| 1. |
- Prigge, R., et al.
(författare)
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International comparison of glycaemic control in people with type 1 diabetes: an update and extension
- 2022
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Ingår i: Diabetic Medicine. - : Wiley. - 0742-3071 .- 1464-5491. ; 39:5
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To update and extend a previous cross-sectional international comparison of glycaemic control in people with type 1 diabetes. Methods: Data were obtained for 520,392 children and adults with type 1 diabetes from 17 population and five clinic-based data sources in countries or regions between 2016 and 2020. Median HbA1c(IQR) and proportions of individuals with HbA1c < 58mmol/mol (<7.5%), 58–74mmol/mol (7.5–8.9%) and ≥75mmol/mol (≥9.0%) were compared between populations for individuals aged <15, 15–24 and ≥25 years. Logistic regression was used to estimate the odds ratio (OR) of HbA1c < 58mmol/mol (<7.5%) relative to ≥58mmol/mol (≥7.5%), stratified and adjusted for sex, age and data source. Where possible, changes in the proportion of individuals in each HbA1c category compared to previous estimates were calculated. Results: Median HbA1c varied from 55 to 79mmol/mol (7.2 to 9.4%) across data sources and age groups so a pooled estimate was deemed inappropriate. OR (95% CI) for HbA1c< 58mmol/mol (<7.5%) were 0.91 (0.90–0.92) for women compared to men, 1.68 (1.65–1.71) for people aged <15years and 0.81 (0.79–0.82) aged15–24years compared to those aged ≥25years. Differences between populations persisted after adjusting for sex, age and data source. In general, compared to our previous analysis, the proportion of people with an HbA1c<58mmol/l (<7.5%) increased and proportions of people with HbA1c≥ 75mmol/mol (≥9.0%) decreased. Conclusions: Glycaemic control of type 1 diabetes continues to vary substantially between age groups and data sources. While some improvement over time has been observed, glycaemic control remains sub-optimal for most people with Type 1 diabetes.
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| 2. |
- McLoughlin, M. R., et al.
(författare)
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TrxR1, Gsr, and oxidative stress determine hepatocellular carcinoma malignancy
- 2019
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 116:23, s. 11408-11417
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Tidskriftsartikel (refereegranskat)abstract
- Thioredoxin reductase-1 (TrxR1)-, glutathione reductase (Gsr)-, and Nrf2 transcription factor-driven antioxidant systems form an integrated network that combats potentially carcinogenic oxidative damage yet also protects cancer cells from oxidative death. Here we show that although unchallenged wild-type (WT), TrxR1-null, or Gsr-null mouse livers exhibited similarly low DNA damage indices, these were 100-fold higher in unchallenged TrxR1/Gsr-double-null livers. Notwithstanding, spontaneous cancer rates remained surprisingly low in TrxR1/Gsr-null livers. All genotypes, including TrxR1/Gsr-null, were susceptible to N-diethylnitrosamine (DEN)-induced liver cancer, indicating that loss of these antioxidant systems did not prevent cancer cell survival. Interestingly, however, following DEN treatment, TrxR1-null livers developed threefold fewer tumors compared with WT livers. Disruption of TrxR1 in a marked subset of DEN-initiated cancer cells had no effect on their subsequent contributions to tumors, suggesting that TrxR1-disruption does not affect cancer progression under normal care, but does decrease the frequency of DEN-induced cancer initiation. Consistent with this idea, TrxR1-null livers showed altered basal and DEN-exposed metabolomic profiles compared with WT livers. To examine how oxidative stress influenced cancer progression, we compared DEN-induced cancer malignancy under chronically low oxidative stress (TrxR1-null, standard care) vs. elevated oxidative stress (TrxR1/Gsr-null livers, standard care or phenobarbital-exposed TrxR1-null livers). In both cases, elevated oxidative stress was correlated with significantly increased malignancy. Finally, although TrxR1-null and TrxR1/Gsr-null livers showed strong Nrf2 activity in noncancerous hepatocytes, there was no correlation between malignancy and Nrf2 expression within tumors across genotypes. We conclude that TrxR1, Gsr, Nrf2, and oxidative stress are major determinants of liver cancer but in a complex, context-dependent manner.
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| 3. |
- Franke, A., et al.
(författare)
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Operationalizing Ocean Health : Toward Integrated Research on Ocean Health and Recovery to Achieve Ocean Sustainability
- 2020
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Ingår i: One Earth. - : Elsevier BV. - 2590-3330 .- 2590-3322. ; 2:6, s. 557-565
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Tidskriftsartikel (refereegranskat)abstract
- Protecting the ocean has become a major goal of international policy as human activities increasingly endanger the integrity of the ocean ecosystem, often summarized as “ocean health.” By and large, efforts to protect the ocean have failed because, among other things, (1) the underlying socio-ecological pathways have not been properly considered, and (2) the concept of ocean health has been ill defined. Collectively, this prevents an adequate societal response as to how ocean ecosystems and their vital functions for human societies can be protected and restored. We review the confusion surrounding the term “ocean health” and suggest an operational ocean-health framework in line with the concept of strong sustainability. Given the accelerating degeneration of marine ecosystems, the restoration of regional ocean health will be of increasing importance. Our advocated transdisciplinary and multi-actor framework can help to advance the implementation of more active measures to restore ocean health and safeguard human health and well-being.
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| 4. |
- Locy, Morgan L, et al.
(författare)
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Thioredoxin reductase inhibition elicits Nrf2-mediated responses in Clara cells : implications for oxidant-induced lung injury
- 2012
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Ingår i: Antioxidants and Redox Signaling. - Stockholm : Karolinska Institutet, Dept of Medical Biochemistry and Biophysics. - 1557-7716 .- 1523-0864.
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Pulmonary oxygen toxicity contributes to lung injury in newborn and adult humans.We previously reported that thioredoxin reductase (TrxR1) inhibition with aurothioglucose (ATG) attenuates hyperoxic lung injury in adult mice. The present studies tested the hypothesis that TrxR1 inhibition protects against the effects of hyperoxia via nuclear factor E2-related factor 2 (Nrf2)-dependent mechanisms. Results: Both pharmacologic and siRNA-mediated TrxR1 inhibition induced robust Nrf2 responses in murine-transformed Clara cells (mtCC). While TrxR1 inhibition did not alter the susceptibility of cells to the effects of hyperoxia, glutathione (GSH) depletion after TrxR1 inhibition markedly enhanced the hyperoxic susceptibility of cultured mtCCs. Finally, in vivo data revealed dose-dependent increases in the expression of the Nrf2 target gene NADPH:quinone oxidoreductase 1 (NQO1) in the lungs of ATGtreated adult mice. Innovation: TrxR1 inhibition activates Nrf2-dependent antioxidant responses in mtCCs in vitro and in adult murine lungs in vivo, providing a plausible mechanism for the protective effects of TrxR1 inhibition in vivo. Conclusion: GSH-dependent enzyme systems in mtCCs may be of greater importance for protection against hyperoxic exposure than are TrxR-dependent systems. The induction of Nrf2 activation via TrxR1 inhibition represents a novel therapeutic strategy that attenuates oxidant-mediated lung injury. Similar expression levels of TrxR1 in newborn and adult mouse or human lungs broaden the potential clinical applicability of the present findings to both neonatal and adult oxidant lung injury.
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| 5. |
- Prigge, Justin R., et al.
(författare)
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Hepatocyte Hyperproliferation upon Liver-Specific Co-disruption of Thioredoxin-1, Thioredoxin Reductase-1, and Glutathione Reductase
- 2017
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Ingår i: Cell Reports. - : Cell Press. - 2211-1247. ; 19:13, s. 2771-2781
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Tidskriftsartikel (refereegranskat)abstract
- Energetic nutrients are oxidized to sustain high intracellular NADPH/NADP(+) ratios. NADPH-dependent reduction of thioredoxin-1 (Trx1) disulfide and glutathione disulfide by thioredoxin reductase-1 (TrxR1) and glutathione reductase (Gsr), respectively, fuels antioxidant systems and deoxyribonucleotide synthesis. Mouse livers lacking both TrxR1 and Gsr sustain these essential activities using an NADPH-independent methionine-consuming pathway; however, it remains unclear how this reducing power is distributed. Here, we show that liver-specific co-disruption of the genes encoding Trx1, TrxR1, and Gsr (triplenull) causes dramatic hepatocyte hyperproliferation. Thus, even in the absence of Trx1, methionine-fueled glutathione production supports hepatocyte S phase deoxyribonucleotide production. Also, Trx1 in the absence of TrxR1 provides a survival advantage to cells under hyperglycemic stress, suggesting that glutathione, likely via glutaredoxins, can reduce Trx1 disulfide in vivo. In triple-null livers like in many cancers, deoxyribonucleotide synthesis places a critical yet relatively low-volume demand on these reductase systems, thereby favoring high hepatocyte turnover over sustained hepatocyte integrity.
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