| 1. |
- Katsu-Jimenez, Yurika, et al.
(författare)
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Absence of TXNIP in Humans Leads to Lactic Acidosis and Low Serum Methionine Linked to Deficient Respiration on Pyruvate
- 2019
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Ingår i: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 68:4, s. 709-723
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Tidskriftsartikel (refereegranskat)abstract
- Thioredoxin-interacting protein (TXNIP) is an -arrestin that can bind to and inhibit the antioxidant protein thioredoxin (TXN). TXNIP expression is induced by glucose and promotes -cell apoptosis in the pancreas, and deletion of its gene in mouse models protects against diabetes. TXNIP is currently studied as a potential new target for antidiabetic drug therapy. In this study, we describe a family with a mutation in the TXNIP gene leading to nondetectable expression of TXNIP protein. Symptoms of affected family members include lactic acidosis and low serum methionine levels. Using patient-derived TXNIP-deficient fibroblasts and myoblasts, we show that oxidative phosphorylation is impaired in these cells when given glucose and pyruvate but normalized with malate. Isolated mitochondria from these cells appear to have normal respiratory function. The cells also display a transcriptional pattern suggestive of a high basal activation of the Nrf2 transcription factor. We conclude that a complete lack of TXNIP in human is nonlethal and leads to specific metabolic distortions that are, at least in part, linked to a deficient respiration on pyruvate. The results give important insights into the impact of TXNIP in humans and thus help to further advance the development of antidiabetic drugs targeting this protein.
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| 2. |
- Mu, Cuicui, et al.
(författare)
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Ecosystem CO2 Exchange and Its Economic Implications in Northern Permafrost Regions in the 21st Century
- 2023
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Ingår i: Global Biogeochemical Cycles. - 0886-6236. ; 37:11
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Tidskriftsartikel (refereegranskat)abstract
- Climate warming increases carbon assimilation by plant growth and also accelerates permafrost CO2 emissions; however, the overall ecosystem CO2 balance in permafrost regions and its economic impacts remain largely unknown. Here we synthesize in situ measurements of net ecosystem CO2 exchange to assess current and future carbon budgets across the northern permafrost regions using the random forest model and calculate their economic implications under the Shared Socio-economic Pathways (SSPs) based on the PAGE-ICE model. We estimate a contemporary CO2 emission of 1,539 Tg C during the nongrowing season and CO2 uptake of 2,330 Tg C during the growing season, respectively. Air temperature and precipitation exert the most control over the net ecosystem exchange in the nongrowing season, while leaf area index plays a more important role in the growing season. This region will probably shift to a carbon source after 2,057 under SSP5-8.5, with a net emission of 17 Pg C during 2057–2100. The net economic benefits of CO2 budget will be $4.5, $5.0, and $2.9 trillion under SSP1-2.6, SSP2-4.5, and SSP5-8.5, respectively. Our results imply that a high-emission pathway will greatly reduce the economic benefit of carbon assimilation in northern permafrost regions.
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| 3. |
- Peng, Xiaoxiao
(författare)
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Mammalian thioredoxin reductase 1 in antioxidant defense, regulation of adipocyte differentiation and as an anticancer drug target
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Reactive oxygen species (ROS) are oxygen containing reactive molecules generated as by-products of cellular metabolism. At physiological concentrations, ROS acts as secondary messengers in cellular signaling transduction, but excessive amounts of ROS result in oxidative stress and cellular damage. Several antioxidant enzyme systems include the thioredoxin (Trx)- and glutathione (GSH)-dependent systems together with superoxide dismutases and catalases may act in concert to protect cells and organisms from the toxic effects of excessive ROS. Mammalian thioredoxin reductase 1 (TrxR1), which is a cytosolic selenoprotein with a selenocysteine (Sec, U) residue in a conserved C-terminal GCUG motif, catalyzes the reduction of thioredoxin using NADPH and is known to be involved in antioxidant defense, redox regulation and cell proliferation. This thesis has focused on studying multiple aspects of cellular events and signaling pathways that are modulated by TrxR1. Paper I. The Sec residue in the C-terminal motif of TrxR1 is highly nucleophilic and can be easily targeted by electrophiles. In this study, we found the mutant p53 activator and anticancer drug lead named APR-246 (PRIMA-1Met) targeted and inhibited both recombinant and cellular TrxR activity. The inhibited TrxR1 still maintained its NADPH oxidase activity, which thus could contribute to the oxidative stress and cell death that are triggered by APR-246. Our findings provide insights into the p53 independent cytotoxicity mechanisms of APR-246 on tumor cells. Paper II. In this study, we used thiophosphate (SPO3) and selenite to modulate the Sec incorporation into TrxR1 in mammalian cells. We found that SPO3 promoted expression of Sec-to-cysteine substituted forms of TrxR1 and, conversely, selenite increased Sec incorporation in TrxR1. SPO3 treatment also attenuated cisplatin induced toxicity on A549 and HCT116 cells, while selenite supplementation sensitized NIH 3T3 cells to cisplatin but decreased the dependence of these cells on GSH. Taken together, these results show that the selenium status of cells can modulate the cytotoxicity of drugs that target TrxR1 and the glutathione dependence of the cells. Paper III. Here we utilized Txnrd1 depleted (Txnrd1-/-) mouse embryonic fibroblasts (MEFs) and observed massive cell death upon cultured at low-density in high-glucose medium. The cell death was linked to excessive H2O2 production promoted by high-glucose metabolism. Reconstitution of the cells with Sec-containing TrxR1, but not with the Sec-to-Cys substituted variant, rescued the MEFs from this lethality. These results show that Sec-containing TrxR1 is essential to maintain self-sufficiency of MEFs under high-glucose conditions, due to an essential role in control of glucose-derived H2O2 production. This study is, to our knowledge, the first time identified an essential biological role of Seccontaining TrxR1 that cannot be sustained by the Cys-mutant of the enzyme. Paper IV. Txnrd1-/- MEFs revealed a strong increase of spontaneous lipogenesis and hormonally induced adipocyte differentiation. The highly promoted adipocyte differentiation capacity was due to unlimited mitotic clonal expansion capacity and dramatically upregulated PPARγ expression. These effects were likely to be connected to increased oxidative signaling in Txnrd1-/- MEFs, because NAC treatment abolished the adipocyte differentiation by blocking mitotic clonal expansion. An increased Akt signaling in Txnrd1-/- MEFs induced by decreased cellular PTEN activity and increased ROS, also contributes to the enhanced adipogenesis. These results suggest that the selenoprotein TrxR1 suppress adipocyte differentiation through inhibition insulin signaling events, mitotic clonal expansion and PPARγ expression. In summary, this study shows that TrxR1 plays an essential role in antioxidant defense, regulation of adipocyte differentiation and servers as an anticancer drug target.
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| 4. |
- Stafford, William C., et al.
(författare)
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Irreversible inhibition of cytosolic thioredoxin reductase 1 as a mechanistic basis for anticancer therapy
- 2018
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Ingår i: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 10:428
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Tidskriftsartikel (refereegranskat)abstract
- Cancer cells adapt to their inherently increased oxidative stress through activation of the glutathione (GSH) and thioredoxin (TXN) systems. Inhibition of both of these systems effectively kills cancer cells, but such broad inhibition of antioxidant activity also kills normal cells, which is highly unwanted in a clinical setting. We therefore evaluated targeting of the TXN pathway alone and, more specifically, selective inhibition of the cytosolic selenocysteine-containing enzyme TXN reductase 1 (TXNRD1). TXNRD1 inhibitors were discovered in a large screening effort and displayed increased specificity compared to pan-TXNRD inhibitors, such as auranofin, that also inhibit the mitochondrial enzyme TXNRD2 and additional targets. For our lead compounds, TXNRD1 inhibition correlated with cancer cell cytotoxicity, and inhibitor-triggered conversion of TXNRD1 from an antioxidant to a pro-oxidant enzyme correlated with corresponding increases in cellular production of H2O2. In mice, the most specific TXNRD1 inhibitor, here described as TXNRD1 inhibitor 1 (TRi-1), impaired growth and viability of human tumor xenografts and syngeneic mouse tumors while having little mitochondrial toxicity and being better tolerated than auranofin. These results display the therapeutic anticancer potential of irreversibly targeting cytosolic TXNRD1 using small molecules and present potent and selective TXNRD1 inhibitors. Given the pronounced up-regulation of TXNRD1 in several metastatic malignancies, it seems worthwhile to further explore the potential benefit of specific irreversible TXNRD1 inhibitors for anticancer therapy.
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