| 1. |
- Björkhem Bergman, Linda
(författare)
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Thioredoxin reductase and selenium in carcinogenesis and multidrug resistance
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The thioredoxin system, comprising thioredoxin, thioredoxin reductase (TrxR) and NADPH, is a redox system of great importance in the defence against oxidative stress and is involved in the regulation of several cellular processes, such as apoptosis and cell proliferation. In addition, TrxR is a selenoenzyme and is a key enzyme in selenium metabolism. The aim of this study was to elucidate the role of TrxR in carcinogenesis and in resistant cancer cells and to investigate the tumor preventive effects and the cytotoxicity of selenium compounds. In this study we have defined the subcellular localisation and recorded activity alterations of TrxR in a rat model for chemically induced hepatocarcinogenesis. Enzymatic activity as well as mRNA expression of TrxR was found to be four times higher in premalignant neoplastic liver lesions than in normal liver. The cytosolic TrxR activity increased in the premalignant liver tissue during the carcinogenetic process compared to control tissue whereas the mitochondrial activity decreased. During the promotion phase selenite administration significantly decreased the volume fraction of preneoplastic liver nodules in parallel with a decrease in cell proliferation in the lesions. Selenite administration during the progression phase resulted in a lower volume fraction of liver tumors and a decreased proliferation within the tumors. If the selenite treatment was limited to the phase of diethylnitrosamine initiation only, no effect was seen on the number or volume fraction of preneoplastic liver lesions. In an attempt to find new therapeutic strategies to cancers resistant to common chemotherapy we have examined the cytotoxic effect of selenite in multidrug resistant cancer cells. Drugresistant cells appeared to be considerably more sensitive to selenite cytotoxicity than drugsensitive cells. Further studies showed presence of caspase-independent selenite-induced apoptosis in the drug-resistant cells. The selenite sensitivity observed in the drug-resistant cells was not associated with the up-regulation of TrxR seen in the drug-sensitive cells during selenite exposure. To further investigate the role of TrxR in selenite cytotoxicity, we used cells over-expressing this enzyme. The TrxR over-expressing cells showed an increased resistance towards selenite cytotoxicity compared to control cells. After preincubation with selenite, in a low, enzymesaturating dose, an even higher resistance against selenite toxicity was obtained. In conclusion, our data suggest that TrxR is important in neoplastic liver lesions and demonstrate that selenium supplementation prevent the carcinogenetic process both during the promotion and progression phases. Moreover, we report selenite-induced apoptosis occurring in the drug-resistant cells and an increase in TrxR activity appears to be crucial for cell resistance against selenium cytotoxicity.
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| 2. |
- Hedman, Christel, et al.
(författare)
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Deprescribing in Palliative Cancer Care
- 2022
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Ingår i: Life. - : MDPI AG. - 0024-3019 .- 2075-1729. ; 12:5
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Forskningsöversikt (refereegranskat)abstract
- The aim of palliative care is to maintain as high a quality of life (QoL) as possible despite a life-threatening illness. Thus, the prescribed medications need to be evaluated and the benefit of each treatment must be weighed against potential side effects. Medications that contribute to symptom relief and maintained QoL should be prioritized. However, studies have shown that treatment with preventive drugs that may not benefit the patient in end-of-life is generally deprescribed very late in the disease trajectory of cancer patients. Yet, knowing how and when to deprescribe drugs can be difficult. In addition, some drugs, such as beta-blockers, proton pump inhibitors, anti-depressants and cortisone need to be scaled down slowly to avoid troublesome withdrawal symptoms. In contrast, other medicines, such as statins, antihypertensives and vitamins, can be discontinued directly. The aim of this review is to give some advice according to when and how to deprescribe medications in palliative cancer care according to current evidence and clinical praxis. The review includes antihypertensive drugs, statins, anti-coagulants, aspirin, anti-diabetics, proton pump inhibitors, histamin-2-blockers, bisphosphonates denosumab, urologicals, anti-depressants, cortisone, thyroxin and vitamins.
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| 3. |
- Humbert, Marion, et al.
(författare)
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Functional SARS-CoV-2 cross-reactive CD4+ T cells established in early childhood decline with age
- 2023
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 120:12
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Tidskriftsartikel (refereegranskat)abstract
- Pre-existing SARS-CoV-2-reactive T cells have been identified in SARS-CoV-2-unexposed individuals, potentially modulating COVID-19 and vaccination outcomes. Here, we provide evidence that functional cross-reactive memory CD4+ T cell immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is established in early childhood, mirroring early seroconversion with seasonal human coronavirus OC43. Humoral and cellular immune responses against OC43 and SARS-CoV-2 were assessed in SARS-CoV-2-unexposed children (paired samples at age two and six) and adults (age 26 to 83). Pre-existing SARS-CoV-2-reactive CD4+ T cell responses targeting spike, nucleocapsid, and membrane were closely linked to the frequency of OC43-specific memory CD4+ T cells in childhood. The functional quality of the cross-reactive memory CD4+ T cell responses targeting SARS-CoV-2 spike, but not nucleocapsid, paralleled OC43-specific T cell responses. OC43-specific antibodies were prevalent already at age two. However, they did not increase further with age, contrasting with the antibody magnitudes against HKU1 (β-coronavirus), 229E and NL63 (α-coronaviruses), rhinovirus, Epstein–Barr virus (EBV), and influenza virus, which increased after age two. The quality of the memory CD4+ T cell responses peaked at age six and subsequently declined with age, with diminished expression of interferon (IFN)-γ, interleukin (IL)-2, tumor necrosis factor (TNF), and CD38 in late adulthood. Age-dependent qualitative differences in the pre-existing SARS-CoV-2-reactive T cell responses may reflect the ability of the host to control coronavirus infections and respond to vaccination. Copyright © 2023 the Author(s).
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| 4. |
- Jönsson-Videsäter, Kerstin, et al.
(författare)
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Selenite-induced apoptosis in doxorubicin-resistant cells and effects on the thioredoxin system.
- 2004
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Ingår i: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952. ; 67:3, s. 513-522
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Tidskriftsartikel (refereegranskat)abstract
- Selenium treatment of the doxorubicin-resistant cell line, U-1285dox, derived from human small cell carcinoma of the lung, resulted in massive apoptosis. This effect appeared maximal at 2 days after addition of selenite. The apoptosis was caspase-3 independent as revealed by Western blot analysis, activity measurement and by using caspase inhibitors. Induction of apoptosis was significantly more pronounced and occurred after addition of lower concentrations of selenite in the doxorubicin-resistant cells compared to the parental doxorubicin-sensitive cells. High levels of selenite caused necrosis in the doxorubicin-sensitive cells. Analysis of enzymatic activity (insulin reduction) of thioredoxin reductase (TrxR) and TrxR protein concentration, measured by ELISA, revealed increasing activity and protein levels after treatment with increasing concentrations of selenium. Maximum relative increase was induced up to 1 μM in both sublines and at this selenium level the concentrations of TrxR measured as insulin reducing activity or ELISA immunoreactivity were nearly identical. Increasing concentrations of selenite up to 10 μM resulted in increased activity and concentration of TrxR in the sensitive subline but decreasing levels in the resistant subline. The level of truncated Trx (tTrx) was higher in the resistant U-1285dox cells but the level did not change with increasing selenite concentrations. Our results demonstrate pronounced selective selenium-mediated apoptosis in therapy-resistant cells and suggest that redox regulation through the thioredoxin system is an important target for cancer therapy.
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| 5. |
- Klasson, Caritha, et al.
(författare)
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Fatigue in Cancer Patients in Palliative Care : A Review on Pharmacological Interventions.
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:5
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Forskningsöversikt (refereegranskat)abstract
- Fatigue is one of the most distressing symptoms experienced by cancer patients. The suggested biological mechanism for cancer related fatigue (CRF) includes immune activation triggered by tumor tissue or by anticancer treatment but other mechanisms have also been proposed. Previous large meta-analysis of interventions on fatigue focuses mostly on patients early in the disease trajectory, with only one tenth of included studies performed in palliative cohorts. The aim of this narrative review is therefore to present a background on CRF with focus on the palliative setting. A summary of recent randomized, controlled trials on pharmacological interventions on CRF in palliative care is presented, including studies on psychostimulants, corticosteroids, testosterone and melatonin. Interestingly, in several of these studies there was a positive and similar effect on fatigue in both the intervention and the placebo arm-indicating an important placebo effect for any pharmacological treatment. In addition, studies on dietary supplements and on pharmacological complementary medicines are discussed. To conclude, the evidence is still weak for using pharmacological treatments on CRF in palliative care patients-although methylphenidate and corticosteroids might be considered.
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| 6. |
- Klasson, Caritha, et al.
(författare)
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Sex Differences in the Effect of Vitamin D on Fatigue in Palliative Cancer Care : A Post Hoc Analysis of the Randomized, Controlled Trial 'Palliative-D'
- 2022
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:3
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Tidskriftsartikel (refereegranskat)abstract
- In the randomized, placebo-controlled, double-blind trial 'Palliative-D', vitamin D treatment of 4000 IE/day for 12 weeks reduced opioid use and fatigue in vitamin-D-deficient cancer patients. In screening data from this trial, lower levels of vitamin D were associated with more fatigue in men but not in women. The aim of the present study was to investigate possible sex differences in the effect of vitamin D in patients with advanced cancer, with a specific focus on fatigue. A post hoc analysis of sex differences in patients completing the Palliative-D study (n = 150) was performed. Fatigue assessed with the Edmonton Symptom Assessment Scale (ESAS) was reduced in vitamin-D-treated men; -1.50 ESAS points (95%CI -2.57 to -0.43; p = 0.007) but not in women; -0.75 (95%CI -1.85 to 0.36; p = 0.18). Fatigue measured with EORTC QLQ-C15-PAL had a borderline significant effect in men (-0.33 (95%CI -0.67 to 0.03; p = 0.05)) but not in women (p = 0.55). The effect on fatigue measured with ESAS in men remained the same after adjustment for opioid doses (p = 0.01). In conclusion, the positive effect of the correction of vitamin D deficiency on fatigue may be more pronounced in men than in women. However, studies focused on analyzing sex differences in this context must be performed before firm conclusions can be drawn.
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| 7. |
- Klasson, Caritha, et al.
(författare)
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Vitamin D and Fatigue in Palliative Cancer : A Cross-Sectional Study of Sex Difference in Baseline Data from the Palliative D Cohort
- 2021
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Ingår i: Journal of Palliative Medicine. - : Mary Ann Liebert Inc. - 1096-6218 .- 1557-7740. ; 24:3, s. 433-437
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Tidskriftsartikel (refereegranskat)abstract
- Background: Fatigue is one of the most distressing symptoms in patients with advanced cancer. Previous studies have shown an association between low vitamin D levels and fatigue. Objectives: The aim of this study was to investigate the association between vitamin D levels and self-assessed fatigue in cancer patients admitted to palliative care, with focus on possible sex differences. Design: This is a cross-sectional study. Subjects: Baseline data from 530 screened patients, 265 women and 265 men, from the randomized placebo-controlled trial "Palliative-D" were analyzed. Measurements: Vitamin D status was measured as 25-hydroxyvitamin D (25-OHD) and fatigue was assessed with EORTC-QLQ-PAL15 and with Edmonton Symptom Assessment System (ESAS). Results: In men, there was a significant correlation between 25-OHD and fatigue measured with the "Tiredness question" (Q11) in EORTC-QLQ-PAL15 (p < 0.05), where higher 25-OHD levels were associated with less fatigue. No correlation between 25-OHD and fatigue was seen for women. Fatigue measured with ESAS did not show any significant association with 25-OHD levels neither in men nor in women. Conclusion: Low vitamin D levels were associated with more fatigue in men but not in women. The study underscores the importance of subgroup analysis of men and women when evaluating the effect of vitamin D in clinical trials since the effect may differ between the sexes. The ongoing "Palliative-D study" will reveal whether vitamin D supplementation may counteract fatigue in both men and women.ClinicalTrial.gov: NCT03038516.
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| 8. |
- Larsson, Maria, et al.
(författare)
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Omvårdnad vid cancersjukdom
- 2021. - 3
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Ingår i: Klinisk omvårdnad 2. - Stockholm : Liber. - 9789147113606 ; , s. 403-499
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Klinisk omvårdnad 2 är del två av en serie om två böcker. Klinisk omvårdnad del 1 och 2 tydliggör vilka konsekvenser olika sjukdomar och skador har för patienten. Hur upplever patienten att vara sjuk, hur påverkas hens grundläggande behov och vilka copingstrategier behövs? Böckerna tillhandahåller systematisk kunskap om datainsamling, de kliniska bedömningar och omvårdnadsåtgärder som behövs för att kunna tillgodose patientens grundläggande behov samt om sjuksköterskans ansvar och kompetens i sin professionsutövning. Alla kapitel har en liknande struktur, vilket gör det enkelt att orientera sig. Texterna är granskade av svenska experter och anpassade till svenska förhållanden. Böckerna vänder sig till blivande sjuksköterskor och kan användas som referens för sjuksköterskor inom olika verksamhetsområden.
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| 9. |
- Madeja, Zbigniew, et al.
(författare)
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The role of thioredoxin reductase activity in selenium-induced cytotoxicity
- 2005
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Ingår i: Biochemical Pharmacology. - : Elsevier. - 0006-2952 .- 1356-1839. ; 69:12, s. 1765-1772
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Tidskriftsartikel (refereegranskat)abstract
- The selenoprotein thioredoxin reductase is a key enzyme in selenium metabolism, reducing selenium compounds and thereby providing selenide to synthesis of all selenoproteins. We evaluated the importance of active TrxR1 in selenium-induced cytotoxicity using transfected TrxR1 over-expressing stable Human Embryo Kidney (HEK-293) cells and modulation of activity by pretreatment with low concentration of selenite. Treatment with sodium selenite induced cytotoxity in a dose-dependent manner in both TrxR1 over-expressing and control cells. However, TrxR1 over-expressing cells, which were preincubated for 72h with 0.1 microM selenite, were significantly more resistant to selenite cytotoxicity than control cells. To demonstrate the early effects of selenite on behaviour of HEK-293 cells, we also investigated the influence of this compound on cell motility. We observed inhibition of cell motility by 50 microM selenite immediately after administration. Moreover, TrxR1 over-expressing cells preincubated with a low concentration of selenite were more resistant to the inhibitory effect of 50 microM selenite than those not preincubated. It was also observed that the TrxR over-expressing cells showed higher TrxR1 activity than control cells and the preincubation of over-expressing cells with 0.1 microM selenite induced further significant increase in the activity of TrxR1. On the other hand, we demonstrated that TrxR1 over-expressing cells showed decreased glutathione peroxidase activity compared to control cells. These data strongly suggest that TrxR1 may be a crucial enzyme responsible for cell resistance against selenium cytotoxicity.
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| 10. |
- Nordman, Tomas, et al.
(författare)
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Regeneration of the antioxidant ubiquinol by lipoamide dehydrogenase, thioredoxin reductase and glutathione reductase
- 2003
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Ingår i: Biofactors. - : IOS Press. - 0951-6433 .- 1872-8081. ; 18:1-4, s. 45-50
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Tidskriftsartikel (refereegranskat)abstract
- Ubiquinol is a powerful antioxidant, which is oxidized in action and needs to be replaced or regenerated to be capable of a sustained effort. This article summarises current knowledge of extramitochondrial reduction of ubiquinone by three flavoenzymes, i.e. lipoamide dehydrogenase, glutathione reductase and thioredoxin reductase, belonging to the same pyridine nucleotide-disulfide oxidoreductase family. These three enzymes are the most efficient extramitochondrial ubiquinone reductases so far described. The reduction of ubiquinone by lipoamide dehydrogenase and glutathione reductase is potently stimulated by zinc and the highest rate of reduction is achieved at acidic pH and the rates are equal with either NADPH or NADH as co-factors. The most efficient ubiquinone reductases are mammalian cytosolic thioredoxin reductases, which are selenoenzymes with a number of biological functions. Reduction of ubiquinone by thioredoxin reductase is in contrast to the other two enzymes investigated, inhibited by zinc and shows a sharp physiological pH optimum at pH 7.5. Furthermore, the reaction is selenium dependent as revealed from experiments using truncated and mutant forms of the enzyme and also in a cellular context by selenium treatment of transfected thioredoxin reductase overexpressing stable cell lines. The reduction of ubiquinone by the three enzymes offers a multifunctional system for extramitochondrial regeneration of an important antioxidant.
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