescence-based detection of carbonic anhydrase enzymes using small molecule affinity-based chemical probes is reviewed.
Publisher: Bioscientifica
Date: 11-1991
Abstract: An isolated preparation from ovine placental extracts which was active in the rosette inhibition assay mimicking the activity of the so-called 'early pregnancy factor' (EPF) has been shown to contain a 12 kDa polypeptide which could be partially resolved from low-molecular-weight active moieties. N-terminal amino acid sequence analysis of the polypeptide indicated that it was ovine thioredoxin, an identification confirmed by isolation and complete sequence analysis of the corresponding cDNA. The cDNA for human thioredoxin was expressed in Escherichia coli and the recombinant protein isolated and purified. Pure recombinant thioredoxin alone did not induce the expression of increased rosette inhibition titres (RITs) when tested in the rosette inhibition assay but, when tested in combination with cell stimuli such as platelet-activating factor (PAF) or serum, it allowed the expression of increased RITs where none was achieved in its absence. Thioredoxin acted in the assay to reverse a refractory state normally induced by these stimuli, allowing lipoxygenase-dependent moieties also induced by the stimuli to exert their effects, resulting in the expression of increased RITs. Antibodies to recombinant thioredoxin removed from pregnancy sera the capacity to induce increased RITs, i.e. to express EPF activity, thus establishing a role for thioredoxin or thioredoxin-like proteins and associated molecules in the mechanisms which allow pregnancy sera to induce increased RITs. Based on a consideration of these and other results, a new model for the study of the EPF phenomenon is presented and discussed.
Publisher: Elsevier BV
Date: 08-2016
Publisher: MDPI AG
Date: 04-05-2021
Abstract: Chronic myeloid leukemia (CML) is a myeloproliferative disorder that is caused by the formation of a fusion onco-protein, BCR-ABL. Since BCR-ABL plays a role in the progression of CML, the most common treatments of CML are tyrosine kinase inhibitors (TKIs) that specifically target BCR-ABL. However, resistance to TKIs is a major problem in CML treatment. A promising target in overcoming drug resistance in other cancers is the thioredoxin (TRX) system, an antioxidant system that maintains cellular redox homeostasis. The TRX system is upregulated in many cancers and this is associated with a poor prognosis. Analysis of a patient database showed that the expression of the TRX system was upregulated in CML patients compared to healthy donors. Our experiments revealed a significant link between the TRX and BCR-ABL systems since inhibition of BCR-ABL with chemical inhibitors and siRNA resulted in a decrease in the activity and expression of the TRX system in CML cells. This is notable as it shows that the TRX system may be a viable target in the treatment of CML.
Publisher: Elsevier BV
Date: 11-2003
DOI: 10.1016/S0378-1119(03)00799-6
Abstract: In recent years, redox control has emerged as a fundamental mechanism of gene regulation through transcriptional control. Thioredoxin (Trx) is a dithiol-reducing enzyme known to be involved in the redox regulation of a number of transcription factors, and in this study, we have investigated the redox-dependent regulation of the DNA binding activity of Sp1 by thioredoxin. Electrophoretic mobility shift assays were used to show that both recombinant Sp1 produced in Escherichia coli and endogenous Sp1 expressed by MDA-MB-231 breast cancer cells is subject to redox regulation. We found that thioredoxin alone or in conjunction with the full thioredoxin system (comprising thioredoxin, thioredoxin reductase [TR], and alpha-nicotinamide adenine dinucleotide phosphate [NADPH]) can increase Sp1 DNA binding activity in vitro to an oligonucleotide containing the Sp1 consensus sequence. Furthermore, we have provided evidence that recombinant Sp1 can bind to Sp1 consensus sequences within a 330-base pair (bp) thioredoxin promoter fragment and that this interaction can also be enhanced by the presence of thioredoxin. Luciferase reporter assays using this same minimal thioredoxin promoter region demonstrated that both Sp1 and Sp3 can bind to the promoter and act to enhance transcription. When the three identified Sp1 consensus sequences within the reporter construct were deleted, there was a loss of basal promoter activity, showing that these closely positioned sites are important for regulation of thioredoxin gene expression.
Publisher: Elsevier BV
Date: 2020
Publisher: Wiley
Date: 23-12-2008
Abstract: The thioredoxin (Trx) system is a major antioxidant system integral to maintaining the intracellular redox state. It contains Trx, a redox active protein, which regulates the activity of various enzymes including those that function to counteract oxidative stress within the cell. Trx can also scavenge reactive oxygen species (ROS) and directly inhibits proapoptotic proteins such as apoptosis signal-regulating kinase 1 (ASK1). The oxidized form of Trx is reduced by thioredoxin reductase (TrxR). The cytoplasm and mitochondria contain equivalent Trx systems and inhibition of either system can lead to activation of apoptotic signaling pathways. There are a number of inhibitors with chemotherapy applications that target either Trx or TrxR to induce apoptosis in cancer cells. Suberoylanilide hydroxamic acid (SAHA) is effective against many cancer cells and functions by up-regulating an endogenous inhibitor of Trx. Other compounds target the selenocysteine-containing active site of TrxR. These include gold compounds, platinum compounds, arsenic trioxide, motexafin gadolinium, nitrous compounds, and various flavonoids. Inhibition of TrxR leads to an accumulation of oxidized Trx resulting in cellular conditions that promote apoptosis. In addition, some compounds also convert TrxR to a ROS generating enzyme. The role of Trx system inhibitors in cancer therapy is discussed in this review.
Publisher: American Chemical Society (ACS)
Date: 29-06-2016
DOI: 10.1021/ACS.JMEDCHEM.6B00623
Abstract: Tumor hypoxia contributes resistance to chemo- and radiotherapy, while oxygenated tumors are sensitive to these treatments. The indirect detection of hypoxic tumors is possible by targeting carbonic anhydrase IX (CA IX), an enzyme overexpressed in hypoxic tumors, with sulfonamide-based imaging agents. In this study, we present the design and synthesis of novel gallium-radiolabeled small-molecule sulfonamides targeting CA IX. The compounds display favorable in vivo pharmacokinetics and stability. We demonstrate that our lead compound, [(68)Ga]-2, discriminates CA IX-expressing tumors in vivo in a mouse xenograft model using positron emission tomography (PET). This compound shows specific tumor accumulation and low uptake in blood and clears intact to the urine. These findings were reproduced in a second study using PET/computed tomography. Small molecules investigated to date utilizing (68)Ga for preclinical CA IX imaging are scarce, and this is one of the first effective (68)Ga compounds reported for PET imaging of CA IX.
Publisher: Elsevier BV
Date: 08-2016
Publisher: Informa UK Limited
Date: 04-05-2003
DOI: 10.4161/CBT.2.5.441
Abstract: Human HOX genes are expressed in a spatio-temporal fashion during embryogenesis and early development where they act as master transcriptional regulators. HOX genes are also expressed in normal adult cells, potentially in a tissue specific manner involving maintenance of the normal phenotype. In selected oncogenic transformations, mis-expression of many HOX genes have been shown, indicating an involvement of these transcriptional regulators in carcinogenesis and metastasis. Utilising quantitative real-time RT-PCR assays, the expression of 20 HOX genes and two known HOX co-factors, PBX1B and MEIS1, were analysed in human melanoma and breast cancer cell lines, comparing results against non-malignant cells. Alterations in HOX gene expression were observed for all malignant cells examined, with some dysregulated transcript levels seemingly random, and the expression of other HOX genes apparently following the same patterns in both skin and breast cancer establishment. Furthermore, HOX gene expression was correlated with the invasive capacity of the cells. The expression of the HOX co-factors PBX1B and MEIS1 showed no marked changes from the non-malignant to the malignant phenotypes, further indicating that it is dysregulated HOX gene expression, rather than dysregulated gene expression of HOX co-factors, that potentially commit the cell to re-differentiate and undergo oncogenic transformation.
Publisher: Wiley
Date: 22-03-2017
Abstract: Chemical probes are small-molecule reagents used by researchers for labelling and detection of biomolecules. We present the design, synthesis, and characterisation of a panel of 11 structurally erse photoaffinity labelling (PAL) probes as research tools for labelling the model enzyme carbonic anhydrase (CA) in challenging environments, including in protein mixtures and cell lysates. We targeted the ubiquitous CA II as well as the two cancer-associated CAs (CA IX and CA XII) that are of high priority as potential biomarkers of aggressive and/or multidrug-resistant cancer. We utilise an atypical biophysical approach, native state mass spectrometry, to monitor the initial protein-probe binding and subsequent UV crosslinking efficiency of the protein:probe complex. This mass spectrometry methodology represents a new approach for chemical probe optimisation and development that might have broader applications to chemical probe characterisation beyond this study. This also represents one of the first studies, to the best of our knowledge, in which a comprehensive set of PAL probes has been used to establish the relationship between probe structure, noncovalent protein-probe binding, and covalent protein-probe crosslinking efficiency. Our results demonstrate the benefits of a comprehensive analysis of chemical probe structure-activity relationships to support the development of optimum chemical probes.
Publisher: Informa UK Limited
Date: 29-11-2020
Publisher: Springer Science and Business Media LLC
Date: 12-10-2016
DOI: 10.1007/S10495-016-1303-9
Abstract: Multiple myeloma (MM) is an incurable plasma B cell malignancy. Despite recent advancements in anti-MM therapies, development of drug resistance remains a major clinical hurdle. DJ-1, a Parkinson's disease-associated protein, is upregulated in many cancers and its knockdown suppresses tumor growth and overcomes chemoresistance. However, the role of DJ-1 in MM remains unknown. Using gene expression databases we found increased DJ-1 expression in MM patient cells, which correlated with shorter overall survival and poor prognosis in MM patients. Targeted DJ-1 knockdown using siRNAs induced necroptosis in myeloma cells. We found that Krüppel-like factor 6 (KLF6) is expressed at lower levels in myeloma cells compared to PBMCs, and DJ-1 knockdown increased KLF6 expression in myeloma cells. Targeted knockdown of KLF6 expression in DJ-1 knockdown myeloma cells rescued these cells from undergoing cell death. Higher DJ-1 levels were observed in bortezomib-resistant myeloma cells compared to parent cells, and siRNA-mediated DJ-1 knockdown reversed bortezomib resistance. DJ-1 knockdown increased KLF6 expression in bortezomib-resistant myeloma cells, and subsequent siRNA-mediated KLF6 knockdown rescued bortezomib-resistant myeloma cells from undergoing cell death. We also demonstrated that specific siRNA-mediated DJ-1 knockdown reduced myeloma cell growth under a hypoxic microenvironment. DJ-1 knockdown reduced the expression of HIF-1α and its target genes in hypoxic-myeloma cells, and overcame hypoxia-induced bortezomib resistance. Our findings demonstrate that elevated DJ-1 levels correlate with myeloma cell survival and acquisition of bortezomib resistance. Thus, we propose that inhibiting DJ-1 may be an effective therapeutic strategy to treat newly diagnosed as well as relapsed/refractory MM patients.
Publisher: Elsevier BV
Date: 05-2021
Publisher: Portland Press Ltd.
Date: 15-08-2006
DOI: 10.1042/BJ20060076
Abstract: Thioredoxin is a redox-active protein that plays multiple roles in regulating cell growth, cell signalling and apoptosis. Here, we have demonstrated that a complex mechanism involving multiple regulatory elements is involved in the tBHQ [tert-butylhydroquinone or 2,5-di-(t-butyl)-1,4-hydroquinone]-mediated activation of the thioredoxin gene. Luciferase assays, utilizing various wild-type and mutated thioredoxin promoter fragments, revealed roles for the ORE (oxidative stress responsive element), ARE (antioxidant responsive element), three Sp1 (specificity protein 1)-binding sites and the TATA box in the activation of the thioredoxin gene by tBHQ. The ORE required the presence of the ARE to elicit its response, whereas the independent removal of three Sp1-binding sites and the TATA box also decreased activation of the thioredoxin gene, with mutation of the TATA box having the greatest effect. Real-time RT (reverse transcriptase)–PCR analysis also revealed varying roles for two TSSs (transcription start sites) in the activation of the thioredoxin gene by tBHQ. Transcription was initiated from both TSSs however, different response rates and fold inductions were observed. Together, these results suggest that the thioredoxin gene is controlled by a novel arrangement of two overlapping core promoter regions, one containing a TATA box and the other TATA-less. Altering the intracellular levels of thioredoxin in a breast cancer cell line also influenced the induction of thioredoxin transcription in response to tBHQ. Stable transfections with a redox-inactive thioredoxin mutant produced 3.6 times higher induction levels of thioredoxin transcription compared with control cells, indicating an intrinsic form of control of promoter activity by the thioredoxin system itself.
Publisher: Impact Journals, LLC
Date: 27-04-2021
Publisher: Elsevier BV
Date: 03-2012
DOI: 10.1016/J.BBRC.2012.02.027
Abstract: The thioredoxin system is a key cellular antioxidant system and is highly expressed in cancer cells, especially in more aggressive and therapeutic resistant tumors. We analysed the expression of the thioredoxin system in the MDA-MB-231 breast cancer cell line under conditions mimicking the tumor oxygen microenvironment. We grew breast cancer cells in either prolonged hypoxia or hypoxia followed by various lengths of reoxygenation and in each case cells were cultured with or without a hypoxic cycling preconditioning (PC) phase preceding the hypoxic growth. Flow cytometry-based assays were used to measure reactive oxygen species (ROS) levels. Cells grown in hypoxia showed a significant decrease in ROS levels compared to normoxic cells, while a significant increase in ROS levels over normoxic cells was observed after 4 h of reoxygenation. The PC pre-treatment did not have a significant effect on ROS levels. Thioredoxin levels were also highest after 4 h of reoxygenation, however cells subjected to PC pre-treatment displayed even higher thioredoxin levels. The high level of intracellular thioredoxin was also reflected on the cell surface. Reporter assays showed that activity of the thioredoxin and thioredoxin reductase gene promoters was also highest in the reoxygenation phase, although PC pre-treatment did not result in a significant increase over non-PC treated cells. The use of a dominant negative Nrf-2 negated the increased thioredoxin promoter activity during reoxygenation. This data suggests that the high levels of thioredoxin observed in tumors may arise due to cycling between hypoxia and reoxygenation.
Publisher: Wiley
Date: 2001
DOI: 10.1002/1098-2795(20010401)58:4<359::AID-MRD2>3.0.CO;2-K
Publisher: Elsevier BV
Date: 05-1993
DOI: 10.1016/0378-1119(93)90727-K
Abstract: Expression of genes encoding neural-cell adhesion molecules (NCAM) is regulated to a large extent at the level of alternative splicing. Xenopus laevis contains two functional copies of the NCAM gene and comparison of the amino acid sequences of NCAM proteins derived from both genes shows that they differ at approximately 8% of positions. Differential expression of these proteins during development or in adult tissues could provide an additional level of regulation above that obtained by alternative splicing. PCR analysis however, shows that both NCAM genes are expressed at similar levels throughout embryonic development and in all adult tissues examined.
Publisher: Elsevier BV
Date: 03-1994
Abstract: We have isolated a Xenopus homeodomain sequence, XNkx-2.5, which shows significant similarity to mouse Nkx-2.5 and to the Drosophila tinman gene product. In Drosophila, tinman is required for formation of the heart and visceral mesoderm structures. In situ hybridization studies show that XNkx-2.5 is expressed in the heart region during early Xenopus development and later is also expressed in gut tissue. The observed similarity of sequences and expression patterns suggests that the regulatory mechanisms underlying heart formation may be conserved between distant species.
Publisher: Elsevier BV
Date: 06-1991
DOI: 10.1016/0378-1119(91)90081-L
Abstract: Thioredoxin (Trx) has recently been demonstrated to be an essential component of the early pregnancy factor activity of pregnancy serum. Here, we report the structure and sequence of human Trx-encoding genes (Trx) by analysis of genomic clones. The Trx gene extends over 13 kb and consists of five exons encoding a 12-kDa protein. A 700-bp fragment upstream from the start codon functions as a promoter when inserted in front of a human growth hormone-encoding reporter gene in tissue-culture cells. This promoter region is very G + C rich and does not contain a classical TATA or CCAAT box, but has three consensus sequences for high-affinity Sp1 binding. Southern analysis demonstrated the presence of several Trx genes in the human genome. The number includes at least one inactive copy as shown by the isolation and sequencing of an inactive pseudogene.
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.PHRS.2022.106134
Abstract: Lymphoma refers to a group of cancers that arise from lymphocytes and is the most common form of hematological malignancy in adults. While the recent availability of specific chemotherapy regimes has resulted in good patient outcomes for some lymphoma subtypes, relapsed and refractory lymphoma is still a challenge that needs to be overcome. This review discusses how Nrf-2 regulated antioxidant systems such as the thioredoxin and glutathione systems are upregulated in lymphomas and have been linked with several signaling pathways involved in lymphoma development and progression, including the B cell receptor, the NF-κB, and the STAT3 signaling pathways. Thioredoxin reductase (TrxR) has been recognized as a potential anticancer target and, as a consequence, the synthesis of TrxR inhibitors, along with the discovery of inhibitors from natural resources and evaluation of their anti-cancer effects, is an ongoing active area of research. Targeting antioxidant systems, especially TrxR, may represent a new valid therapeutic approach for lymphoma, potentially in combination with existing therapies.
Publisher: Elsevier BV
Date: 2014
DOI: 10.1016/J.BBAGEN.2013.09.013
Abstract: The thioredoxin system maintains redox balance through the action of thioredoxin and thioredoxin reductase. Thioredoxin regulates the activity of various substrates, including those that function to counteract cellular oxidative stress. These include the peroxiredoxins, methionine sulfoxide reductase A and specific transcription factors. Of particular relevance is Redox Factor-1, which in turn activates other redox-regulated transcription factors. Experimentally defined transcription factor binding sites in the human thioredoxin and thioredoxin reductase gene promoters together with promoters of the major thioredoxin system substrates involved in regulating cellular redox status are discussed. An in silico approach was used to identify potential putative binding sites for these transcription factors in all of these promoters. Our analysis reveals that many redox gene promoters contain the same transcription factor binding sites. Several of these transcription factors are in turn redox regulated. The ARE is present in several of these promoters and is bound by Nrf2 during various oxidative stress stimuli to upregulate gene expression. Other transcription factors also bind to these promoters during the same oxidative stress stimuli, with this redundancy supporting the importance of the antioxidant response. Putative transcription factor sites were identified in silico, which in combination with specific regulatory knowledge for that gene promoter may inform future experiments. Redox proteins are involved in many cellular signalling pathways and aberrant expression can lead to disease or other pathological conditions. Therefore understanding how their expression is regulated is relevant for developing therapeutic agents that target these pathways.
Publisher: MDPI AG
Date: 25-03-2010
Publisher: Oxford University Press (OUP)
Date: 12-2001
Abstract: Thioredoxin is a powerful redox protein expressed in invasive cytotrophoblasts and essential for blastocyst implantation in mice. Isolated marmoset thioredoxin cDNA showed that the deduced amino acid sequence differed from the human sequence by four amino acids. The close homology of thioredoxin in the two species enabled us to use monoclonal antibodies against human thioredoxin to detect marmoset thioredoxin in implantation sites, blastocysts and culture medium. Immunocytochemistry on marmoset implantation sites, on pregnancy days 12 and 15, showed that thioredoxin is highly expressed in uterine luminal epithelium, glands and in some endometrial stromal cells. In attached blastocysts, thioredoxin staining was detected in mural and polar trophoblast cells and both visceral and parietal endoderm, whereas no staining was present in the inner cell mass. A similar pattern of thioredoxin expression was detected in hatched blastocysts attached to Matrigel in tissue culture. Trophoblastic vesicles derived from blastocysts expressed thioredoxin in inner endoderm-like cells and outer trophoblast-like cells and secreted thioredoxin into the culture medium. These experiments have demonstrated thioredoxin expression during early stages of embryo-maternal interaction. We propose that thioredoxin protects the early placenta from oxidative damage and that the marmoset is a valuable model for studying thioredoxin regulation and function during implantation and blastocyst differentiation.
Publisher: Scientific Research Publishing, Inc.
Date: 2012
Publisher: Future Science Ltd
Date: 12-2002
DOI: 10.2144/02336BM12
Publisher: Impact Journals, LLC
Date: 02-01-2014
Abstract: Oxidative stress, which is associated with an increased concentration of reactive oxygen species (ROS), is involved in the pathogenesis of numerous diseases including cancer. In response to increased ROS levels, cellular antioxidant molecules such as thioredoxin, peroxiredoxins, glutaredoxins, DJ-1, and superoxide dismutases are upregulated to counteract the detrimental effect of ROS. However, cancer cells take advantage of upregulated antioxidant molecules for protection against ROS-induced cell damage. This review focuses on two antioxidant systems, Thioredoxin and DJ-1, which are upregulated in many human cancer types, correlating with tumour proliferation, survival, and chemo-resistance. Thus, both of these antioxidant molecules serve as potential molecular targets to treat cancer. However, targeting one of these antioxidants alone may not be an effective anti-cancer therapy. Both of these antioxidant molecules are interlinked and act on similar downstream targets such as NF-κβ, PTEN, and Nrf2 to exert cytoprotection. Inhibiting either thioredoxin or DJ-1 alone may allow the other antioxidant to activate downstream signalling cascades leading to tumour cell survival and proliferation. Targeting both thioredoxin and DJ-1 in conjunction may completely shut down the antioxidant defence system regulated by these molecules. This review focuses on the cross-talk between thioredoxin and DJ-1 and highlights the importance and consequences of targeting thioredoxin and DJ-1 together to develop an effective anti-cancer therapeutic strategy.
Publisher: MDPI AG
Date: 07-07-2019
Abstract: Norway is the largest producer and exporter of farmed Atlantic salmon (Salmo salar) worldwide. Skin disorders correlated with bacterial infections represent an important challenge for fish farmers due to the economic losses caused. Little is known about this topic, thus studying the skin–mucus of Salmo salar and its bacterial community depict a step forward in understanding fish welfare in aquaculture. In this study, we used label free quantitative mass spectrometry to investigate the skin–mucus proteins associated with both Atlantic salmon and bacteria. In particular, the microbial temporal proteome dynamics during nine days of mucus incubation with sterilized seawater was investigated, in order to evaluate their capacity to utilize mucus components for growth in this environment. At the start of the incubation period, the largest proportion of proteins (~99%) belonged to the salmon and many of these proteins were assigned to protecting functions, confirming the defensive role of mucus. On the contrary, after nine days of incubation, most of the proteins detected were assigned to bacteria, mainly to the genera Vibrio and Pseudoalteromonas. Most of the predicted secreted proteins were affiliated with transport and metabolic processes. In particular, a large abundance and variety of bacterial proteases were observed, highlighting the capacity of bacteria to degrade the skin–mucus proteins of Atlantic salmon.
Publisher: Portland Press Ltd.
Date: 05-2021
DOI: 10.1042/BSR20210427
Abstract: Different skin colour among in iduals is determined by the varying amount and types of melanin pigment. Melanin is produced in melanocytes, a type of dendritic cell located in the basal layer of the epidermis, through the process of melanogenesis. Melanogenesis consists of a series of biochemical and enzymatic reactions catalysed by tyrosinase and other tyrosinase-related proteins, leading to the formation of two types of melanin, eumelanin and pheomelanin. Melanogenesis can be regulated intrinsically by several signalling pathways, including the cyclic adenosine monophosphate (cAMP) rotein kinase A (PKA), stem cell factor (SCF)/c-kit and wingless-related integration site (Wnt)/β-catenin signalling pathways. Ultraviolet radiation (UVR) is the major extrinsic factor in the regulation of melanogenesis, through the generation of reactive oxygen species (ROS). Antioxidants or antioxidant systems, with the ability to scavenge ROS, may decrease melanogenesis. This review focuses on the two main cellular antioxidant systems, the thioredoxin (Trx) and glutathione (GSH) systems, and discusses their roles in melanogenesis. In the Trx system, high levels/activities of thioredoxin reductase (TrxR) are correlated with melanin formation. The GSH system is linked with regulating pheomelanin formation. Exogenous addition of GSH has been shown to act as a depigmenting agent, suggesting that other antioxidants may also have the potential to act as depigmenting agents for the treatment of human hyperpigmentation disorders.
Publisher: Wiley
Date: 31-05-2019
DOI: 10.1002/IJC.32410
Abstract: Triple-negative breast cancer (TNBCs) is a very aggressive and lethal form of breast cancer with no effective targeted therapy. Neoadjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25-30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. TNBC cells have increased intracellular oxidative stress and suppressed glutathione, a major antioxidant system, but still, are protected against higher oxidative stress. We screened a panel of antioxidant genes using the TCGA and METABRIC databases and found that expression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non-TNBC patients and is correlated with adverse survival outcomes. Treatment with auranofin (AF), an FDA-approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC cells grown as spheroids. Furthermore, AF treatment exerted a significant in vivo antitumor activity in multiple TNBC models including the syngeneic 4T1.2 model, MDA-MB-231 xenograft and patient-derived tumor xenograft by inhibiting thioredoxin redox activity. We, for the first time, showed that AF increased CD8
Publisher: Informa UK Limited
Date: 06-1999
Publisher: Elsevier BV
Date: 10-1999
Publisher: Impact Journals, LLC
Date: 12-04-2015
Abstract: Multiple myeloma (MM) is a hematological malignancy characterized by the aberrant accumulation of clonal plasma cells in the bone marrow. Despite recent advancement in anti-myeloma treatment, MM remains an incurable disease. This study showed higher intrinsic oxidative stress and higher Trx1 and TrxR1 protein levels in MM cells compared to normal cells. Drug-induced Trx1 (PX-12) and TrxR1 (Auranofin) inhibition disrupted redox homeostasis resulting in ROS-induced apoptosis in MM cells and a reduction in clonogenic activity. Knockdown of either Trx1 or TrxR1 reduced MM cell viability. Trx1 inhibition by PX-12 sensitized MM cells to undergo apoptosis in response to the NF-κβ inhibitors, BAY 11-7082 and curcumin. PX-12 treatment decreased the expression of the NF-κβ subunit p65 in MM cells. Bortezomib-resistant MM cells contained higher Trx1 protein levels compared to the parental cells and PX-12 treatment resulted in apoptosis. Thus, increased Trx1 enhances MM cell growth and survival and exerts resistance to NF-κβ inhibitors. Therefore inhibiting the thioredoxin system may be an effective therapeutic strategy to treat newly diagnosed as well as relapsed/refractory MM.
Publisher: Elsevier BV
Date: 12-2022
Publisher: Bentham Science Publishers Ltd.
Date: 11-2007
DOI: 10.2174/187221507782360227
Abstract: Redox control is an important determinant of cellular function and viability. The thioredoxin system is a major antioxidant system that influences cellular redox state, stimulates cell growth, inhibits apoptosis, activates numerous transcription factors and regulates immune function. Both over and under expression of the thioredoxin system can result in a disease phenotype and therefore it has been the target of many therapeutic strategies. High levels of thioredoxin expression have been associated with aggressive cancers, poor patient prognosis and resistance to some chemotherapy treatments. In contrast, low levels of thioredoxin can cause diseases that develop because of an imbalance between antioxidant systems and oxidative stress, stimulants. A number of recent patents and patent applications have been published that describe inventions that either inhibit or enhance thioredoxin functionality. Thioredoxin expression levels have been decreased through antisense approaches and thioredoxin functionality has been inhibited by synthetic compounds or by stimulating the production of VDUP1, a natural thioredoxin inhibitor. Strategies designed to enhance thioredoxin functionality include the addition of recombinant thioredoxin or using gene delivery to treat hepatic disease, inflammatory bowel disease, cardiovascular disease, skin damage or cystic fibrosis. Mutant thioredoxin molecules that target specific pathways or that exhibit increased stability are also utilised.
No related grants have been discovered for Kathryn Tonissen.