The daily dietary intake of selenium (Se), an essential trace element, is still low in Sweden in spite of decades of nutritional information campaigns and the effect of this on the public health is ...presently not well known. The objective of this study was to determine the serum Se levels in an elderly Swedish population and to analyze whether a low Se status had any influence on mortality.
Six-hundred sixty-eight (n=668) elderly participants were invited from a municipality and evaluated in an observational study. Individuals were followed for 6.8 years and Se levels were re-evaluated in 98 individuals after 48 months. Clinical examination of all individuals included functional classification, echocardiography, electrocardiogram and serum Se measurement. All mortality was registered and endpoints of mortality were assessed by Kaplan-Meier plots, and Cox proportional hazard ratios adjusted for potential confounding factors were calculated.
The mean serum Se level of the study population (n=668) was 67.1 μg/l, corresponding to relatively low Se intake. After adjustment for male gender, smoking, ischemic heart disease, diabetes, chronic obstructive pulmonary disease and impaired heart function, persons with serum Se in the lowest quartile had 43% (95% confidence interval (CI): 1.02-2.00) and 56% (95% CI: 1.03-2.36) increased risk for all-cause and cardiovascular mortality, respectively. The result was not driven by inflammatory effects on Se concentration in serum.
The mean serum Se concentration in an elderly Swedish population was 67.1 μg/l, which is below the physiological saturation level for several selenoprotein enzymes. This result may suggest the value of modest Se supplementation in order to improve the health of the Swedish population.
Malignancies are still responsible for a large share of lethalities. Macroscopical evaluation of the surgical resection margins is uncertain. Big data based imaging approaches have emerged in the ...recent decade (mass spectrometry, two-photon microscopy, infrared and Raman spectroscopy). Indocianine green labelled MS is the most common approach, however, label free mid-infrared imaging is more promising for future practical application. We aimed to identify and separate different transformed (A-375, HT-29) and non-transformed (CCD986SK) cell lines by a label-free infrared spectroscopy method. Our approach applied a novel set-up for label-free mid-infrared range classification method. Transflection spectroscopy was used on aluminium coated glass slides. Both whole range spectra (4000–648 cm
−1
) and hypersensitive fingerprint regions (1800–648 cm
−1
) were tested on the imaged areas of cell lines fixed in ethanol. Non-cell spectra were possible to be excluded based on mean transmission values being above 90%. Feasibility of a mean transmission based spectra filtering method with principal component analysis and linear discriminant analysis was shown to separate cell lines representing different tissue types. Fingerprint region resulted the best separation of cell lines spectra with accuracy of 99.84% at 70–75 mean transmittance range. Our approach in vitro was able to separate unique cell lines representing different tissues of origin. Proper data handling and spectra processing are key steps to achieve the adaptation of this dye-free technique for intraoperative surgery. Further studies are urgently needed to test this novel, marker-free approach.
Sex-driven immune differences can affect tumor progression and the landscape of the tumor microenvironment. Deeper understanding of these differences in males and females can inform patient selection ...to improve sex-optimized immunotherapy treatments. In this study, single-cell RNA sequencing and protein analyses uncovered a subpopulation of myeloid cells in pancreatic lesions associated with an immune-excluded tumor phenotype and effector T-cell exhaustion exclusively in females. This myeloid subpopulation was positively correlated with poor survival and genetic signatures of M2-like macrophages and T-cell exhaustion in females. The G-protein coupled receptor formyl peptide receptor 2 (FPR2) mediated these immunosuppressive effects. In vitro, treatment of myeloid cells with a specific FPR2 antagonist prevented exhaustion and enhanced cytotoxicity of effector cells. Proteomic analysis revealed high expression of immunosuppressive secretory proteins PGE2 and galectin-9, enriched integrin pathway, and reduced proinflammatory signals like TNFα and IFNγ in female M2-like macrophages upon FPR2 agonist treatment. In addition, myeloid cells treated with FPR2 agonists induced TIM3 and PD-1 expression only in female T cells. Treatment with anti-TIM3 antibodies reversed T-cell exhaustion and stimulated their ability to infiltrate and kill pancreatic spheroids. In vivo, progression of syngeneic pancreatic tumors was significantly suppressed in FPR2 knockout (KO) female mice compared with wild-type (WT) female mice and to WT and FPR2 KO male mice. In female mice, inoculation of tumors with FPR2 KO macrophages significantly reduced tumor growth compared with WT macrophages. Overall, this study identified an immunosuppressive function of FPR2 in females, highlighting a potential sex-specific precision immunotherapy strategy.
FPR2 is a sex-dependent mediator of macrophage function in pancreatic cancer and can be targeted to reprogram macrophages and stimulate antitumor immunity in females.
Selenium compounds like selenite (SeO3(2-) may form a covalent adduct with glutathione (GSH) in the form of selenodiglutathione
(GS-Se-SG), which is assumed to be important in the metabolism of ...selenium. We have isolated GS-Se-SG and studied its reactions
with NADPH and thioredoxin reductase from calf thymus or with thioredoxin reductase and thioredoxin from Escherichia coli.
Incubation of 0.1 microM calf thymus thioredoxin reductase or 0.1 microM thioredoxin reductase and 1 microM thioredoxin from
E. coli with 5, 10, or 20 microM GS-Se-SG resulted in a fast initial reaction, followed by a large and continued oxidation
of NADPH. However, anaerobic incubation of 0.1 microM calf thymus thioredoxin reductase and 20 microM GS-Se-SG resulted only
in oxidation of a stoichiometric amount of NADPH; admission of oxygen started continuous NADPH oxidation. Contrary to the
mammalian enzyme, GS-Se-SG was not a substrate for thioredoxin reductase from E. coli. The rate of the oxygen-dependent reaction
between calf thymus thioredoxin reductase and GS-Se-SG was increased 2-fold in the presence of 4 mM GSH, indicating that HSe-
was the reactive intermediate. Glutathione reductase from rat liver reduced GS-Se-SG with a very slow continued oxidation
of NADPH, and the presence of the enzyme did not affect the oxygen-dependent nonstoichiometric oxidation of NADPH by GS-Se-SG
and thioredoxin reductase. Fluorescence spectroscopy showed GS-Se-SG to be a very efficient oxidant of reduced thioredoxin
from E. coli and kinetically superior to insulin disulfides. Thioredoxin-dependent reduction of CDP to dCDP by ribonucleotide
reductase was effectively inhibited by GS-Se-SG.
Selenium is an essential trace element for regulating immune functions through redox-regulating activity of selenoproteins (e.g. glutathione peroxidase), protecting immune cells from oxidative ...stress. However, in cancer, selenium has biological bimodal action depending on the concentration. At nutritional low doses, selenium, depending on its form, may act as an antioxidant, protecting against oxidative stress, supporting cell survival and growth, thus, plays a chemo-preventive role; while, at supra-nutritional higher pharmacological doses, selenium acts as pro-oxidant inducing redox signalling and cell death. To date, many studies have been conducted on the benefits of selenium intake in reducing the risk of cancer incidence at the nutritional level, indicating that likely selenium functions as an immunostimulator, i.e. reversing the immunosuppression in tumour microenvironment towards antitumour immunity by activating immune cells (e.g. M1 macrophages and CD8+ T-lymphocytes) and releasing pro-inflammatory cytokines such as interferon-gamma; whereas, fewer studies have explored the effects of supra-nutritional or pharmacological doses of selenium in cancer immunity. This review, thus, systematically analyses the current knowledge about how selenium stimulates the immune system against cancer and lay the groundwork for future research. Such knowledge can be promising to design combinatorial therapies with Selenium-based compounds and other modalities like immunotherapy to lower the adverse effects and increase the efficacy of treatments.
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•Se is an essential element for regulating immune functions.•Se reverses immunosuppression in the tumour microenvironment.•Effects of Se on cancer immunity are neglected and require more detailed studies.
Selenium compounds have pronounced effects on cell growth and proliferation. Nutritional levels induce selenoproteins. However, the antineoplastic effects of supra-nutritional selenium levels are not ...mediated by selenoproteins. The most studied compound, selenite, was shown in a clinical trial to possess extraordinary pharmacological properties. The uptake of selenite as for GS-Se-SG and selenocystine is dependent on the extracellular reducing environment maintained by the X
cystine transporter (x
antiporter) ensuring a high level of extracellular cysteine. The expression of the x
antiporter is vital for selenium cytotoxicity and any xenobiotic or media constituents modulating the expression of this antiporter will greatly affect the cellular response. Cytotoxicity determinations are often difficult to interpret and repeat due to differences in culture conditions. In the current chapter, factors influencing the cellular response, e.g., media composition, cell culturing conditions, assays for key enzymes of importance for selenium metabolism and effects, along with selenium mediated modulation of microRNA expression and immune responses are treated.
Selenium is generally known as an antioxidant due to its presence in selenoproteins as selenocysteine, but it is also toxic. The toxic effects of selenium are, however, strictly concentration and ...chemical species dependent. One class of selenium compounds is a potent inhibitor of cell growth with remarkable tumor specificity. These redox active compounds are pro-oxidative and highly cytotoxic to tumor cells and are promising candidates to be used in chemotherapy against cancer. Herein we elaborate upon the major forms of dietary selenium compounds, their metabolic pathways, and their antioxidant and pro-oxidant potentials with emphasis on cytotoxic mechanisms. Relative cytotoxicity of inorganic selenite and organic selenocystine compounds to different cancer cells are presented as evidence to our perspective. Furthermore, new novel classes of selenium compounds specifically designed to target tumor cells are presented and the potential of selenium in modern oncology is extensively discussed.
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