Jan Olav Aaseth

• Alehagen, Urban; Aaseth, Jan; Schomburg, Lutz; Opstad, Trine Baur; Larsson, Anders & Alexander, Jan (2025). Selenium and Coenzyme Q10 Supplementation and Sex Differences in Cardiovascular Mortality Results from a Prospective Randomized Double-Blind Placebo-Controlled Trial in Elderly People Low in Selenium. Antioxidants. 14(6), s. 1–21. doi: 10.3390/antiox14060685. Fulltekst i vitenarkiv Vis sammendrag

  Background: Low selenium intake and age-related decline of coenzyme Q10 (CoQ10) have been associated with an increased risk of cardiovascular disease (CVD) and oxidative stress. In a randomised placebo-controlled trial (RTC) in elderly people with low selenium levels, the supplementation with selenium and CoQ10 reduced CVD and mortality. However, whether the supplementation elicited sex-specific benefits remained to be explored. Methods: Elderly Swedish persons (n = 443; balanced sex ratio) receiving selenium yeast (200 µg/day) and CoQ10 (200 mg/day) combined or a placebo for four years were followed for additional six years. The response to supplementation, cardiovascular (CV) mortality, and risk factors were determined at four and ten years. Kaplan–Meier analyses, ANCOVA, repeated measurements of variance, and Cox proportional hazard regression analyses were performed. Results: The measured 10-year CV mortality rate was lower in females, and supplementation reduced this risk to a greater extent compared to in males. The improved survival rate apparently kicked in later in females than in males. At baseline, males had a higher smoking rate, increased inflammation and oxidative stress, and a higher prevalence of more advanced ischaemic heart disease (IHD) and signs of heart failure. When stratified by sex, in individuals with IHD, the intervention improved CV survival in both sexes, whereas supplementation had a more pronounced effect in females without IHD at inclusion. Supplementation diminished inflammation and oxidative stress, impaired the increase of NT-proBNP, and improved renal function in both sexes. Conclusions: The supplementation improved CV survival, especially in women. The higher prevalence of structural CVD and smoking in males may have contributed to the observed greater supplementation benefits in females. The preventive impact of selenium and CoQ10 supplementation in elderly males and females may be particularly strong and meaningful in the early stages of CVD development.

• Roer, Grethe Emilie; Bolstad, Ingeborg; Abebe, Dawit Shawel; Aaseth, Jan; Haugen, Morten & Lien, Lars (2025). Metabolic Syndrome and Associated Risk Factors in Norwegian Trauma-Exposed Inpatients: A Cross-Sectional Comparison with Blood Donors. Diabetes, Metabolic Syndrome and Obesity. 18, s. 2667–2680. doi: 10.2147/dmso.s536015. Fulltekst i vitenarkiv
• Alehagen, Urban; Aaseth, Jan; Opstad, Trine Baur; Larsson, Anders; Asaad, Sabrina & Schomburg, Lutz [Vis alle 7 forfattere av denne artikkelen] (2025). Serum CD5L Responds Positively to Selenium and Coenzyme Q10 Supplementation with Relation to Thyroid Hormones, Mortality, and Health-Related Quality-of-Life—A Sub-Analysis of a Double-Blind Randomised Placebo-Controlled Trial in Elderly Low in Selenium. Antioxidants. 14(3). doi: 10.3390/antiox14030366. Fulltekst i vitenarkiv Vis sammendrag

  The Cluster of Differentiation 5-like protein (CD5L) is produced by tissue-resident macrophages. It is an innate immune mediator protein with a multitude of functions, such as binding of invading microorganisms and oxidised LDL, and it is associated with clinical conditions, i.e., atherosclerosis and inflammation. The circulating CD5L level has been reported to correlate to selenium status and thyroid hormone activity. In order to test this hypothesis, we analysed CD5L in serum samples from a randomized controlled trial (RCT) with selenium and coenzyme Q10 supplementation and examined associations between CD5L and thyroid hormones, health-related quality-of-life (Hr-QoL), and mortality in an elderly population low in selenium. Circulating levels of CD5L and thyroid hormones were determined in 359 elderly community-living individuals enrolled in an RCT at inclusion and after 48 months of supplementation (179 received selenium and coenzyme Q10, and 180 placebo). Hr-QoL was recorded at both time-points using Short Form 36. Pre-intervention plasma selenium was low, mean 67 µg/L. CD5L correlated positively to free tri-iodothyronine (fT3) and showed an inverse relation with thyroid stimulating hormone (TSH). Low CD5L concentrations at inclusion in the placebo group were associated with increased cardiovascular mortality during 10 years of follow-up, and impaired Hr-QoL at 48 months. Selenium and coenzyme Q10 supplementation significantly increased CD5L and fT3 levels, in association with a better health outcome. The data indicate that circulating CD5L positively responds to selenium and coenzyme Q10 supplementation, correlates with thyroid hormone status, and associates with positive health indices. The observed effect may be due to increased selenium-dependent deiodinase isozyme expression that converts thyroxine (T4) to T3 locally and supports thyroid hormone activities. Whether the observed associations with Hr-QoL and cardiovascular mortality are a direct effect of circulating CD5L or local thyroid hormone activity is unclear and should be further investigated.

• Aaseth, Jan; Retterstøl, Kjetil; Rootwelt, Helge & Farup, Per Grønaas (2025). Reduction in Remnant Cholesterol in Obese Individuals After Bariatric Surgery with Gastric Bypass or Sleeve Gastrectomy. Nutrients. 17(1). doi: 10.3390/nu17010189. Fulltekst i vitenarkiv Vis sammendrag

  Background: The effectiveness of bariatric surgery in reducing remnant cholesterol (RC) levels, particularly when obesity is accompanied by elevated glycated hemoglobin (HbA1c), is insufficiently investigated. In this study, we aimed to examine the impacts of two common bariatric procedures, Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), as regards their effects on RC and HbA1c levels. Methods: Adult morbidly obese subjects were included and assigned to receive either RYGB or SG. The levels of RC and HbA1c were determined 6 and 12 months after surgery and compared to preoperative levels to assess the efficacy of these surgical methods. In the statistical evaluation of covariations between RC and other biomarkers, previously determined C-reactive protein (CRP), triglycerides, apolipoprotein B, apolipoprotein A1, and low- and high-density lipoprotein cholesterol 6 and 12 months after surgery were included. A linear mixed regression model for repeated analyses was used. Results: The RC levels were markedly reduced both after RYGB and SG but without significant differences between the RYGB and the SG surgery. Furthermore, the RC values were strongly associated with the levels of CRP and HbA1c. Conclusions: A significant lowering of RC values after bariatric surgery appeared paralleled by concomitant reductions in HbA1c values and CRP levels. Together, these effects lead to a lower risk of cardiovascular disease.

• Hestad, Knut; Aaseth, Jan & Kropotov, Juri D. (2024). Neuropsychological Characteristics and Quantitative Electroencephalography in Skogholt’s Disease—A Rare Neurodegenerative Disease in a Norwegian Family. Brain Sciences. 14(9). doi: 10.3390/brainsci14090905. Fulltekst i vitenarkiv
• Alehagen, U.; Aaseth, Jan; Schomburg, L.; Larsson, Anders; Opstad, Trine Baur & Alexander, Jan (2024). Selenoprotein P increases upon selenium and coenzyme Q10 supplementation and is associated with telomere length, quality of life and reduced inflammation and mortality. Free Radical Biology & Medicine. ISSN 0891-5849. 222, s. 403–413. doi: 10.1016/j.freeradbiomed.2024.06.027. Fulltekst i vitenarkiv Vis sammendrag

  Background Selenoprotein P (SELENOP) transports selenium to extrahepatic tissues and is a biomarker of selenium status. Low soil selenium leads to low dietary selenium intake. A consequence is an increased risk of cardiovascular disease. Objective To investigate clinical aspects associated with SELENOP deficiency, including biomarkers of inflammation, quality of life, and mortality within 12 years, and the effect of dietary selenium and coenzyme Q10 supplementation on SELENOP. Methods SELENOP was determined at inclusion and after four years of supplementation in 403 elderly community-living participants low in selenium receiving selenium yeast (200 μg/day) and coenzyme Q10 (200 mg/day), or placebo. Pre-intervention, the average serum selenium level was 67 μg/L. T-tests, repeated measures of variance, Cox proportional regressions analyses, Kaplan-Meier graphs and ANCOVA analyses were applied. Associations with biomarkers of inflammation, telomere length, quality of life and mortality were investigated. Benchmark modelling was used to determine the serum selenium concentration at which the saturation levels of SELENOP and GPx3 was achieved. Comparison with GPx3 and serum selenium to identify increased mortality risk was performed, and the effect of supplementation on SELENOP levels were evaluated. Results Inverse associations were observed between the level of SELENOP at inclusion and biomarkers for inflammation. At follow-up, shorter telomere lengths were seen in those with low levels of SELENOP at inclusion, whereas high levels of SELENOP were associated with better quality of life and decreased mortality. SELENOP had increased prognostic power compared to GPx3 and selenium. Saturation of SELENOP was achieved at a serum selenium level of 146 μg/L, and for GPx3 at 99 μg/L. Supplementation induced higher levels of SELENOP. Conclusion Significant associations between SELENOP and inflammation, length of telomeres, quality of life, and mortality were observed. Thus, selenium supplementation improved SELENOP expression, thereby facilitating systemic selenium bioavailability and resulting in the observed positive health effects.

• Aaseth, Jan; Finnes, Trine Elisabeth; Askim, Merete & Alexander, Jan (2024). The Importance of Vitamin K and the Combination of Vitamins K and D for Calcium Metabolism and Bone Health: A Review. Nutrients. 16(15). doi: 10.3390/nu16152420. Fulltekst i vitenarkiv Vis sammendrag

  The aim of the present review is to discuss the roles of vitamin K (phylloquinone or menaquinones) and vitamin K-dependent proteins, and the combined action of the vitamins K and D, for the maintenance of bone health. The most relevant vitamin K-dependent proteins in this respect are osteocalcin and matrix Gla-protein (MGP). When carboxylated, these proteins appear to have the ability to chelate and import calcium from the blood to the bone, thereby reducing the risk of osteoporosis. Carboxylated osteocalcin appears to contribute directly to bone quality and strength. An adequate vitamin K status is required for the carboxylation of MGP and osteocalcin. In addition, vitamin K acts on bone metabolism by other mechanisms, such as menaquinone 4 acting as a ligand for the nuclear steroid and xenobiotic receptor (SXR). In this narrative review, we examine the evidence for increased bone mineralization through the dietary adequacy of vitamin K. Summarizing the evidence for a synergistic effect of vitamin K and vitamin D3, we find that an adequate supply of vitamin K, on top of an optimal vitamin D status, seems to add to the benefit of maintaining bone health. More research related to synergism and the possible mechanisms of vitamins D3 and K interaction in bone health is needed.

• Lachowicz, Joanna Izabela; Alexander, Jan & Aaseth, Jan (2024). Cyanide and Cyanogenic Compounds — Toxicity, Molecular Targets, and Therapeutic Agents. Biomolecules. 14(11). doi: 10.3390/biom14111420. Fulltekst i vitenarkiv Vis sammendrag

  Cyanide (CN) is a well-known mitochondrial poison. CN poisoning may result from acute or long-term exposure to a number of CN compounds. Recent insight into the chemical affinities of the CN anion has increased our understanding of its toxicity and the mechanisms of antidotal actions, which, together with information on various exposure sources, are reviewed in the present article. A literature search in Scopus, Embase, Web of Science, PubMed, and Google Scholar for the period 2001–2024 revealed that the CN anion after exposure or degradation of CN compounds is distributed to vulnerable copper and iron-containing targets, especially in mitochondria, thus blocking the electron transport chain. Intake of cyanogenic compounds may exert subacute or chronic toxic effects, also because of the interaction with cobalt in vitamin B12. Antidotal agents exert their effects through the affinity of CN for cobalt- or iron-containing compounds. Research on CN interactions with metalloproteins may increase our insight into CN toxicity and efficient antidotal regimens.

• Bjørklund, Geir; Semenova, Yuliya; Hangan, Tony; Pen, Joeri J.; Aaseth, Jan & Peana, Massimiliano (2024). Perspectives on Iron Deficiency as a Cause of Human Disease in Global Public Health. Current Medicinal Chemistry. ISSN 0929-8673. 31(12), s. 1428–1440. doi: 10.2174/0929867330666230324154606. Fulltekst i vitenarkiv
• Thomassen, Yngvar & Aaseth, Jan (2024). Human Tissues. I Ihnat, Milan (Red.), Occurence & Distribution of Selenium. CRC Press. ISSN 9781003574392. s. 169–212. doi: 10.1201/9781003574392. Fulltekst i vitenarkiv
• Alexander, Jan; Aaseth, Jan; Schomburg, Lutz; Chillon, Thilo Samson; Larsson, Anders & Alehagen, Urban (2024). Circulating Glutathione Peroxidase-3 in Elderly—Association with Renal Function, Cardiovascular Mortality, and Impact of Selenium and Coenzyme Q10 Supplementation. Antioxidants. 13(12). doi: 10.3390/antiox13121566. Fulltekst i vitenarkiv Vis sammendrag

  Low-selenium status was associated with impaired renal function, which improved after selenium and coenzyme Q10 supplementation in an RCT. Here, we evaluated serum glutathione peroxidase-3 (GPx3) and its relation to serum selenium, selenoprotein P (SELENOP), renal function, mortality, and the impact of supplementation, which are all important, especially in elderly individuals. In total, 383 study participants (197 receiving selenium yeast and coenzyme Q10 and 186 on a placebo) were evaluated. We applied benchmark dose modelling to determine GPx3 saturation, ANCOVA, Kaplan-Meier, and multivariate Cox proportional regression analyses for mortality evaluations. Selenium and GPx3 activity were modestly correlated. In comparison with SELENOP, GPx3 levelled off at a much lower value, 100 vs. 150 µg Se/L. GPx3 was associated with renal function, but not SELENOP. Supplementation increased glomerular function by ≈23% with an increase in GPx3. Being low in GPx3 displayed twice the risks of mortality in both placebos and active treatments. At serum selenium <100 µg/L, GPx3 activity was dependent on both selenium status and renal function. As renal function is reduced in the elderly, GPx3 is not an appropriate marker of selenium status. Low GPx3 was associated with an increased risk of mortality dependent of selenium status and independent of renal function.

• Alehagen, Urban; Alexander, Jan; Aaseth, Jan; Larsson, Anders & Opstad, Trine Baur (2024). Supplementation with selenium and coenzyme Q10 in an elderly Swedish population low in selenium — positive effects on thyroid hormones, cardiovascular mortality, and quality of life. BMC Medicine. 22(1). doi: 10.1186/s12916-024-03411-1. Fulltekst i vitenarkiv Vis sammendrag

  Background Selenium-dependent deiodinases play a central role in thyroid hormone regulation and metabolism. In many European countries, insufficient selenium intake may consequently lead to adverse effects on thyroid function. In this randomised placebo-controlled double-blind study, we examined the effect of supplementation with selenium and coenzyme Q10 on thyroid hormonal status, cardiovascular (CV) mortality and health-related quality of life (Hr-QoL). Methods Free T3, free T4, reverse T3, and TSH were determined in 414 individuals at baseline, and the effect of selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/day) supplementation on hormone concentrations, CV mortality and Hr-QoL was evaluated after 48 months using Short Form 36 (SF-36). Pre-intervention plasma selenium was low, mean 67 µg/L, corresponding to an estimated intake of 35 µg/day. Changes in concentrations of thyroid hormones following the intervention were assessed using T-tests, repeated measures of variance, and ANCOVA analyses. Results In the total population, the group with the lowest selenium concentration at baseline presented with significantly higher levels of TSH and lower levels of fT3 as compared to subjects with the highest selenium concentration. Supplementation with selenium and coenzyme Q10 for 4 years significantly increased fT3 and rT3, decreased fT4, and diminished the increase in TSH levels compared with placebo treatment (p = 0.03, all). In the placebo group, TSH and fT4 values above the median were associated with an increase in 10-year CV mortality, as compared with the mortality rate among those with TSH and fT4 below the median (p < 0.04, both), with no difference in mortality rate according to TSH and fT4 levels in the active intervention group. Similarly, TSH > median and fT3 < median were associated with a decline in mental Hr-QoL measures vs. TSH < and fT3 > median in the placebo group during 4 years of follow-up, but this was wiped out in the active group. Conclusions Supplementation with selenium and coenzyme Q10 had a beneficial effect on thyroid hormones with respect to CV mortality and Hr-QoL outcomes. The initial deficient selenium status was associated with an impaired thyroid function and the changes in thyroid hormone levels can be explained by increased activity of deiodinases. We conclude that a substantial part of the elderly study population might suffer from suboptimal thyroidal function with adverse clinical implications due to selenium deficiency. Trial registration This study was registered at ClinicalTrials.gov and has the identifier NCT01443780. Since it was not mandatory to register at the time the study began, the study has been registered retrospectively.

• Roer, Grethe Emilie; Lien, Lars; Bolstad, Ingeborg; Aaseth, Jan Olav & Abebe, Dawit Shawel (2023). The impact of PTSD on risk of cardiometabolic diseases: a national patient cohort study in Norway. BMC Psychiatry. 23(1). doi: 10.1186/s12888-023-04866-x. Fulltekst i vitenarkiv Vis sammendrag

  Background: Posttraumatic stress disorder (PTSD) is associated with cardiometabolic diseases, concurrent anxiety, alcohol use disorder and depression. The relationship between PTSD and cardiometabolic diseases are still unclear, and less is known about the effects of socioeconomic status, comorbid anxiety, comorbid alcohol use disorder and comorbid depression. The study, therefore, aims to examine the risk of developing cardiometabolic diseases including type 2 diabetes mellitus over time in PTSD patients, and to what extent socioeconomic status, comorbid anxiety, comorbid alcohol use disorder and comorbid depression attenuate associations between PTSD and risk of developing cardiometabolic diseases. Method: A retrospective, register-based cohort study with 6-years follow-up of adult (> 18 years) PTSD patients (N = 7 852) compared with the general population (N = 4 041 366), was performed. Data were acquired from the Norwegian Patient Registry and Statistic Norway. Cox proportional regression models were applied to estimate hazard ratios (HRs) (99% confidence intervals) of cardiometabolic diseases among PTSD patients. Results: Significantly (p < 0.001) higher age and gender adjusted HRs were disclosed for all cardiometabolic diseases among PTSD patients compared to the population without PTSD, with a variation in HR from 3.5 (99% CI 3.1-3.9) for hypertensive diseases to HR = 6.5 (5.7-7.5) for obesity. When adjusted for socioeconomic status and comorbid mental disorders, reductions were observed, especially for comorbid depression, for which the adjustment resulted in HR reduction of about 48.6% for hypertensive diseases and 67.7% for obesity. Conclusions: PTSD was associated with increased risk of developing cardiometabolic diseases, though attenuated by socioeconomic status and comorbid mental disorders. Health care professionals should be attentive towards the burden and increased risk that low socioeconomic status and comorbid mental disorders may represent for PTSD patients' cardiometabolic health. Keywords: Alcohol use disorder; Cardiovascular diseases; Cohort study; Comorbidity; Depression; Diabetes mellitus; Epidemiology; Metabolic diseases; Posttraumatic stress disorder; Register data. © 2023. The Author(s).

• Aaseth, Jan; Alehagen, Urban; Opstad, Trine Baur & Alexander, Jan (2023). Vitamin K and Calcium Chelation in Vascular Health. Biomedicines. 11(12). doi: 10.3390/biomedicines11123154. Fulltekst i vitenarkiv Vis sammendrag

  The observation that the extent of artery calcification correlates with the degree of atherosclerosis was the background for the alternative treatment of cardiovascular disease with chelator ethylenediamine tetraacetate (EDTA). Recent studies have indicated that such chelation treatment has only marginal impact on the course of vascular disease. In contrast, endogenous calcium chelation with removal of calcium from the cardiovascular system paralleled by improved bone mineralization exerted, i.e., by matrix Gla protein (MGP) and osteocalcin, appears to significantly delay the development of cardiovascular diseases. After post-translational vitamin-K-dependent carboxylation of glutamic acid residues, MGP and other vitamin-K-dependent proteins (VKDPs) can chelate calcium through vicinal carboxyl groups. Dietary vitamin K is mainly provided in the form of phylloquinone from green leafy vegetables and as menaquinones from fermented foods. Here, we provide a review of clinical studies, addressing the role of vitamin K in cardiovascular diseases, and an overview of vitamin K kinetics and biological actions, including vitamin-K-dependent carboxylation and calcium chelation, as compared with the action of the exogenous (therapeutic) chelator EDTA. Consumption of vitamin-K-rich foods and/or use of vitamin K supplements appear to be a better preventive strategy than EDTA chelation for maintaining vascular health.

• Henriksen, Christine & Aaseth, Jan (2023). Magnesium: a scoping review for Nordic Nutrition Recommendations 2023. Food & Nutrition Research (FNR). ISSN 1654-6628. 67. doi: 10.29219/fnr.v67.10314. Fulltekst i vitenarkiv Vis sammendrag

  Magnesium is a divalent ion involved in a range of biochemical reactions and cellular functions. The metabolism and requirements for magnesium are still insufficiently understood. In the Nordic Nutrition Recommendations from 2012, a recommended intake was set based on balance studies. However, the average requirement (AR) was not set. Functional indicators of magnesium status have been lacking. This scoping review reveals new research activity related to the beneficial effect of magnesium intake on several health outcomes (cardiovascular disease, diabetes and some cancers). Based on meta-analyses of cohort studies and Randomized Controlled Trials (RCTs), as well as on plausible mechanisms, a causal association is suggested. However, the optimal intake cannot be set based on these study designs and no new balance studies were found.

• Aaseth, Jan & Alexander, Jan (2023). Postoperative Osteoporosis in Subjects with Morbid Obesity Undergoing Bariatric Surgery with Gastric Bypass or Sleeve Gastrectomy. Nutrients. 15(6). doi: 10.3390/nu15061302. Fulltekst i vitenarkiv Vis sammendrag

  Obesity has become a worldwide epidemic accompanied by adverse health effects. The limited efficiency of traditional weight reduction regimens has led to a substantial increase in the use of bariatric surgery. Today, sleeve gastrectomy (SG) and Roux-en-Y-gastric bypass (RYGB) are the most used procedures. The present narrative review focuses on the risk of developing postoperative osteoporosis and summarizes some of the most relevant micronutrient deficiencies associated with RYGB and SG. Preoperatively, the dietary habits of obese individuals might lead to precipitated deficiencies in vitamin D and other nutrients affecting bone mineral metabolism. Bariatric surgery with SG or RYGB can aggravate these deficiencies. The various surgical procedures appear to affect nutrient absorption differently. Being purely restrictive, SG may particularly affect the absorption of vitamin B12 and also vitamin D. In contrast, RYGB has a more profound impact on the absorption of fat-soluble vitamins and other nutrients, although both surgical methods induce only a mild protein deficiency. Despite adequate supplementation of calcium and vitamin D, osteoporosis may still occur after the surgery. This might be due to deficiencies in other micronutrients, e.g., vitamin K and zinc. Regular follow-ups with individual assessments and nutritional advice are indispensable to prevent osteoporosis and other adverse postoperative issues.

• Dunning, Belinda J.; Bourgonje, Arno R.; Bulthuis, Marian L.C.; Alexander, Jan; Aaseth, Jan & Larsson, Anders [Vis alle 8 forfattere av denne artikkelen] (2023). Selenium and coenzyme Q10 improve the systemic redox status while reducing cardiovascular mortality in elderly population-based individuals. Free Radical Biology & Medicine. ISSN 0891-5849. 204, s. 207–214. doi: 10.1016/j.freeradbiomed.2023.04.024. Fulltekst i vitenarkiv Vis sammendrag

  Background Serum sulfhydryl groups (R–SH, free thiols) reflect the systemic redox status in health and disease, and may be amenable to therapeutic modulation. Since R–SH are readily oxidized by reactive species, oxidative stress is characterized by reduced serum R–SH levels. Selenium and coenzyme Q10 supplementation may improve the systemic redox status. This study aimed to evaluate the effect of supplementation with selenium and coenzyme Q10 on serum free thiols and to study associations with the risk of cardiovascular mortality in elderly community-dwelling individuals. Methods In this randomized, double-blind, placebo-controlled trial, serum R–SH were measured colorimetrically and adjusted for albumin in 434 individuals at baseline and after 48 months of intervention. Selenium yeast (200 μg/day) and coenzyme Q10 (200 mg/day) or placebo were provided as dietary supplements. Results After 48 months of intervention, participants receiving combined selenium and coenzyme Q10 supplementation demonstrated increased levels of serum R–SH compared to placebo (P = 0.002). In prospective association analysis, the highest rate of cardiovascular mortality after a median follow-up of 10 years (IQR: 6.8–10.5) was observed in the lowest quartile (Q1) of R–SH levels. Baseline albumin-adjusted serum R–SH were significantly associated with the risk of cardiovascular mortality, even after adjustment for potential confounding factors (hazard ratio [HR] 1.98 per SD, 95% CI: 1.34–2.91, P < 0.001). Conclusion Supplementation with selenium and coenzyme Q10 to an elderly community-dwelling population low on the two substances, significantly improved serum R–SH levels, supporting a reduction in systemic oxidative stress. Low serum R–SH levels were significantly associated with an increased risk of cardiovascular mortality in elderly individuals.

• Alehagen, Urban; Alexander, Jan; Aaseth, Jan; Larsson, Anders; Svensson, Erland & Opstad, Trine Baur (2023). Effects of an Intervention with Selenium and Coenzyme Q10 on Five Selected Age-Related Biomarkers in Elderly Swedes Low in Selenium: Results That Point to an Anti-Ageing Effect—A Sub-Analysis of a Previous Prospective Double-Blind Placebo-Controlled Randomised Clinical Trial. Cells. 12(13). doi: 10.3390/cells12131773. Fulltekst i vitenarkiv Vis sammendrag

  Background: Ageing is associated with cardiovascular disease (CVD). As no single biomarker reflects the full ageing process, we aimed to investigate five CVD- and age-related markers and the effects of selenium and coenzyme Q10 intervention to elucidate the mechanisms that may influence the course of ageing. Methods: This is a sub-study of a previous prospective double-blind placebo-controlled randomized clinical trial that included 441 subjects low in selenium (mean age 77, 49% women). The active treatment group (n = 220) received 200 µg/day of selenium and 200 mg/day of coenzyme Q10, combined. Blood samples were collected at inclusion and after 48 months for measurements of the intercellular adhesion molecule (ICAM-1), adiponectin, leptin, stem cell factor (SCF) and osteoprotegerin (OPG), using ELISAs. Repeated measures of variance and ANCOVA evaluations were used to compare the two groups. In order to better understand and reduce the complexity of the relationship between the biomarkers and age, factor analyses and structural equation modelling (SEM) were performed, and a structural model is presented. Results: Correlation analyses of biomarker values at inclusion in relation to age, and relevant markers related to inflammation, endothelial dysfunction and fibrosis, demonstrated the biomarkers' association with these pathological processes; however, only ICAM1 and adiponectin were directly correlated with age. SEM analyses showed, however, that the biomarkers ICAM-1, adiponectin, SCF and OPG, but not leptin, all had significant associations with age and formed two independent structural factors, both significantly related to age. While no difference was observed at inclusion, the biomarkers were differently changed in the active treatment and placebo groups (decreasing and increasing levels, respectively) at 48 months (p ≤ 0.02 in all, adjusted), and in the SEM model, they showed an anti-ageing impact. Conclusions: Supplementation with selenium/Q10 influenced the analysed biomarkers in ways indicating an anti-ageing effect, and by applying SEM methodology, the interrelationships between two independent structural factors and age were validated.

• Aspli, Klaus Thanke; Aaseth, Jan; Holmøy, Trygve; Blennow, Kaj; Zetterberg, Henrik & Kirsebom, Bjørn-Eivind Seljelid [Vis alle 8 forfattere av denne artikkelen] (2023). CSF, Blood, and MRI Biomarkers in Skogholt’s Disease—A Rare Neurodegenerative Disease in a Norwegian Kindred. Brain Sciences. 13(11). doi: 10.3390/brainsci13111511. Fulltekst i vitenarkiv Vis sammendrag

  Skogholt’s disease is a rare neurological disorder that is only observed in a small Norwegian kindred. It typically manifests in adulthood with uncharacteristic neurological symptoms from both the peripheral and central nervous systems. The etiology of the observed cerebral white matter lesions and peripheral myelin pathology is unclear. Increased cerebrospinal fluid (CSF) concentrations of protein have been confirmed, and recently, very high concentrations of CSF total and phosphorylated tau have been detected in Skogholt patients. The symptoms and observed biomarker changes in Skogholt’s disease are largely nonspecific, and further studies are necessary to elucidate the disease mechanisms. Here, we report the results of neurochemical analyses of plasma and CSF, as well as results from the morphometric segmentation of cerebral magnetic resonance imaging. We analyzed the biomarkers Aβ_1––42, Aβ_1–40, Aβ_x–38, Aβ_x–40, Aβ_x–42, total and phosphorylated tau, glial fibrillary acidic protein, neurofilament light chain, platelet-derived growth factor receptor beta, and beta-trace protein. All analyzed CSF biomarkers, except neurofilament light chain and Aβ1/_x–42, were increased several-fold. In blood, none of these biomarkers were significantly different between the Skogholt and control groups. MRI volumetric segmentation revealed decreases in the ventricular, white matter, and choroid plexus volumes in the Skogholt group, with an accompanying increase in white matter lesions. The cortical thickness and subcortical gray matter volumes were increased in the Skogholt group. Pathophysiological changes resulting from choroidal dysfunction and/or abnormal CSF turnover, which may cause the increases in CSF protein and brain biomarker levels, are discussed.

• Opstad, Trine Baur; Alexander, Jan; Aaseth, Jan; Larsson, Anders; Seljeflot, Ingebjørg & Alehagen, Urban (2023). Increased SIRT1 Concentration Following Four Years of Selenium and Q10 Intervention Associated with Reduced Cardiovascular Mortality at 10-Year Follow-Up—Sub-Study of a Previous Prospective Double-Blind Placebo-Controlled Randomized Clinical Trial. Antioxidants. 12(3). doi: 10.3390/antiox12030759. Fulltekst i vitenarkiv Vis sammendrag

  Background: Selenium and coenzyme Q10 (SeQ10) possess antioxidant and anti-inflammatory properties, potentially mediated via Sirtuin1 (SIRT1). We aimed to investigate the influence of a SeQ10 intervention on SIRT1 concentration, with potential interactions with microRNAs. Methods: In this sub-study of a prospective double-blind placebo-controlled clinical trial, healthy subjects (mean age 76 years) were randomized to receive an active treatment (n = 165, combined 200 µg/day of Se and 200 mg/day of Q10) or a placebo (n = 161). SIRT1 concentration and microRNAs were measured with ELISA and PCR, respectively. Results: After four years, SIRT1 concentration was increased in the active treatment group, with mean (SD) ng/mL of 469 (436) vs. 252 (162), p < 0.001, and decreased in the placebo group, 190 (186) vs. 269 (172), p = 0.002, and the differences between the groups were significant (p = 0.006, adjusted). Those who suffered CV death during a 10-year follow-up (n = 25 and n = 52 in the active treatment and placebo groups, respectively) had significantly lower baseline SIRT1 concentrations compared to the survivors (p < 0.001). MiR-130a-3p was significantly downregulated during the intervention and correlated inversely with SIRT1 at baseline (r = −0.466, p = 0.007). Conclusion: The increased SIRT1 concentration after the SeQ10 intervention associated with reduced CV mortality, partly mediated via miR-1303a-3p, suggests that SIRT1 is an additional mediator of the intervention, preventing vascular ageing.

• Hestad, Knut; Alexander, Jan; Rootwelt, Helge & Aaseth, Jan (2022). The Role of Tryptophan Dysmetabolism and Quinolinic Acid in Depressive and Neurodegenerative Diseases. Biomolecules. 12(7). doi: 10.3390/biom12070998. Fulltekst i vitenarkiv Vis sammendrag

  Emerging evidence suggests that neuroinflammation is involved in both depression and neurodegenerative diseases. The kynurenine pathway, generating metabolites which may play a role in pathogenesis, is one of several competing pathways of tryptophan metabolism. The present article is a narrative review of tryptophan metabolism, neuroinflammation, depression, and neurodegeneration. A disturbed tryptophan metabolism with increased activity of the kynurenine pathway and production of quinolinic acid may result in deficiencies in tryptophan and derived neurotransmitters. Quinolinic acid is an N-methyl-D-aspartate receptor agonist, and raised levels in CSF, together with increased levels of inflammatory cytokines, have been reported in mood disorders. Increased quinolinic acid has also been observed in neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and HIV-related cognitive decline. Oxidative stress in connection with increased indole-dioxygenase (IDO) activity and kynurenine formation may contribute to inflammatory responses and the production of cytokines. Increased formation of quinolinic acid may occur at the expense of kynurenic acid and neuroprotective picolinic acid. While awaiting ongoing research on potential pharmacological interventions on tryptophan metabolism, adequate protein intake with appropriate amounts of tryptophan and antioxidants may offer protection against oxidative stress and provide a balanced set of physiological receptor ligands.

• Opstad, Trine Baur; Alexander, Jan; Aaseth, Jan; Larsson, Anders; Seljeflot, Ingebjørg & Alehagen, Urban (2022). Selenium and Coenzyme Q10 Intervention Prevents Telomere Attrition, with Association to Reduced Cardiovascular Mortality-Sub-Study of a Randomized Clinical Trial. Nutrients. 14(16). doi: 10.3390/nu14163346. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Short telomeres have been associated with ageing and cardiovascular disease. The influence on leukocyte telomere length (LTL) of long-term intervention with combined selenium and coenzyme Q10 is unknown. Our aim was to determine whether 42 months of selenium and coenzyme Q10 supplementation prevented telomere attrition and further cardiovascular mortality. The investigation is an explorative sub-study of a double-blind, placebo-controlled, randomized trial. Swedish citizens low in selenium (n = 118), aged 70–80 years, were included. Intervention time was 4 years, with 10 years’ follow-up time. LTL was relatively quantified with PCR at baseline and after 42 months. At baseline, LTL (SD) was 0.954 (0.260) in the active treatment group and 1.018 (0.317) in the placebo group (p = 0.23). At 42 months, less shortening of LTL was observed after active treatment compared with placebo (+0.019 vs. −0.129, respectively, p = 0.02), with a significant difference in change basing the analysis on individual changes in LTL (p &lt; 0.001). Subjects suffering future death presented with significantly shorter LTL at 42 months than survivors [0.791 (0.190) vs. 0.941 (0.279), p = 0.01], with a significant difference in change of LTL according to cardiovascular mortality and survival (p = 0.03). To conclude, preservation of LTL after selenium and coenzyme Q10 supplementation associated with reduced cardiovascular mortality.

• Blomqvist, Lennart; Nordberg, Gunnar F.; Nurchi, Valeria M. & Aaseth, Jan (2022). Gadolinium in Medical Imaging - Usefulness, Toxic Reactions and Possible Countermeasures - A Review. Biomolecules. 12(6). doi: 10.3390/biom12060742. Fulltekst i vitenarkiv Vis sammendrag

  Gadolinium (Gd) is one of the rare-earth elements. The properties of its trivalent cation (Gd3+) make it suitable to serve as the central ion in chelates administered intravenously to patients as a contrast agent in magnetic resonance imaging. Such Gd-chelates have been used for more than thirty years. During the past decades, knowledge has increased about potential harmful effects of Gd-chelates in patients with severe renal dysfunction. In such patients, there is a risk for a potentially disabling and lethal disease, nephrogenic systemic fibrosis. Restricting the use of Gd-chelates in persons with severely impaired renal function has decreased the occurrence of this toxic effect in the last decade. There has also been an increasing awareness of Gd-retention in the body, even in patients without renal dysfunction. The cumulative number of doses given, and the chemical structure of the chelate given, are factors of importance for retention in tissues. This review describes the chemical properties of Gd and its medically used chelates, as well as its toxicity and potential side effects related to injection of Gd-chelates. Keywords: chelates; contrast induced nephropathy; gadolinium; gadolinium induced respiratory distress syndrome; gadolinium kinetics; gadolinium toxicity; nephrogenic systemic fibrosis; side effects of gadolinium chelates; treatment of gadolinium toxicity. © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/ 4.0/).

• Dusek, Petr; Hofer, Tim; Alexander, Jan; Roos, Per M. & Aaseth, Jan Olav (2022). Cerebral Iron Deposition in Neurodegeneration. Biomolecules. 12(5). doi: 10.3390/biom12050714. Fulltekst i vitenarkiv Vis sammendrag

  Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the determination of metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes the whole brain, cellular, and subcellular patterns of iron accumulation in neurodegenerative diseases of genetic and sporadic origin. We also provide an update on mechanisms, biomarkers, and effects of brain iron accumulation in these disorders, focusing on recent publications. In Parkinson’s disease, Friedreich’s disease, and several disorders within the neurodegeneration with brain iron accumulation group, there is a focal siderosis, typically in regions with the most pronounced neuropathological changes. The second group of disorders including multiple sclerosis, Alzheimer’s disease, and amyotrophic lateral sclerosis shows iron accumulation in the globus pallidus, caudate, and putamen, and in specific cortical regions. Yet, other disorders such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest with diffuse iron accumulation in the deep gray matter in a pattern comparable to or even more extensive than that observed during normal aging. On the microscopic level, brain iron deposits are present mostly in dystrophic microglia variably accompanied by iron-laden macrophages and in astrocytes, implicating a role of inflammatory changes and blood–brain barrier disturbance in iron accumulation. Options and potential benefits of iron reducing strategies in neurodegeneration are discussed. Future research investigating whether genetic predispositions play a role in brain Fe accumulation is necessary. If confirmed, the prevention of further brain Fe uptake in individuals at risk may be key for preventing neurodegenerative disorders.

• Alehagen, Urban; Aaseth, Jan Olav; Larsson, Anders & Alexander, Jan (2022). Decreased Concentration of Fibroblast Growth Factor 23 (FGF-23) as a Result of Supplementation with Selenium and Coenzyme Q10 in an Elderly Swedish Population: A Sub-Analysis. Cells. 11(3), s. 1–11. doi: 10.3390/cells11030509. Fulltekst i vitenarkiv Vis sammendrag

  There is a reduced intake of selenium in many countries due to low levels of selenium in the soil. This results in an increased cardiovascular risk. Fibroblast growth factor 23 (FGF-23) is active mainly in the metabolism of vitamin D and phosphorus. However, there are indications that FGF-23 may also provide information both on cardiovascular function and prognosis. The aim of the study was to evaluate the effect of supplementation with selenium and coenzyme Q10 on the FGF-23 concentration in an elderly population with low concentrations of both selenium and coenzyme Q10 and in which the supplementation improved cardiac function and mortality. In a randomised double-blind placebo-controlled trial, FGF-23 was measured in 219 individuals at the start and after 48 months. Selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/day) (n = 118) or placebo (n = 101) were given as a dietary supplement. The intervention time was 48 months. t-Tests, repeated measures of variance, and ANCOVA analyses were used to evaluate the differences in FGF-23 concentration. Following supplementation with selenium and coenzyme Q10, a significantly lower level of FGF-23 could be seen (p = 0.01). Applying 10 years of follow-up, those who later died a cardiovascular death had a significantly higher FGF-23 concentration after 48 months compared with those who survived (p = 0.036), and a significantly lower FGF-23 concentration could be seen in those with a normal renal function compared to those with an impaired renal function (p = 0.027). Supplementation with selenium and coenzyme Q10 to an elderly community-living population low in both substances prevented an increase of FGF-23 and also provided a reduced cardiovascular risk. Trial registration: ClinicalTrials.gov NCT01443780. Keywords: FGF-23; coenzyme Q10; elderly; intervention; selenium.

• Aaseth, Jan & Nurchi, Valeria M. (2022). Chelation Combination - A Strategy to Mitigate the Neurotoxicity of Manganese, Iron, and Copper? Biomolecules. 12(11). doi: 10.3390/biom12111713. Fulltekst i vitenarkiv Vis sammendrag

  The chelating thiol dimercaptosuccinate (DMSA) and the traditional agent D-penicillamine (PSH) are effective in enhancing the urinary excretion of copper (Cu) and lead (Pb) in poisoned individuals. However, DMSA, PSH, EDTA (ethylenediamine tetraacetate), and deferoxamine (DFOA) are water-soluble agents with limited access to the central nervous system (CNS). Strategies for mobilization of metals such as manganese (Mn), iron (Fe), and Cu from brain deposits may require the combined use of two agents: one water-soluble agent to remove circulating metal into urine, in addition to an adjuvant shuttler to facilitate the brain-to-blood mobilization. The present review discusses the chemical basis of metal chelation and the ligand exchange of metal ions. To obtain increased excretion of Mn, Cu, and Fe, early experiences showed promising results for CaEDTA, PSH, and DFOA, respectively. Recent experiments have indicated that p-amino salicylate (PAS) plus CaEDTA may be a useful combination to remove Mn from binding sites in CNS, while the deferasirox-DFOA and the tetrathiomolybdate-DMSA combinations may be preferable to promote mobilization of Fe and Cu, respectively, from the CNS. Further research is requested to explore benefits of chelator combinations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

• Aaseth, Jan; Rootwelt, Helge; Retterstøl, Kjetil; Hestad, Knut & Farup, Per Grønaas (2022). Circulating Lipoproteins in Subjects with Morbid Obesity Undergoing Bariatric Surgery with Gastric Bypass or Sleeve Gastrectomy. Nutrients. 14(12). doi: 10.3390/nu14122381. Fulltekst i vitenarkiv Vis sammendrag

  The efficacy of various bariatric procedures on the mitigation of the obese dyslipidemia remains debated, and the impact of these measures on lipoprotein(a) (Lp(a)) levels is unknown. In this study we aimed to compare the two most commonly used procedures: gastric bypass (RYGB) and sleeve gastrectomy (SG). Adult patients with morbid obesity were assigned to receive either RYGB or SG. The levels of non-HDL cholesterol, LDL/HDL-ratio and Lp(a) at examinations conducted 6 and 12 months postoperatively were determined and compared to preoperative levels to estimate the efficacy of the two surgical methods. All results 6 and 12 months after surgery were used in the comparisons with the preoperative results. A linear mixed regression model for repeated analyses was used. The Lp(a) and the non-HDL cholesterol levels were considerably reduced in the RYGB group, in contrast to the minor changes in the SG group. In addition, the LDL/HDL ratio was significantly more reduced in the RYGB group when compared to the SG group. Conclusively, RYGB was found to be more efficient than SG for the mitigation of obese dyslipidemia, including preoperative high Lp(a)-levels. This might have important individual and societal implications, especially regarding the potential to reduce the risk of cardiovascular disease and the related societal costs.

• Jansen, Aina; Aaseth, Jan Olav; Lyche, Jan Ludvig; Berg, Jens Petter; Müller, Mette Helen Bjørge & Lydersen, Stian [Vis alle 7 forfattere av denne artikkelen] (2022). Do changes in persistent organic pollutants after bariatric surgery cause endocrine disruption? Chemosphere. ISSN 0045-6535. 313, s. 1–8. doi: 10.1016/j.chemosphere.2022.137461. Fulltekst i vitenarkiv Vis sammendrag

  Background Bariatric surgery results in weight loss, marked endocrine changes and the release of persistent organic pollutants (POPs). The release of POPs might cause endocrine disruption. The study aimed to explore associations between POPs and adiponectin, leptin and ghrelin in subjects undergoing bariatric surgery. Methods: The study included 63 subjects with severe obesity (men/women: 13/50), age (years): 45.0 (8.5), and BMI (kg/m2) 39.1 (3.4). Analyses of adiponectin, leptin and ghrelin and POPs (hexachlorobenzene (HCB), dichlorodiphenyldichloroethylene (p,p’-DDE), polychlorinated biphenyl (PCB) 118 (dioxin-like compound; dl), and sum 6 PCB (PCB 28, -52, −101, −138, −153, and −180) were performed before and 12 months after bariatric surgery. Results: There were significant increases in adiponectin and all POPs and a fall in leptin after surgery. The main finding was the highly significant associations between adiponectin and all POPs. The increase in HCB explained 38% of the variation in adiponectin. Conclusions: If the POP-associated increase in adiponectin is a causal effect, the release of POPs might have important clinical consequences. Adiponectin has both positive and negative clinical effects exerted by essentially unknown mechanisms. The effects of released POPs on the metabolic functions in subjects undergoing bariatric surgery deserve further evaluation. © 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

• Alehagen, Urban; Johansson, Peter; Svensson, Erland; Aaseth, Jan & Alexander, Jan (2022). Improved cardiovascular health by supplementation with selenium and coenzyme Q10: applying structural equation modelling (SEM) to clinical outcomes and biomarkers to explore underlying mechanisms in a prospective randomized double-blind placebo-controlled intervention project in Sweden. European Journal of Nutrition. ISSN 1436-6207. 61(6), s. 3135–3148. doi: 10.1007/s00394-022-02876-1. Fulltekst i vitenarkiv Vis sammendrag

  Purpose Selenium and coenzyme Q10 have synergistic antioxidant functions. In a four-year supplemental trial in elderly Swedes with a low selenium status, we found improved cardiac function, less cardiac wall tension and reduced cardiovascular mortality up to 12 years of follow-up. Here we briefly review the main results, including those from studies on biomarkers related to cardiovascular risk that were subsequently conducted. In an effort, to explain underlying mechanisms, we conducted a structured analysis of the inter-relationship between biomarkers. Methods Selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/ day), or placebo was given to 443 elderly community-living persons, for 48 months. Structural Equation Modelling (SEM) was used to investigate the statistical inter-relationships between biomarkers related to inflammation, oxidative stress, insulin-like growth factor 1, expression of microRNA, fibrosis, and endothelial dysfunction and their impact on the clinical effects. The main study was registered at Clinicaltrials.gov at 30th of September 2011, and has the identifier NCT01443780. Results In addition to positive clinical effects, the intervention with selenium and coenzyme Q10 was also associated with favourable effects on biomarkers of cardiovascular risk. Using these results in the SEM model, we showed that the weights of the first-order factors inflammation and oxidative stress were high, together forming a second-order factor inflammation/oxidative stress influencing the factors, fibrosis (β = 0.74; p < 0.001) and myocardium (β = 0.65; p < 0.001). According to the model, the intervention impacted fibrosis and myocardium through these factors, resulting in improved cardiac function and reduced CV mortality. Conclusion Selenium reduced inflammation and oxidative stress. According to the SEM analysis, these effects reduced fibrosis and improved myocardial function pointing to the importance of supplementation in those low on selenium and coenzyme Q10. © The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/

• Aaseth, Jan; Javorac, Dragana; Djordjevic, Aleksandra Buha; Bulat, Zorica; Skalny, Anatoly V. & Zaitseva, Irina P. [Vis alle 8 forfattere av denne artikkelen] (2022). The Role of Persistent Organic Pollutants in Obesity: A Review of Laboratory and Epidemiological Studies. Toxics. ISSN 2305-6304. 10(2). doi: 10.3390/toxics10020065. Fulltekst i vitenarkiv Vis sammendrag

  Persistent organic pollutants (POPs) are considered as potential obesogens that may affect adipose tissue development and functioning, thus promoting obesity. However, various POPs may have different mechanisms of action. The objective of the present review is to discuss the key mechanisms linking exposure to POPs to adipose tissue dysfunction and obesity. Laboratory data clearly demonstrate that the mechanisms associated with the interference of exposure to POPs with obesity include: (a) dysregulation of adipogenesis regulators (PPARγ and C/EBPα); (b) affinity and binding to nuclear receptors; (c) epigenetic effects; and/or (d) proinflammatory activity. Although in vivo data are generally corroborative of the in vitro results, studies in living organisms have shown that the impact of POPs on adipogenesis is affected by biological factors such as sex, age, and period of exposure. Epidemiological data demonstrate a significant association between exposure to POPs and obesity and obesity-associated metabolic disturbances (e.g., type 2 diabetes mellitus and metabolic syndrome), although the existing data are considered insufficient. In conclusion, both laboratory and epidemiological data underline the significant role of POPs as environmental obesogens. However, further studies are required to better characterize both the mechanisms and the dose/concentration-response effects of exposure to POPs in the development of obesity and other metabolic diseases.

• Opstad, Trine Baur; Farup, Per Grønaas; Rootwelt, Helge & Aaseth, Jan (2022). Changes in circulating sirtuin 1 after bariatric surgery. NMCD. Nutrition Metabolism and Cardiovascular Diseases. ISSN 0939-4753. 32(12), s. 2858–2864. doi: 10.1016/j.numecd.2022.09.009. Fulltekst i vitenarkiv Vis sammendrag

  Obesity is associated with chronic inflammation and oxidative stress. Weight loss after bariatric surgery improves the inflammatory state and risk of cardiovascular disease. Improvement in metabolic dysfunction might be associated with changes in the activity of sirtuin 1 (SIRT1) and we aimed to investigate the effect of bariatric surgery on its circulating levels. Methods and results This is a sub-study of a prospective cohort study, including 110 subjects with morbid obesity. The surgical procedure was either laparoscopic Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). Blood was sampled at inclusion and six and 12 months after surgery. SIRT1 was measured in EDTA plasma with an enzyme-linked immunosorbent assay. The mean age in the population was 43 years, 80% were women and mean body mass index (BMI) was 38.8 kg/m2. RYGB and SG were performed in 89 and 21 subjects, respectively. SIRT1 concentration was significantly reduced from baseline to six and 12 months after surgery, with mean values (SD) 156.8 (82.6), 119.5 (65.6) and 94.9 (45.6) ng/mL, respectively, (p ≤ 0.002, all), accompanied by significant reductions in C-reactive protein (CRP), BMI and triglycerides from inclusion (p < 0.001, all). Type of surgery did not differently modify SIRT1 levels (p = 0.09). CRP and triglycerides were both positively predictive of SIRT1 levels (p ≤ 0.001, both). Conclusion SIRT1 concentration was significantly lower six and 12 months after bariatric surgery. CRP and triglycerides independently predicted SIRT1 levels, suggesting that reduction in SIRT1 levels might not intrinsically be related to weight reduction, but to improvement in metaflammation. ª 2022 The Author(s). Published by Elsevier B.V. on behalf of The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

• Skalny, Anatoly V.; Aschner, Michael; Sekacheva, Marina I.; Santamaria, Abel; Barbosa, Fernando & Ferrer, Beatriz [Vis alle 10 forfattere av denne artikkelen] (2022). Mercury and cancer: Where are we now after two decades of research? Food and Chemical Toxicology (FCT). ISSN 0278-6915. 164. doi: 10.1016/j.fct.2022.113001. Fulltekst i vitenarkiv Vis sammendrag

  The present study aims to review epidemiological and experimental toxicology studies published over the last two decades linking mercury (Hg) exposure and carcinogenesis, with a special emphasis on the potential underlying mechanisms. While some epidemiological studies have observed a strong association between environmental/occupational Hg exposure levels, measured in blood, toenail, and hair, and cancer risk and mortality, others failed to reveal any association. In experimental models, high-dose Hg exposure has been linked with cytotoxicity, whereas low-dose exposure was posited to induce proliferative responses in both normal and cancerous cells by interference with estrogen receptor, ERK1/2, JNK, NADPH-oxidase and, potentially, Nrf2 signaling. Combined with reduced apoptosis and pro-survival signaling upon low-dose Hg exposure, accumulation of DNA lesions in cells may predispose to an increased risk of malignant transformation. In addition, the pro-oxidant activity of Hg species may induce oxidative DNA modifications and inhibits DNA repair mechanisms. Furthermore, epigenetic effects of Hg exposure seem to contribute to the carcinogenic activity, although the particular mechanisms have yet to be characterized. Therefore, even after 20 years of research, one cannot consider Hg as a non-carcinogenic agent, whereas specific mechanisms of Hg-induced toxicity may promote carcinogenic risk.

• Farup, Per Grønaas; Jansen, Aina; Hestad, Knut; Aaseth, Jan & Rootwelt, Helge (2022). APOE Polymorphism and Endocrine Functions in Subjects with Morbid Obesity Undergoing Bariatric Surgery. Genes. 13(2). doi: 10.3390/genes13020222. Fulltekst i vitenarkiv Vis sammendrag

  Background: Obesity is an interplay between genes and the environment, including lifestyle. The genetics of obesity is insufficiently understood. Apolipoprotein E (APOE) genetic polymorphism has been associated with a wide range of disorders. Knowing that some APOE alleles are associated with obesity and endocrine disorders that are common in obesity, the present study aimed at exploring associations between APOE polymorphisms and endocrine functions in subjects with obesity undergoing bariatric surgery. Methods: Analyses of hormones in blood collected before and one year after bariatric surgery were examined. The APOE alleles were grouped as follows: E2 = ε2ε2 + ε2ε3; E3 = ε3ε3 + ε2ε4; E4 = ε3ε4 + ε4ε4. The APOE groups were analysed as nominal and ordered groups (E2-E3-E4) with a linear mixed model to predict the hormonal effects of the groups. Results: Forty-nine women (79%) and thirteen (21%) men with a mean age of 47.7 (SD 8.5) years were included in the study. The adiponectin level was significantly lower (p < 0.05) in the E2 group compared with the E4 group. Adiponectin and cortisol were positively and negatively associated, respectively, with the ordered APOE groups. Conclusions: The ordered APOE groups E2-E3-E4 were significantly associated with high and low levels of adiponectin and cortisol, respectively. The findings indicate APOE-mediated effects on body weight and metabolic functions in subjects with morbid obesity.

• Skalny, Anatoly V.; Timashev, Peter S.; Aschner, Michael; Aaseth, Jan; Chernova, Lyubov N. & Belyaev, Vladimir E. [Vis alle 14 forfattere av denne artikkelen] (2021). Serum zinc, copper, and other biometals are associated with covid-19 severity markers. Metabolites. 11(4). doi: 10.3390/metabo11040244. Fulltekst i vitenarkiv Vis sammendrag

  The objective of the present study was to evaluate of serum metal levels in COVID-19 patients with different disease severity, and to investigate the independent association between serum metal profile and markers of lung damage. The cohort of COVID-19 patients consisted of groups of subjects with mild, moderate, and severe illness, 50 examinees each. Forty-four healthy subjects of the respective age were involved in the current study as the control group. Serum metal levels were evaluated using inductively-coupled plasma mass-spectrometry. Examination of COVID-19 patients demonstrated that heart rate, respiratory rate, body temperature, C-reactive protein levels, as well as lung damage increased significantly with COVID-19 severity, whereas SpO2 decreased gradually. Increasing COVID-19 severity was also associated with a significant gradual decrease in serum Ca, Fe, Se, Zn levels as compared to controls, whereas serum Cu and especially Cu/Zn ratio were elevated. No significant group differences in serum Mg and Mn levels were observed. Serum Ca, Fe, Se, Zn correlated positively with SpO2, being inversely associated with fever, lung damage, and C-reactive protein concentrations. Opposite correlations were observed for Cu and Cu/Zn ratio. In regression models, serum Se levels were inversely associated with lung damage independently of other markers of disease severity, anthropometric, biochemical, and hemostatic parameters. Cu/Zn ratio was also considered as a significant predictor of lower SpO2 in adjusted regression models. Taken together, these findings demonstrated that metal metabolism significantly interferes with COVID-19 pathogenesis, although the causal relations as well as precise mechanisms are yet to be characterized. Keywords: novel coronavirus infection; lung damage; trace elements; selenium; iron

• Tinkov, Alexey A.; Paoliello, Monica M.B.; Mazilina, Aksana N.; Skalny, Anatoly V.; Martins, Airton C. & Voskresenskaya, Olga N. [Vis alle 13 forfattere av denne artikkelen] (2021). Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update. International Journal of Molecular Sciences. ISSN 1661-6596. 22(9). doi: 10.3390/ijms22094646. Fulltekst i vitenarkiv Vis sammendrag

  Understanding of the immediate mechanisms of Mn-induced neurotoxicity is rapidly evolving. We seek to provide a summary of recent findings in the field, with an emphasis to clarify existing gaps and future research directions. We provide, here, a brief review of pertinent discoveries related to Mn-induced neurotoxicity research from the last five years. Significant progress was achieved in understanding the role of Mn transporters, such as SLC39A14, SLC39A8, and SLC30A10, in the regulation of systemic and brain manganese handling. Genetic analysis identified multiple metabolic pathways that could be considered as Mn neurotoxicity targets, including oxidative stress, endoplasmic reticulum stress, apoptosis, neuroinflammation, cell signaling pathways, and interference with neurotransmitter metabolism, to name a few. Recent findings have also demonstrated the impact of Mn exposure on transcriptional regulation of these pathways. There is a significant role of autophagy as a protective mechanism against cytotoxic Mn neurotoxicity, yet also a role for Mn to induce autophagic flux itself and autophagic dysfunction under conditions of decreased Mn bioavailability. This ambivalent role may be at the crossroad of mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis. Yet very recent evidence suggests Mn can have toxic impacts below the no observed adverse effect of Mn-induced mitochondrial dysfunction. The impact of Mn exposure on supramolecular complexes SNARE and NLRP3 inflammasome greatly contributes to Mn-induced synaptic dysfunction and neuroinflammation, respectively. The aforementioned effects might be at least partially mediated by the impact of Mn on α-synuclein accumulation. In addition to Mn-induced synaptic dysfunction, impaired neurotransmission is shown to be mediated by the effects of Mn on neurotransmitter systems and their complex interplay. Although multiple novel mechanisms have been highlighted, additional studies are required to identify the critical targets of Mn-induced neurotoxicity. Keywords: manganese; neurotoxicity; neuroinflammation; apoptosis; cell signaling

• Aaseth, Jan; Alexander, Jan & Alehagen, Urban (2021). Coenzyme Q10 supplementation – In ageing and disease. Mechanisms of Ageing and Development. ISSN 0047-6374. 197. doi: 10.1016/j.mad.2021.111521. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Coenzyme Q10 (CoQ10) is an essential component of the mitochondrial electron transport chain. It is also an antioxidant in cellular membranes and lipoproteins. All cells produce CoQ10 by a specialized cytoplasmatic-mitochondrial pathway. CoQ10 deficiency can result from genetic failure or ageing. Some drugs including statins, widely used by inter alia elderly, may inhibit endogenous CoQ10 synthesis. There are also chronic diseases with lower levels of CoQ10 in tissues and organs. High doses of CoQ10 may increase both circulating and intracellular levels, but there are conflicting results regarding bioavailability. Here, we review the current knowledge of CoQ10 biosynthesis and primary and acquired CoQ10 deficiency, and results from clinical trials based on CoQ10 supplementation. There are indications that supplementation positively affects mitochondrial deficiency syndrome and some of the symptoms of ageing. Cardiovascular disease and inflammation appear to be alleviated by the antioxidant effect of CoQ10. There is a need for further studies and well-designed clinical trials, with CoQ10 in a formulation of proven bioavailability, involving a greater number of participants undergoing longer treatments in order to assess the benefits of CoQ10 treatment in neurodegenerative disorders, as well as in metabolic syndrome and its complications.

• Bjørklund, Geir; Peana, Massimiliano; Pivina, Lyudmila; Dosa, Alexandru; Aaseth, Jan & Semenova, Yuliya [Vis alle 10 forfattere av denne artikkelen] (2021). Iron Deficiency in Obesity and After Bariatric Surgery. Biomolecules. 11(5). doi: 10.3390/biom11050613. Fulltekst i vitenarkiv Vis sammendrag

  Iron deficiency (ID) is particularly frequent in obese patients due to increased circulating levels of acute-phase reactant hepcidin and adiposity-associated inflammation. Inflammation in obese subjects is closely related to ID. It induces reduced iron absorption correlated to the inhibition of duodenal ferroportin expression, parallel to the increased concentrations of hepcidin. Obese subjects often get decreased inflammatory response after bariatric surgery, accompanied by decreased serum hepcidin and therefore improved iron absorption. Bariatric surgery can induce the mitigation or resolution of obesity-associated complications, such as hypertension, insulin resistance, diabetes mellitus, and hyperlipidemia, adjusting many parameters in the metabolism. However, gastric bypass surgery and sleeve gastrectomy can induce malabsorption and may accentuate ID. The present review explores the burden and characteristics of ID and anemia in obese patients after bariatric surgery, accounting for gastric bypass technique (Roux-en-Y gastric bypass—RYGB) and sleeve gastrectomy (SG). After bariatric surgery, obese subjects’ iron status should be monitored, and they should be motivated to use adequate and recommended iron supplementation. Keywords: obesity; iron deficiency; iron metabolism; bariatric surgery; iron supplement

• Tinkov, Alexey A.; Bogdański, Paweł; Skrypnik, Damian; Skrypnik, Katarzyna; Skalny, Anatoly V. & Aaseth, Jan [Vis alle 8 forfattere av denne artikkelen] (2021). Trace Element and Mineral Levels in Serum, Hair, and Urine of Obese Women in Relation to Body Composition, Blood Pressure, Lipid Profile, and Insulin Resistance. Biomolecules. 11(5). doi: 10.3390/biom11050689. Fulltekst i vitenarkiv Vis sammendrag

  The objective of this study was to evaluate serum, hair, and urinary trace element and mineral content in normal-weight and obese women in relation to metabolic risk factors. A total of 80 women aged 30–70 y.o. were enrolled in the obese group (n = 40) and normal-weight group (n = 40). Serum, hair, and urinary trace element and mineral levels were assessed using inductively coupled plasma spectrometry. Body fat percentage was evaluated using bioimpedance. Obese subjects were characterized by significantly higher body fat percentage, blood pressure, serum triglyceride concentration, and insulin resistance. Serum Ca, Fe, Mg, Se, V, Zn levels, hair Fe, Mg, V content, and urinary Se and V concentrations were found to be lower in obese subjects as compared to lean controls. In turn, serum Cu and urinary Fe levels in obese women were characterized by a significant increase. In multiple regression models serum Cu, Se, and Zn levels were significantly associated with BMI even after adjustment for blood biochemistry, body composition, and blood pressure. Serum trace element and mineral levels also significantly contributed to group discrimination. These findings allow to propose that obesity-associated disturbances in trace element and mineral status may at least partially contribute to metabolic risk in obese subjects. View Full-Text Keywords: obesity; metabolic syndrome; insulin resistance; copper; selenium

• Aaseth, Jan; Ellefsen, Stian; Alehagen, Urban; Sundfør, Tine M. & Alexander, Jan (2021). Diets and drugs for weight loss and health in obesity – An update. Biomedicine & Pharmacotherapy. ISSN 0753-3322. 140. doi: 10.1016/j.biopha.2021.111789. Fulltekst i vitenarkiv Vis sammendrag

  Numerous combinations of diets and pharmacological agents, including lifestyle changes, have been launched to treat obesity. There are still ambiguities regarding the efficacies of different approaches despite many clinical trials and the use of animal models to study physiological mechanisms in weight management and obesity comorbidities, Here, we present an update on promising diets and pharmacological aids. Literature published after the year 2005 was searched in PubMed, Medline and Google scholar. Among recommended diets are low-fat (LF) and low-carbohydrate (LC) diets, in addition to the Mediterranean diet and the intermittent fasting approach, all of which presumably being optimized by adequate contents of dietary fibers. A basic point for weight loss is to adopt a diet that creates a permanently negative and acceptable energy balance, and prolonged dietary adherence is a crucial factor. As for pharmacological aids, obese patients with type 2 diabetes or insulin resistance seem to benefit from LC diet combined with a GLP-1 agonist, e.g. semaglutide, which may improve glycemic control, stimulate satiety, and suppress appetite. The lipase inhibitor orlistat is still used to maintain a low-fat approach, which may be favorable e.g. in hypercholesterolemia. The bupropion-naltrexone-combination appears promising for interruption of the vicious cycle of addictive over-eating. Successful weight loss seems to improve almost all biomarkers of obesity comorbidities. Until more support for specific strategies is available, clinicians should recommend an adapted lifestyle, and when necessary, a drug combination tailored to individual needs and comorbidities. Different diets may change hormonal secretion, gut-brain signaling, and influence hunger, satiety and energy expenditure. Further research is needed to clarify mechanisms and how such knowledge can be used in weight management.

• Skalny, Anatoly V.; Kopylov, Philippe Yu; Paoliello, Monica M.B.; Chang, Jung-Su; Aschner, Michael & Bobrovnitsky, Igor P. [Vis alle 10 forfattere av denne artikkelen] (2021). Hair Lead, Aluminum, and Other Toxic Metals in Normal-Weight and Obese Patients with Coronary Heart Disease. International Journal of Environmental Research and Public Health (IJERPH). ISSN 1661-7827. 18(15). doi: 10.3390/ijerph18158195. Fulltekst i vitenarkiv Vis sammendrag

  Abstract The objective of the present study was to evaluate hair toxic metal levels in patients with obesity and/or coronary heart disease (CHD). Following a 2 × 2 factorial design, subjects without CHD were grouped into normal weight control (n = 123) and obese groups (n = 140). Patients suffering from CHD were divided into normal weight (n = 180) and obese CHD subjects (n = 240). Hair Al, As, Cd, Hg, Ni, and Pb levels were evaluated using inductively-coupled plasma mass-spectrometry. The data demonstrate that hair Al and Hg levels were higher in obese subjects as compared to normal weight controls. Normal weight CHD patients were characterized by significantly higher hair Al, As, Cd, and Pb levels when compared to healthy subjects. The highest hair Al, As, and Pb levels were observed in obese CHD patients, significantly exceeding the respective values in other groups. Factorial analysis revealed significant influence of factorial interaction (CHD*obesity) only for hair Pb content. Given the role of obesity as a risk factor for CHD, it is proposed that increased toxic metal accumulation in obesity may promote further development of cardiovascular diseases. Keywords: coronary heart disease; ischemic heart disease; lead; obesity; toxicity.

• Alehagen, Urban; Opstad, Trine B.; Alexander, Jan; Larsson, Anders & Aaseth, Jan (2021). Impact of Selenium on Biomarkers and Clinical Aspects Related to Ageing. A Review. Biomolecules. 11(10). doi: 10.3390/biom11101478. Fulltekst i vitenarkiv Vis sammendrag

  Selenium (Se) is an essential dietary trace element that plays an important role in the prevention of inflammation, cardiovascular diseases, infections, and cancer. Selenoproteins contain selenocysteine in the active center and include, i.a., the enzymes thioredoxin reductases (TXNRD1–3), glutathione peroxidases (GPX1–4 and GPX6) and methionine sulfoxide reductase, involved in immune functions, metabolic homeostasis, and antioxidant defense. Ageing is an inevitable process, which, i.a., involves an imbalance between antioxidative defense and reactive oxygen species (ROS), changes in protein and mitochondrial renewal, telomere attrition, cellular senescence, epigenetic alterations, and stem cell exhaustion. These conditions are associated with mild to moderate inflammation, which always accompanies the process of ageing and age-related diseases. In older individuals, Se, by being a component in protective enzymes, operates by decreasing ROS-mediated inflammation, removing misfolded proteins, decreasing DNA damage, and promoting telomere length. Se-dependent GPX1–4 and TXNRD1–3 directly suppress oxidative stress. Selenoprotein H in the cell nucleus protects DNA, and selenoproteins residing in the endoplasmic reticulum (ER) assist in the removal of misfolded proteins and protection against ER stress. In this review, we highlight the role of adequate Se status for human ageing and prevention of age-related diseases, and further its proposed role in preservation of telomere length in middle-aged and elderly individuals.

• Shakeri, Mohammad Taghi; Nezami, Hossein; Nakhaee, Samaneh; Aaseth, Jan & Mehrpour, Omid (2021). Assessing Heavy Metal Burden Among Cigarette Smokers and Non-smoking Individuals in Iran: Cluster Analysis and Principal Component Analysis. Biological Trace Element Research. ISSN 0163-4984. 199, s. 4036–4044. doi: 10.1007/s12011-020-02537-6. Fulltekst i vitenarkiv Vis sammendrag

  Smoking is one of the major causes of mortality and numerous diseases, both directly and indirectly. The role of smoking as a significant risk factor is already known in several human diseases such as cardiovascular diseases, lung cancer, and chronic obstructive pulmonary disease. We aimed to compare the toxicity of heavy metal levels in the two groups of cigarette smokers and non-smokers in Birjand during 2018. In this case-control study, 70 smokers were enrolled as the case group and 70 individuals with no history of smoking as control group. The cases were selected from among those who smoked 10 cigarettes per day without a drug use history. Heavy metal concentrations were collected in participants’ serum samples. Cluster analysis and principal components analysis were employed to compare heavy metal toxicity between the groups. The duration of smoking and the number of cigarettes consumed per day were 14.36 ± 12.75 years and 11.32 ± 7.23, respectively. The concentration of thallium (Ti), arsenic (As), manganese (Mn), and copper (Cu) was significantly higher in the smoker group than that in the non-smoker group (p < 0.05). Lead (Pb), cadmium (Cd), and cobalt (Co) are among the most important metals accumulated in smokers’ blood, and 21.6% of our study’s total data was associated with them. Cluster analysis in the smoker group, including A1 (Cd), A2 (Co, Pb), B1 (Ti), B2 (mercury (Hg), As, chromium (Cr), iron (Fe), nickel (Ni), and zinc (Zn)) and C (Mn and Cu). In our study, cluster analysis showed a different grouping of elements in patient and control groups. Lead, cadmium, and cobalt were the most critical metals accumulated in the blood of cigarette smokers.

• Alehagen, Urban; Aaseth, Jan; Lindahl, Tomas L.; Larsson, Anders & Alexander, Jan (2021). Dietary supplementation with selenium and coenzyme Q10 prevents increase in plasma D-dimer while lowering cardiovascular mortality in an elderly swedish population. Nutrients. 13(4), s. 1–14. doi: 10.3390/nu13041344. Fulltekst i vitenarkiv Vis sammendrag

  A low intake of selenium is associated with increased cardiovascular mortality. This could be reduced by supplementation with selenium and coenzyme Q10. D-dimer, a fragment of fibrin mirroring fibrinolysis, is a biomarker of thromboembolism, increased inflammation, endothelial dysfunction and is associated with cardiovascular mortality in ischemic heart disease. The objective was to examine the impact of selenium and coenzyme Q10 on the level of D-dimer, and its relationship to cardiovascular mortality. D-dimer was measured in 213 individuals at the start and after 48 months of a randomised double-blind placebo-controlled trial with selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/day) (n = 106) or placebo (n = 107). The follow-up time was 4.9 years. All included individuals were low in selenium (mean 67 μg/L, SD 16.8). The differences in D-dimer concentration were evaluated by the use of T-tests, repeated measures of variance and ANCOVA analyses. At the end, a significantly lower D-dimer concentration was observed in the active treatment group in comparison with those on placebo (p = 0.006). Although D-dimer values at baseline were weakly associated with high-sensitive CRP, while being more strongly associated with soluble tumour necrosis factor receptor 1 and sP-selectin, controlling for these in the analysis there was an independent effect on D-dimer. In participants with a D-dimer level above median at baseline, the supplementation resulted in significantly lower cardiovascular mortality compared to those on placebo (p = 0.014). All results were validated with a persisting significant difference between the two groups. Therefore, supplementation with selenium and coenzyme Q10 in a group of elderly low in selenium and coenzyme Q10 prevented an increase in D-dimer and reduced the risk of cardiovascular mortality in comparison with the placebo group. The obtained results also illustrate important associations between inflammation, endothelial function and cardiovascular risk. Keywords: D-dimer; cardiovascular mortality; coenzyme Q10; elderly; intervention; selenium. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

• Aaseth, Jan; Alexander, Jan; Alehagen, Urban; Tinkov, Alexey; Skalny, Anatoly & Larsson, Anders [Vis alle 8 forfattere av denne artikkelen] (2021). The aging kidney—as influenced by heavy metal exposure and selenium supplementation. Biomolecules. 11(8). doi: 10.3390/biom11081078. Fulltekst i vitenarkiv Vis sammendrag

  Abstract The aging process in the kidneys has been well studied. It is known that the glomerular filtration rate (GFR) declines with age in subjects older than 50–60 years. However, there is still insufficient knowledge regarding the response of the aged kidney to environmental toxicants such as mercury, cadmium, and lead. Here, we present a review on the functional decline and proposed mechanisms in the aging kidney as influenced by metal pollutants. Due to the prevalence of these toxicants in the environment, human exposure is nearly unavoidable. Further, it is well known that acute and chronic exposures to toxic metals may be detrimental to kidneys of normal adults, thus it may be hypothesized that exposure of individuals with reduced GFR will result in additional reductions in renal function. Individuals with compromised renal function, either from aging or from a combination of aging and disease, may be particularly susceptible to environmental toxicants. The available data appear to show an association between exposure to mercury, cadmium and/or lead and an increase in incidence and severity of renal disease in elderly individuals. Furthermore, some physiological thiols, as well as adequate selenium status, appear to exert a protective action. Further studies providing improved insight into the mechanisms by which nephrotoxic metals are handled by aging kidneys, as well as possibilities of therapeutic protection, are of utmost importance. Keywords: renal disease; aging; mercury; cadmium; lead; thiols; selenium

• Aaseth, Jan Olav & Berlinger, Balazs (2021). Lanthanum. I Nordberg, Gunnar & Costa, Max (Red.), Handbook on the Toxicology of Metals: Volume II: Specific Metals. Academic Press. ISSN 9780128231388. s. 419–426. Fulltekst i vitenarkiv Vis sammendrag

  1. Physical and chemical properties 2. Methods and problems of analysis 3. Production and uses 4. Environmental levels and exposure 5. Metabolism and metabolic interactions 6. Biological monitoring 7. Effects and dose–response relationships 8. Treatment of lanthanum poisoning and its prevention

• Blomqvist, Lennart K.; Nordberg, Gunnar F. & Aaseth, Jan Olav (2021). Gadolinium. I Nordberg, Gunnar & Costa, Max (Red.), Handbook on the Toxicology of Metals: Volume II: Specific Metals. Academic Press. ISSN 9780128231388. s. 267–274. Fulltekst i vitenarkiv Vis sammendrag

  1. Physical and chemical properties 2. Methods and challenges in chemical analysis 3. Production and uses 4. Environmental levels and human exposure 5. Kinetics—pharmacokinetics and toxicokinetics 6. Biological monitoring—Gd levels in tissues and fluids 7. Toxic effects and dose–response relationships 8. Treatment of Gd-related side effects in animals and humans (CIN, deposition syndromes including NSF) and their prevention 9. Risk assessment of occupational exposures

• Møller, Lisbeth Birk & Aaseth, Jan Olav (2021). Copper. I Nordberg, Gunnar & Costa, Max (Red.), Handbook on the Toxicology of Metals: Volume II: Specific Metals. Academic Press. ISSN 9780128231388. s. 243–266. Fulltekst i vitenarkiv Vis sammendrag

  1. Physical and chemical properties 2. Methods and problems of analysis 3. Production and uses 4. Environmental levels and exposures 5. Metabolism 6. Levels in tissues and biological fluids 7. Effects and dose–response relationships 8. Preventive measures and treatment

• Samarghandian, Saeed; Shirazi, Farshad M; Saeedi, Farhad; Roshanravan, Babak; Pourbagher-Shahri, Ali Mohammad & Khorasani, Emad Yeganeh [Vis alle 10 forfattere av denne artikkelen] (2021). A systematic review of clinical and laboratory findings of lead poisoning: lessons from case reports. Toxicology and Applied Pharmacology. ISSN 0041-008X. 429. doi: 10.1016/j.taap.2021.115681. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Lead is one of the most toxic heavy metals in the environment. The present review aimed to highlight hazardous pollution sources, management, and review symptoms of lead poisonings in various parts of the world. The present study summarized the information available from case reports and case series studies from 2009 to March 2020 on the lead pollution sources and clinical symptoms. All are along with detoxification methods in infants, children, and adults. Our literature compilation includes results from 126 studies on lead poisoning. We found that traditional medication, occupational exposure, and substance abuse are as common as previously reported sources of lead exposure for children and adults. Ayurvedic medications and gunshot wounds have been identified as the most common source of exposure in the United States. However, opium and occupational exposure to the batteries were primarily seen in Iran and India. Furthermore, neurological, gastrointestinal, and hematological disorders were the most frequently occurring symptoms in lead-poisoned patients. As for therapeutic strategies, our findings confirm the safety and efficacy of chelating agents, even for infants. Our results suggest that treatment with chelating agents combined with the prevention of environmental exposure may be an excellent strategy to reduce the rate of lead poisoning. Besides, more clinical studies and long-term follow-ups are necessary to address all questions about lead poisoning management. Keywords: Lead; chelating; poisoning; pollutant sources; systematic review; toxicities. Copyright © 2021. Published by Elsevier Inc.

• Aaseth, Jan; Nurchi, Valeria Marina & Andersen, Ole (2021). Clinical therapy of patients contaminated with polonium or plutonium. Current Medicinal Chemistry. ISSN 0929-8673. 28(35), s. 7238–7246. doi: 10.2174/0929867327666201020152253. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Although most of the harmful radionuclides are of anthropogenic origin and released from military or industrial processes, radioactive substances, such as uranium, also occur naturally in the environment. Low standards of care at nuclear facilities can lead to the contamination of employees with radionuclides due to inhalation of gases or dust or contamination of skin or wounds. Various sources for radionuclide exposure may present concerns for radioactive polonium or plutonium exposure, for instance, terrorist actions on the infrastructure, such as on drinking water basins. Early health effects after extensive radiation exposure may be vomiting, headaches, and fatigue, followed by bone marrow depression, fever, and diarrhea. The main purpose of radionuclide mobilization is to minimize the radiation dose. Since some of the important radionuclides, such as polonium and plutonium, have very long biological half-times after their deposition in bone, liver or kidneys, rapid initiation of chelation treatment is usually imperative after a contamination event. The antidote DMPS (dimercapto-propanesulfonate) is considered the drug of choice for polonium decorporation. DTPA (diethylenetriamine pentaacetate) is a potent chelator especially approved for radionuclide mobilization, including polonium and other actinides. Other chelators and drugs are under investigation as potential chelators of transuranic elements. Keywords: DMSA; DTPA; actinides; chelating agents.; plutonium; polonium.

• Aaseth, Jan; Skalny, Anatoly V.; Roos, Per M.; Alexander, Jan; Aschner, Michael & Tinkov, Alexey A. (2021). Copper, Iron, Selenium and Lipo-Glycemic Dysmetabolism in Alzheimer's Disease. International Journal of Molecular Sciences. ISSN 1661-6596. 22(17). doi: 10.3390/ijms22179461. Fulltekst i vitenarkiv Vis sammendrag

  Abstract The aim of the present review is to discuss traditional hypotheses on the etiopathogenesis of Alzheimer's disease (AD), as well as the role of metabolic-syndrome-related mechanisms in AD development with a special focus on advanced glycation end-products (AGEs) and their role in metal-induced neurodegeneration in AD. Persistent hyperglycemia along with oxidative stress results in increased protein glycation and formation of AGEs. The latter were shown to possess a wide spectrum of neurotoxic effects including increased Aβ generation and aggregation. In addition, AGE binding to receptor for AGE (RAGE) induces a variety of pathways contributing to neuroinflammation. The existing data also demonstrate that AGE toxicity seems to mediate the involvement of copper (Cu) and potentially other metals in AD pathogenesis. Specifically, Cu promotes AGE formation, AGE-Aβ cross-linking and up-regulation of RAGE expression. Moreover, Aβ glycation was shown to increase prooxidant effects of Cu through Fenton chemistry. Given the role of AGE and RAGE, as well as metal toxicity in AD pathogenesis, it is proposed that metal chelation and/or incretins may slow down oxidative damage. In addition, selenium (Se) compounds seem to attenuate the intracellular toxicity of the deranged tau and Aβ, as well as inhibiting AGE accumulation and metal-induced neurotoxicity. Keywords: GLP-1 agonist; advanced glycation end-products; copper; glycemic dysregulation; iron; selenium. This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

• Tinkov, Alexey A.; Aschner, Michael; Ke, Tao; Ferrer, Beatriz; Zhou, Ji-Chang & Santamaria, Abel [Vis alle 9 forfattere av denne artikkelen] (2021). Adipotropic effects of heavy metals and their potential role in obesity. Faculty Opinions. ISSN 2634-0836. 10(32). doi: 10.12703/r/10-32. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Epidemiological studies demonstrated an association between heavy metal exposure and the incidence of obesity and metabolic syndrome. However, the particular effects of metal toxicity on adipose tissue functioning are unclear. Therefore, recent findings of direct influence of heavy metals (mercury, cadmium, and lead) and metalloid (arsenic) on adipose tissue physiology are discussed while considering existing gaps and contradictions. Here, we provide a literature review addressing adipose tissue as a potential target of heavy metal toxicity. Experimental in vivo studies demonstrated a significant influence of mercury, cadmium, lead, and arsenic exposure on body adiposity. In turn, in vitro experiments revealed both up- and downregulation of adipogenesis associated with aberrant expression of key adipogenic pathways, namely CCAAT/enhancer-binding protein (C/EBP) and peroxisome proliferator-activated receptor gamma (PPARγ). Comparison of the existing studies on the basis of dose and route of exposure demonstrated that the effects of heavy metal exposure on adipose tissue may be dose-dependent, varying from increased adipogenesis at low-dose exposure to inhibition of adipose tissue differentiation at higher doses. However, direct dose-response data are available in a single study only for arsenic. Nonetheless, both types of these effects, irrespective of their directionality, contribute significantly to metabolic disturbances due to dysregulated adipogenesis. Particularly, inhibition of adipocyte differentiation is known to reduce lipid-storage capacity of adipose tissue, leading to ectopic lipid accumulation. In contrast, metal-associated stimulation of adipogenesis may result in increased adipose tissue accumulation and obesity. However, further studies are required to reveal the particular dose- and species-dependent effects of heavy metal exposure on adipogenesis and adipose tissue functioning. Keywords: mercury, cadmium, lead, adipogenesis, adipocyte

• Roer, Grethe Emilie; Solbakken, Heidi Hurlen; Abebe, Dawit Shawel; Aaseth, Jan; Bolstad, Ingeborg & Lien, Lars (2021). Inpatients experiences about the impact of traumatic stress on eating behaviors: an exploratory focus group study. Journal of Eating Disorders. 9(119), s. 1–12. doi: 10.1186/s40337-021-00480-y. Fulltekst i vitenarkiv Vis sammendrag

  This study aimed to explore trauma-exposed inpatients experiences about the impact of traumatic stress on eating behavior. Thirteen female and two male inpatients with a history of trauma, recruited from a psychiatric clinic in Norway, participated in this qualitative explorative focus group study. The results in the present study describe the participants’ experiences about the impact of after effects of traumatic experiences on eating behaviors. The findings are summarized into four main themes: “experiencing eating behaviors as coping strategies”; “experiencing being addicted to food and sweets”; “experiencing eating behaviors controlled by stress and emotions”; and “experiencing lack of appetite and reduced capacity to plan and prepare meals”. The results contribute to the existing literature and provide an important understanding of changes in eating behavior that might appear in people struggling with traumatic stress after traumatic experiences. This knowledge is important and useful for health professionals offering help to those struggling with their eating behavior after traumatic experiences.

• Aspli, Klaus Thanke; Holmøy, Trygve; Flaten, Trond Peder; Whist, Jon Elling & Aaseth, Jan (2021). Skogholt’s disease—A tauopathy precipitated by iron and copper? Journal of Trace Elements in Medicine and Biology. ISSN 0946-672X. 70. doi: 10.1016/j.jtemb.2021.126915. Fulltekst i vitenarkiv Vis sammendrag

  Background It has been suggested that Skogholt’s disease is a new neurological disease entity. The disease, confined to a family line in Hedmark county, Norway, usually affects both the brain and peripheral nerves. Typical findings are white matter lesions in the brain, myelin damage in peripheral nerves, and discolored cerebrospinal fluid with high concentrations of protein, copper, and iron. Little is known about the natural progression of the disease and its underlying cause, but the high level of copper and iron in the cerebrospinal fluid may cause or exacerbate inflammation in the central nervous system. Methods The present clinical study further explores the disease progression with clinical chemistry analyses and mass spectrometry of blood and cerebrospinal fluid (CSF) from patients and controls. Findings are corroborated with cognitive assessments. Results Pathological changes in CSF with low amyloid-β42 and high levels of tau proteins, total protein, copper, and iron, were discovered among Skogholt patients. The Montreal Cognitive Assessment identified 36 % of the patients as below normal range, while most patients performed slower than the norm mean time on the Trail Making Test. Mini-Mental Status Examination disclosed only minor deviations. Conclusion The findings in the present study strengthen our initial suggestion that Skogholt’s disease most likely is a new neurological disorder and provide new clues to its cause: The disease may belong to the family of neurodegenerative disorders termed tauopathies. The increased level of copper and iron may contribute to neuroinflammation as these metals also have been associated with other neurodegenerative disorders. Although the causes of neurodegenerative disorders are currently largely unknown, studies on rare disease entities, such as the present one, may increase the understanding of neurodegeneration in general.

• Skalny, Anatoly V.; Aschner, Michael; Lei, Xin Gen; Gritsenko, Viktor A.; Santamaria, Abel & Alekseenko, Svetlana I. [Vis alle 12 forfattere av denne artikkelen] (2021). Gut Microbiota as a Mediator of Essential and Toxic Effects of Zinc in the Intestines and Other Tissues. International Journal of Molecular Sciences. ISSN 1661-6596. 22(23). doi: 10.3390/ijms222313074. Fulltekst i vitenarkiv Vis sammendrag

  The objective of the present study was to review the existing data on the association between Zn status and characteristics of gut microbiota in various organisms and the potential role of Zn-induced microbiota in modulating systemic effects. The existing data demonstrate a tight relationship between Zn metabolism and gut microbiota as demonstrated in Zn deficiency, supplementation, and toxicity studies. Generally, Zn was found to be a significant factor for gut bacteria biodiversity. The effects of physiological and nutritional Zn doses also result in improved gut wall integrity, thus contributing to reduced translocation of bacteria and gut microbiome metabolites into the systemic circulation. In contrast, Zn overexposure induced substantial alterations in gut microbiota. In parallel with intestinal effects, systemic effects of Zn-induced gut microbiota modulation may include systemic inflammation and acute pancreatitis, autism spectrum disorder and attention deficit hyperactivity disorder, as well as fetal alcohol syndrome and obesity. In view of both Zn and gut microbiota, as well as their interaction in the regulation of the physiological functions of the host organism, addressing these targets through the use of Zn-enriched probiotics may be considered an effective strategy for health management. Keywords: Escherichia coli; gut microbiota; lipopolysaccharide; probiotic; zinc.

• Bjørklund, Geir; Dadar, Maryam; Chirumbolo, Salvatore; Aaseth, Jan & Peana, Massimiliano (2020). Metals, autoimmunity, and neuroendocrinology: Is there a connection? Environmental Research. ISSN 0013-9351. 187, s. 1–8. doi: 10.1016/j.envres.2020.109541. Fulltekst i vitenarkiv Vis sammendrag

  It has been demonstrated that metals can induce autoimmunity. However, few studies have attempted to assess and elucidate the underlying mechanisms of action. Recent research has tried to evaluate the possible interactions of the immune system with metal ions, particularly with heavy metals. Research indicates that metals have the potential to induce or promote the development of autoimmunity in humans. Metal-induced inflammation may dysregulate the hypothalamic-pituitary-adrenal (HPA) axis and thus contribute to fatigue and other non-specific symptoms characterizing disorders related to autoimmune diseases. The toxic effects of several metals are also mediated through free radical formation, cell membrane disturbance, or enzyme inhibition. There are worldwide increases in environmental metal pollution. It is therefore critical that studies on the role of metals in autoimmunity, and neuroendocrine disorders, including effects on the developing immune system and brain and the genetic susceptibility are performed. These studies can lead to efficient preventive strategies and improved therapeutic approaches. In this review, we have retrieved and commented on studies that evaluated the effects of metal toxicity on immune and endocrine-related pathways. This review aims to increase awareness of metals as factors in the onset and progression of autoimmune and neuroendocrine disorders.

• Ajsuvakova, Olga P.; Tinkov, Alexey A.; Aschner, Michael; Rocha, João B.T.; Michalke, Bernhard & Skalnaya, Margarita G. [Vis alle 12 forfattere av denne artikkelen] (2020). Sulfhydryl groups as targets of mercury toxicity. Coordination chemistry reviews. ISSN 0010-8545. 417. doi: 10.1016/j.ccr.2020.213343. Fulltekst i vitenarkiv Vis sammendrag

  The present study addresses existing data on the affinity and conjugation of sulfhydryl (thiol; -SH) groups of low- and high-molecular-weight biological ligands with mercury (Hg). The consequences of these interactions with special emphasis on pathways of Hg toxicity are highlighted. Cysteine (Cys) is considered the primary target of Hg, and link its sensitivity with thiol groups and cellular damage. In vivo, Hg complexes play a key role in Hg metabolism. Due to the increased affinity of Hg to SH groups in Cys residues, glutathione (GSH) is reactive. The geometry of Hg(II) glutathionates is less understood than that with Cys. Both Cys and GSH Hg-conjugates are important in Hg transport. The binding of Hg to Cys mediates multiple toxic effects of Hg, especially inhibitory effects on enzymes and other proteins that contain free Cys residues. In blood plasma, albumin is the main Hg-binding (Hg2+, CH3Hg+, C2H5Hg+, C6H5Hg+) protein. At the Cys34 residue, Hg2+ binds to albumin, whereas other metals likely are bound at the N-terminal site and multi-metal binding sites. In addition to albumin, Hg binds to multiple Cys-containing enzymes (including manganese-superoxide dismutase (Mn-SOD), arginase I, sorbitol dehydrogenase, and δ-aminolevulinate dehydratase, etc.) involved in multiple processes. The affinity of Hg for thiol groups may also underlie the pathways of Hg toxicity. In particular, Hg-SH may contribute to apoptosis modulation by interfering with Akt/CREB, Keap1/Nrf2, NF-κB, and mitochondrial pathways. Mercury-induced oxidative stress may ensue from Cys-Hg binding and inhibition of Mn-SOD (Cys196), thioredoxin reductase (TrxR) (Cys497) activity, as well as limiting GSH (GS-HgCH3) and Trx (Cys32, 35, 62, 65, 73) availability. Moreover, Hg-thiol interaction also is crucial in the neurotoxicity of Hg by modulating the cytoskeleton and neuronal receptors, to name a few. However, existing data on the role of Hg-SH binding in the Hg toxicity remains poorly defined. Therefore, more research is needed to understand better the role of Hg-thiol binding in the molecular pathways of Hg toxicology and the critical role of thiols to counteract negative effects of Hg overload. Keywords: Apoptosis; Conjugates; Cysteine; Mercury; S-mercuration.

• Bjørklund, Geir; Semenova, Yuliya; Pivina, Lyudmila; Dadar, Maryam; Rahman, Md. Mostafizur & Aaseth, Jan [Vis alle 7 forfattere av denne artikkelen] (2020). Uranium in drinking water: a public health threat. Archives of Toxicology. ISSN 0340-5761. 94, s. 1–10. doi: 10.1007/s00204-020-02676-8. Fulltekst i vitenarkiv Vis sammendrag

  Uranium (U) has no known essential biological functions. Furthermore, it is well known for its toxicity, radioactivity, and carcinogenic potency. Impacts on human health due to U exposure have been studied extensively by many researchers. Chronic exposure to low-level U isotopes (radionuclides) may be interlinked with cancer etiology and at high exposure levels, also kidney disease. Other important issues covered U and fertilizers, and also U in soils or human tissues as an easily measurable indicator element in a pathophysiological examination. Furthermore, phosphate fertilization is known as the important source of contamination with U in the agricultural land, mainly due to contamination in the phosphate rock applied for fertilizer manufacture. Therefore, long-term usage of U-bearing fertilizers can substantially increase the concentration of U in fertilized soils. It should also be noted that U is an active redox catalyst for the reaction between DNA and H2O2. This review is aimed to highlight a series on various hydro-geochemical aspects in different water sources and focused on the comparison of different U contents in the drinking water sources and presentation of data in relation to health issues.

• Alehagen, Urban; Aaseth, Jan Olav; Alexander, Jan; Johansson, Peter & Larsson, Anders (2020). Supplemental selenium and coenzyme Q10 reduce glycation along with cardiovascular mortality in an elderly population with low selenium status – A four-year, prospective, randomised, double-blind placebo-controlled trial. Journal of Trace Elements in Medicine and Biology. ISSN 0946-672X. 61. doi: 10.1016/j.jtemb.2020.126541. Fulltekst i vitenarkiv Vis sammendrag

  Background:A low intake of selenium has been shown to increase the risk of cardiovascular mortality, andsupplementation of selenium and coenzyme Q10 influences this. The mechanism behind is unclear althougheffects on inflammation, oxidative stress and microRNA expression have been reported.Fructosamine, a marker of long-term glycaemic control, is also a marker of increased risk of heart disease anddeath, even in non-diabetics.Objective:To analyse the impact of selenium and coenzyme Q10 supplementation on the concentration offructosamine. Also, the relation between pre-intervention serum selenium concentration and the effect onfructosamine of the intervention was studied.Methods:Fructosamine plasma concentration was determined in 219 participants after six and 42 months ofintervention with selenium yeast (200μg/day) and coenzyme Q10 (200 mg/ day) (n = 118 of which 20 haddiabetes at inclusion), or placebo (n = 101 of which 18 had diabetes at inclusion). Pre-intervention, the serumselenium levels were 67μg/L (active treatment group: 66.6μg/L; placebo group: 67.4μg/L), corresponding to anestimated intake of 35μg/day. Changes in concentrations of fructosamine following intervention were assessedby the use of T-tests, repeated measures of variance, and ANCOVA analyses.Results:Post-intervention selenium concentrations were 210μg/L in the active group and 72μg/L in the placebogroup. A lower concentration of fructosamine could be seen as a result of the intervention in the total population(P = 0.001) in both the males (P = 0.04) and in the females (P = 0.01) in the non-diabetic population(P = 0.002), and in both the younger (< 76 years) (P = 0.01) and the older (≥76 years) participants (P = 0.03).No difference could be demonstrated in fructosamine concentration in the diabetic patients, but the total samplewas small (n = 38). In subjects with a low pre-intervention level of serum selenium the intervention gave a morepronounced decrease in fructosamine compared with those with a higher baseline selenium level.Conclusion:A significantly lower concentration of fructosamine was observed in the elderly community-livingparticipants supplemented with selenium and coenzyme Q10 for 42 months compared to those on the placebo.As oxidative mechanisms are involved in the glycation of proteins, less glycoxidation could be a result of thesupplementation of selenium and coenzyme Q10, which could have contributed to lower cardiac mortality andless inflammation, as has earlier been reported.This study was registered at Clinicaltrials.gov, and has the identifier NCT01443780.

• Monsen, Anne-Lise Bjørke; Mikalsen, Solveig Meyer; Ueland, Grethe Åstrøm; Aaseth, Jan & Whist, Jon Elling (2020). Low serum sodium concentrations in patients with obesity normalizes with weight loss. Clinical Nutrition ESPEN. ISSN 2405-4577. 41, s. 405–411. doi: 10.1016/j.clnesp.2020.10.011. Fulltekst i vitenarkiv Vis sammendrag

  Obesity is associated with higher extracellular fluid (ECF) compared to intracellular fluid (ICF) volume and this dysregulation is associated with hypertension and abdominal obesity, associated with metabolic syndrome. As sodium is predominantly an extracellular cation, a higher ECF/ICF ratio will lower serum sodium concentration. The aim of the study was to see whether weight loss, due to dieting and bariatric surgery, had any impact on serum sodium concentrations in patients with severe obesity. Methods Patients with a BMI ≥35 kg/m 2 admitted for bariatric surgery at Innlandet Hospital Trust, Norway during 2012–14 were included in the study (n = 119). Clinical data and blood samples were recorded at inclusion, after mean six months of dieting, as well as six and 12 months after bariatric surgery. Results At inclusion, mean serum sodium was in the lower normal range, 138.3 (SD 2.4) mmol/L, but increased to 141.8 (SD 1.9) mmol/L after weight loss. The increase was significantly correlated to total weight loss (rho: 0.29, p = 0.007). Twelve months after surgery, serum sodium was significantly higher in patients with a normal BMI (<25 kg/m 2 ) compared to patients with overweight. Conclusion Obesity and hypertension are associated with body fluid dysregulation affecting serum sodium concentrations. As mild hyponatremia, even within the normal sodium range, is associated with increased total mortality and major cardiovascular disease events, serum sodium might be a potential risk marker in patients with obesity. Highlights Obesity is associated with higher extracellular fluid compared to intracellular fluid volume and this dysregulation is associated with hypertension and abdominal obesity, associated with metabolic syndrome. Patients with severe obesity had serum sodium concentrations below or in the lower reference range. Weight loss was associated with improved serum sodium concentrations. As both high and low serum sodium concentrations, even within the normal reference range, are reported to increase the risk of cardiovascular disease and mortality, serum sodium might be a potential risk marker for cardiovascular disease in patients with obesity.

• Bjørklund, Geir; Dadar, Maryam; Aaseth, Jan & Chirumbolo, Salvatore (2020). Thymosin β4: A multi-faceted tissue repair stimulating protein in heart injury. Current Medicinal Chemistry. ISSN 0929-8673. 27(37), s. 6294–6305. doi: 10.2174/0929867326666190716125456. Fulltekst i vitenarkiv Vis sammendrag

  Thymosin beta-4 (Tβ4) is known as a major pleiotropic actin-sequestering protein that is involved in tumorigenesis. Tβ4 is a water-soluble protein that has different promising clinical applications in the remodeling and ulcerated tissues repair following myocardial infarction, stroke, plasticity and neurovascular remodeling of the peripheral nervous system (PNS) and the central nervous system (CNS). On the other hand, similar effects have been observed for Tβ4 in other kinds of tissues, including cardiac muscle tissue. In recent reports, as it activates resident epicardial progenitor cells and modulates inflammatory-caused injuries, Tβ4 has been suggested as a promoter of the survival of cardiomyocytes. Furthermore, Tβ4 may act in skeletal muscle and different organs in association/synergism with numerous other tissue repair stimulating factors, including melatonin and C-fiber-derived peptides. For these reasons, the present review highlights the promising role of Tβ4 in cardiac healing.

• Skalny, Anatoly V.; Rink, Lothar; Ajsuvakova, Olga P.; Aschner, Michael; Gritsenko, Viktor A. & Alekseenko, Svetlana I. [Vis alle 12 forfattere av denne artikkelen] (2020). Zinc and respiratory tract infections: Perspectives for COVID‑19. International Journal of Molecular Medicine. ISSN 1107-3756. 46(1), s. 17–26. doi: 10.3892/ijmm.2020.4575. Fulltekst i vitenarkiv Vis sammendrag

  In view of the emerging COVID‑19 pandemic caused by SARS‑CoV‑2 virus, the search for potential protective and therapeutic antiviral strategies is of particular and urgent interest. Zinc is known to modulate antiviral and antibacterial immunity and regulate inflammatory response. Despite the lack of clinical data, certain indications suggest that modulation of zinc status may be beneficial in COVID‑19. In vitro experiments demonstrate that Zn2+ possesses antiviral activity through inhibition of SARS‑CoV RNA polymerase. This effect may underlie therapeutic efficiency of chloroquine known to act as zinc ionophore. Indirect evidence also indicates that Zn2+ may decrease the activity of angiotensin‑converting enzyme 2 (ACE2), known to be the receptor for SARS‑CoV‑2. Improved antiviral immunity by zinc may also occur through up‑regulation of interferon α production and increasing its antiviral activity. Zinc possesses anti‑inflammatory activity by inhibiting NF‑κB signaling and modulation of regulatory T‑cell functions that may limit the cytokine storm in COVID‑19. Improved Zn status may also reduce the risk of bacterial co‑infection by improving mucociliary clearance and barrier function of the respiratory epithelium, as well as direct antibacterial effects against S. pneumoniae. Zinc status is also tightly associated with risk factors for severe COVID‑19 including ageing, immune deficiency, obesity, diabetes, and atherosclerosis, since these are known risk groups for zinc deficiency. Therefore, Zn may possess protective effect as preventive and adjuvant therapy of COVID‑19 through reducing inflammation, improvement of mucociliary clearance, prevention of ventilator‑induced lung injury, modulation of antiviral and antibacterial immunity. However, further clinical and experimental studies are required.

• Kuria, Angelica; Tian, Hongdou; Li, Mei; Wang, Yinhe; Aaseth, Jan & Zang, Jiajie [Vis alle 7 forfattere av denne artikkelen] (2020). Selenium status in the body and cardiovascular disease: a systematic review and meta-analysis. Critical reviews in food science and nutrition. ISSN 1040-8398. s. 1–10. doi: 10.1080/10408398.2020.1803200. Fulltekst i vitenarkiv Vis sammendrag

  Background: Both experimental and observational studies have provided conflicting evidence on the associations of selenium with incidence and mortality of cardiovascular disease (CVD). The aim of this study was to evaluate the association between selenium status in the body and incidence and mortality of CVD by performing a systematic review and meta-analysis of observational studies and randomized controlled trials. Methods: A systematic search for articles in MEDLINE (Ovid), Embase, Web of Science (Thomson Reuters) and Cochrane library (Wiley) was conducted. Thirteen of the 1811 articles obtained from the databases met our inclusion criteria and were considered in the final analysis. The effect sizes were presented as weighted relative risk (RR) and 95% confidence intervals (CIs) using random-effects model. To detect dose-response relationships, we used meta-regression. Results: Overall, there was a reduced risk of CVD incidence (RR = 0.66; 95% CI: 0.40-1.09) and mortality (RR = 0.69; 95% CI: 0.57-0.84) in physiologically high selenium status compared to low selenium status in the body. There was a 15% (RR = 0.85, 95% CI: 0.76-0.94) decreased risk of CVD incidence per 10 µg increment in blood selenium concentration. In addition, a statistically significantly nonlinear dose-response relationship was found between CVD mortality and increased blood selenium concentration with the lowest risk at the 30-35 µg increment in blood selenium. Conclusions: Physiologically high selenium levels in the body are associated with decreased risk for CVD incidence and mortality, however, people should be cautious about the potential harmful effects from excessive intake of selenium.

• Alehagen, Urban; Alexander, Jan; Aaseth, Jan; Larsson, A. & Lindahl, T. L. (2020). Significant decrease of von Willebrand factor and plasminogen activator inhibitor-1 by providing supplementation with selenium and coenzyme Q10 to an elderly population with a low selenium status. European Journal of Nutrition. ISSN 1436-6207. 59(8). doi: 10.1007/s00394-020-02193-5. Fulltekst i vitenarkiv Vis sammendrag

  Purpose: Endothelial dysfunction and inflammation are conditions which fuel atherosclerosis and ischaemic heart disease. We have previously reported reduced cardiovascular (CV) mortality following supplementation with selenium and coenzyme Q10 to 443 elderly individuals with low selenium status (mean 67 μg/L) for 4 years. Here, we wanted to evaluate a possible association between the supplementation and the plasma concentrations of the von Willebrand factor (vWf), and the plasminogen activator inhibitor-1 (PAI-1), as they, besides other functions, are also strongly associated with endothelial function. Methods: In this sub-study, 308 individuals (active substance: 157, placebo: 151) were included. Blood samples were drawn after 6 and 36 months and vWf and PAI-1 were determined in plasma by ELISA. Changes in concentrations of the biomarkers were evaluated by the use of T tests, repeated measures of variance, and ANCOVA analyses. Results: The active treatment group presented a lower level of vWf after 36 months compared with the placebo group (1.08 U/mL vs. 5.10 U/mL; p = 0.0007). The results were validated through the repeated measures of variance evaluation. The PAI-1 levels showed an equally significant decrease in the active group (26.2 ng/mL vs. 49.2 ng/mL; p = 0.0002) and were also validated through repeated measures of variance evaluation. Conclusion: In this sub-study on elderly receiving selenium and coenzyme Q10, or placebo we found significantly lower levels of vWf and PAI-1 in the active treatment group as compared to the placebo group. We interpret this as a better endothelial function because of the intervention, which accords with a previous finding of reduced CV mortality. Keywords: Coenzyme Q10; Elderly; Intervention; PAI-1; Selenium; Von willebrand factor.

• Skalny, Anatoly V.; Lima, Thania Rios Rossi; Ke, Tao; Zhou, Ji-Chang; Bornhorst, Julia & Alekseenko, Svetlana I. [Vis alle 12 forfattere av denne artikkelen] (2020). Toxic metal exposure as a possible risk factor for COVID-19 and other respiratory infectious diseases. Food and Chemical Toxicology (FCT). ISSN 0278-6915. 146, s. 1–12. doi: 10.1016/j.fct.2020.111809. Fulltekst i vitenarkiv
• Aaseth, Jan Olav (2020). Cyanidforgiftning. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 140(11), s. 1–2. doi: 10.4045/tidsskr.20.0610. Fulltekst i vitenarkiv
• Mikalsen, Solveig Meyer; Aaseth, Jan; Flaten, Trond Peder; Whist, Jon Elling & Monsen, Anne Lise Bjørke (2020). Essential trace elements in Norwegian obese patients before and 12 months after Roux-en-Y gastric bypass surgery: Copper, manganese, selenium and zinc. Journal of Trace Elements in Medicine and Biology. ISSN 0946-672X. 62:126650, s. 1–6. doi: 10.1016/j.jtemb.2020.126650. Fulltekst i vitenarkiv Vis sammendrag

  Objectives: The objective of the present study was to assess trace element status in morbidly obese subjects before and one year after Roux-en-Y gastric bypass (RYGB) in order to identify possible deficiencies. Methods: The study population included 46 patients in the age range 27–59 years, the majority (85 %) were women. The enrolled patients attended an eight week course on lifestyle changes before bariatric surgery. After RYGB they were recommended daily micronutrient supplements with a commonly used multivitamin-mineral tablet in addition to intramuscular vitamin B12 injections (1 mg) every third month for 12 months. Whole blood concentrations of Cu, Mn, Se and Zn were determined using high resolution inductively coupled plasma mass spectrometry. Results: During the 12 months follow up after bariatric surgery, the patients had lost mean 32.3 kg and median whole blood concentrations of Cu (-16 %) were reduced, Mn (+14 %) and Zn (+6%) were increased, while the Se values were essentially unchanged. Compared with reference ranges, median postoperative concentrations of all essential trace elements were either below (Zn) or in the lower reference range (Cu, Mn, Se). Conclusion: Essential trace elements were below or in the lower reference range twelve months after RYGB. Our results indicate a need for updated guidelines in Nordic countries for trace metal monitoring and supplements in patients after bariatric surgery, especially when gastric bypass surgery is used. Further studies are required to explore and prevent trace element deficiency related to obesity and bariatric surgery.

• Benahmed, Asma Gasmi; Gasmi, Amin; Dosa, Alexandru; Chirumbolo, Salvatore; Mujawdiya, Pavan Kumar & Aaseth, Jan Olav [Vis alle 8 forfattere av denne artikkelen] (2020). Association between the gut and oral microbiome with obesity. Anaerobe. ISSN 1075-9964. doi: 10.1016/j.anaerobe.2020.102248. Fulltekst i vitenarkiv Vis sammendrag

  In recent decades, obesity has become one of the most common lifestyle-associated disorders. Obesity is a major contributing factor for several other lifestyles associated disorders such as type 2 diabetes mellitus, hypertension, and cardiovascular disease. Although genetics and lifestyle have been directly implicated in the onset and progression of obesity, recent studies have established that gut microbiome plays a crucial role in obesity progression. A higher proportion of Firmicutes and a skewed Firmicutes/Bacteroidetes ratio may contribute to gut dysbiosis and subsequent disturbances in the overall body metabolisms. Like gut microbiome, the oral cavity of humans also harbors a characteristic microbial population called "oral microbiome". The oral microbiome has also been implicated in the development of obesity due to its modulating effects on the gut microbiome. Due to its critical role in obesity, alteration in the gut microbiome has been suggested as one of the therapeutic strategies to manage obesity itself. For example, fecal microbiome transfer, or the use of probiotics and prebiotics have been suggested. These therapies not only restore the gut microbiome to the "pre-obese stage" but also ameliorate many functional aspects of the metabolic syndrome such as systemic inflammation, insulin resistance, and fat accumulation. However, the efficacy and safety of some of the methods have not been tested for their long-term implications, and further research in this area is warranted to understand the molecular mechanisms involved in this process completely. Keywords: Dietary compounds; Metabolic; Microbiome; Obesity.

• Bjørklund, Geir; Tinkov, Alexey A.; Hosnedlova, Bozena; Kizek, Rene; Ajsuvakova, Olga P. & Chirumbolo, Salvatore [Vis alle 14 forfattere av denne artikkelen] (2020). The role of glutathione redox imbalance in autism spectrum disorder: A review. Free Radical Biology & Medicine. ISSN 0891-5849. 160, s. 149–162. doi: 10.1016/j.freeradbiomed.2020.07.017. Fulltekst i vitenarkiv Vis sammendrag

  The role of glutathione in autism spectrum disorder (ASD) is emerging as a major topic, due to its role in the maintenance of the intracellular redox balance. Several studies have implicated glutathione redox imbalance as a leading factor in ASD, and both ASD and many other neurodevelopmental disorders involve low levels of reduced glutathione (GSH), high levels of oxidized glutathione (GSSG), and abnormalities in the expressions of glutathione-related enzymes in the blood or brain. Glutathione metabolism, through its impact on redox environment or redox-independent mechanisms, interferes with multiple mechanisms involved in ASD pathogenesis. Glutathione-mediated regulation of glutamate receptors [e.g., N-methyl-d-aspartate (NMDA) receptor], as well as the role of glutamate as a substrate for glutathione synthesis, may be involved in the regulation of glutamate excitotoxicity. However, the interaction between glutathione and glutamate in the pathogenesis of brain diseases may vary from synergism to antagonism. Modulation of glutathione is also associated with regulation of redox-sensitive transcription factors nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1) and downstream signaling (proinflammatory cytokines and inducible enzymes), thus providing a significant impact on neuroinflammation. Mitochondrial dysfunction, as well as neuronal apoptosis, may also provide a significant link between glutathione metabolism and ASD. Furthermore, it has been recently highlighted that glutathione can affect and modulate DNA methylation and epigenetics. Review analysis including research studies meeting the required criteria for analysis showed statistically significant differences between the plasma GSH and GSSG levels as well as GSH:GSSG ratio in autistic patients compared with healthy individuals (P = 0.0145, P = 0.0150 and P = 0.0202, respectively). Therefore, the existing data provide a strong background on the role of the glutathione system in ASD pathogenesis. Future research is necessary to investigate the role of glutathione redox signaling in ASD, which could potentially also lead to promising therapeutics. Keywords: Antioxidant capacity; Autism; GSH:GSSG ratio; Oxidative stress.

• Bjørklund, Geir; Meguid, Nagwa A.; Dadar, Maryam; Pivina, Lyudmila; Kałużna-Czaplińska, Joanna & Jóźwik-Pruska, Jagoda [Vis alle 13 forfattere av denne artikkelen] (2020). Specialized Diet Therapies: Exploration for Improving Behavior in Autism Spectrum Disorder (ASD). Current Medicinal Chemistry. ISSN 0929-8673. 27(40). doi: 10.2174/0929867327666200217101908. Fulltekst i vitenarkiv Vis sammendrag

  As a major neurodevelopmental disorder, autism spectrum disorder (ASD) encompasses deficits in communication and repetitive and restricted interests or behaviors in childhood and adolescence. Its etiology may come from either a genetic, epigenetic, neurological, hormonal, or an environmental cause, generating pathways that often altogether play a synergistic role in the development of ASD pathogenesis. Furthermore, the metabolic origin of ASD should be important as well. A balanced diet consisting of the essential and special nutrients, alongside the recommended caloric intake, is highly recommended to promote growth and development that withstands the physiologic and behavioral challenges experienced by ASD children. In this review paper, we evaluated many studies that show a relationship between ASD and diet to develop a better understanding of the specific effects of overall diet and the individual nutrients required for this population. This review will add a comprehensive update of knowledge in the field and shed light on the possible nutritional deficiencies, metabolic impairments (particularly in the gut microbiome), and malnutrition in individuals with ASD, which should be recognized in order to maintain improved socio-behavioral habit and physical health. Keywords: Autism; Casein; Diet; Environmental Stressors; Epigenetic Stressors; Genetic; Gluten.

• Bjørklund, Geir; Tippairote, Torsak; Dadar, Maryam; Lizcano, Fernando; Aaseth, Jan Olav & Borisova, Olga (2020). The roles of dietary, nutritional, and lifestyle interventions in adipose tissue adaptation and obesity. Current Medicinal Chemistry. ISSN 0929-8673. doi: 10.2174/0929867327666200505090449. Fulltekst i vitenarkiv Vis sammendrag

  The obesity and the associated non-communicable diseases (NCDs) were globally increasing in their prevalence. While the modern-day lifestyle required less ventilation of metabolic energy through muscular activities, this lifestyle transition also provided the unlimited accession to foods around the clock, which prolonged the daily eating period of foods that contained high calorie and high glycemic load. These situations promoted the high continuous flux of carbon substrate availability in mitochondria and induced the indecisive bioenergetic switches. The disrupted bioenergetic milieu increased the uncoupling respiration due to the excess flow of the substrate-derived reducing equivalents and reduced ubiquinones into the respiratory chain. The diversion of the uncoupling proton gradient through adipocyte thermogenesis was then alleviating the damaging effects of free radicals to mitochondria and other organelles. The adaptive induction of white adipose tissues (WAT) to beige adipose tissues (beAT) showed the beneficial effects on glucose oxidation, ROS protection, and mitochondrial function preservation through the uncoupling protein 1 (UCP1)-independent thermogenesis of beAT. However, the maladaptive stage could eventually initiate with the persistent unhealthy lifestyles. Under this metabolic gridlock, the low oxygen and pro-inflammatory environments promoted the adipose breakdown with sequential metabolic dysregulation, including insulin resistance, systemic inflammation, and clinical NCDs progression. There was unlikely that a single intervention could reverse all these complex interactions. The comprehensive protocol that included dietary, nutritional, and all modifiable lifestyle interventions, could be the preferable choice to decelerate, stop, or reverse the NCDs pathophysiologic processes. Keywords: adaptation; adipocytes; diet; lifestyle; maladaptation; mitochondria; nutrients; obesity; thermogenesis.

• Nurchi, Valeria Marina; Djordjevic, Aleksandra Buha; Crisponi, Guido; Alexander, Jan; Bjørklund, Geir & Aaseth, Jan (2020). Arsenic toxicity: Molecular targets and therapeutic agents. Biomolecules. 10(2). doi: 10.3390/biom10020235. Fulltekst i vitenarkiv Vis sammendrag

  High arsenic (As) levels in food and drinking water, or under some occupational conditions, can precipitate chronic toxicity and in some cases cancer. Millions of people are exposed to unacceptable amounts of As through drinking water and food. Highly exposed individuals may develop acute, subacute, or chronic signs of poisoning, characterized by skin lesions, cardiovascular symptoms, and in some cases, multi-organ failure. Inorganic arsenite(III) and organic arsenicals with the general formula R-As2+ are bound tightly to thiol groups, particularly to vicinal dithiols such as dihydrolipoic acid (DHLA), which together with some seleno-enzymes constitute vulnerable targets for the toxic action of As. In addition, R-As2+-compounds have even higher affinity to selenol groups, e.g., in thioredoxin reductase that also possesses a thiol group vicinal to the selenol. Inhibition of this and other ROS scavenging seleno-enzymes explain the oxidative stress associated with arsenic poisoning. The development of chelating agents, such as the dithiols BAL (dimercaptopropanol), DMPS (dimercapto-propanesulfonate) and DMSA (dimercaptosuccinic acid), took advantage of the fact that As had high affinity towards vicinal dithiols. Primary prevention by reducing exposure of the millions of people exposed to unacceptable As levels should be the prioritized strategy. However, in acute and subacute and even some cases with chronic As poisonings chelation treatment with therapeutic dithiols, in particular DMPS appears promising as regards alleviation of symptoms. In acute cases, initial treatment with BAL combined with DMPS should be considered.

• Bjørklund, Geir; Chirumbolo, Salvatore; Dadar, Maryam; Pen, Joeri J.; Dosa, Monica Daniela & Pivina, Lyudmila [Vis alle 8 forfattere av denne artikkelen] (2020). Insights on nutrients as analgesics in chronic pain. Current Medicinal Chemistry. ISSN 0929-8673. 27(37), s. 6407–6423. doi: 10.2174/0929867326666190712172015. Fulltekst i vitenarkiv Vis sammendrag

  Many serious inflammatory disorders and nutrient deficiencies induce chronic pain, and anti-inflammatory diets have been applied successfully to modify the inflammatory symptoms causing chronic pain. Numerous scientific data and clinical investigations have demonstrated that long-term inflammation could lead to an inappropriate or exaggerated sensibility to pain. In addition, some Non-steroidal Anti-inflammatory Drugs (NSAID), which directly act on the many enzymes involved in pain and inflammation, including cyclooxygenases, are used to dampen the algesic signal to the central nervous system, reducing the responses of soft C-fibers to pain stimuli. On the other hand, there are a few reports from both health authorities and physicians, reporting that decreased transmission of pain signals can be achieved and improved, depending on the patient's dietary habit. Many nutrients, as well as a suitable level of exercise (resistance training), are the best methods for improving the total mitochondrial capacity in muscle cells, which can lead to a reduction in sensitivity to pain, particularly by lowering the inflammatory signaling to C-fibers. According to the current literature, it could be proposed that chronic pain results from the changed ratio of neuropeptides, hormones, and poor nutritional status, often related to an underlying inflammatory disorder. The current review also evaluates the effective role of nutrition-related interventions on the severity of chronic pain. This review pointed out that nutritional interventions can have a positive effect on pain experience through the indirect inhibitory effect on prostaglandin E2 and attenuation of mitochondrial dysfunction caused by ischemia/reperfusion in skeletal muscle, improving the intracellular antioxidant defense system. These data highlight the need for more nutrition studies where chronic pain is the primary outcome, using accurate interventions. To date, no nutritional recommendation for chronic pain has been officially proposed. Therefore, the goal of this article is to explore pain management and pain modulation, searching for a mode of nutrition efficient in reducing pain. Keywords: COX-2; Pain; diet; exercises; nutritional supplementation; omega-3.

• Bjørklund, Geir; Dadar, Maryam; Peana, Massimaliano; Rahaman, Md. Shiblur & Aaseth, Jan (2020). Interactions between iron and manganese in neurotoxicity. Archives of Toxicology. ISSN 0340-5761. 94(3), s. 725–734. doi: 10.1007/s00204-020-02652-2. Fulltekst i vitenarkiv Vis sammendrag

  The essential and naturally occurring transition metal manganese (Mn) is present in the soil, water, air, and various foods. Manganese can accumulate in the brain if the Mn intake or exposure is excessive and this can result in neurotoxic effects. Manganese is important for the proper activation of different metabolic and antioxidant enzymes. There are numerous Mn importers and exporters. However, the exact transport mechanism for Mn is not fully understood. On the other hand, iron (Fe) is another well-known essential metal, which has redox activity in addition to chemical characteristics resembling those of Mn. Existing data show that interactions occur between Fe and Mn due to certain similarities regarding their mechanisms of the absorption and the transport. It has been disclosed that Mn-specific transporters, together with Fe transporters, regulate the Mn distribution in the brain and other peripheral tissues. In PC12 cells, a significant increase of transferrin receptor (TfR) mRNA expression was linked to Mn exposure and accompanied by elevated Fe uptake. In both humans and animals, there is a strong relationship between Fe and Mn metabolism. In the present review, special attention is paid to the interaction between Mn and Fe. In particular, Fe and Mn distribution, as well as the potential molecular mechanisms of Mn-induced neurotoxicity in cases of Fe deficiency, are discussed.

• Aaseth, Jan; Buha, Aleksandra; Wallace, David R. & Bjørklund, Geir (2020). Xenobiotics, trace metals and genetics in the pathogenesis of tauopathies. International Journal of Environmental Research and Public Health (IJERPH). ISSN 1661-7827. 17(4). doi: 10.3390/ijerph17041269. Fulltekst i vitenarkiv Vis sammendrag

  Tauopathies are a disease group characterized by either pathological accumulation or release of fragments of hyperphosphorylated tau proteins originating from the central nervous system. The tau hypotheses of Parkinson’s and Alzheimer’s diseases contain a clinically diverse spectrum of tauopathies. Studies of case records of various tauopathies may reveal clinical phenotype characteristics of the disease. In addition, improved understanding of different tauopathies would disclose environmental factors, such as xenobiotics and trace metals, that can precipitate or modify the progression of the disorder. Important for diagnostics and monitoring of these disorders is a further development of adequate biomarkers, including refined neuroimaging, or proteomics. Our goal is to provide an in-depth review of the current literature regarding the pathophysiological roles of tau proteins and the pathogenic factors leading to various tauopathies, with the perspective of future advances in potential therapeutic strategies.

• Aaseth, Jan; Wallace, David R.; Vejrup, Kristine & Alexander, Jan (2020). Methylmercury and developmental neurotoxicity: A global concern. Current Opinion in Toxicology. ISSN 2468-2020. 19, s. 80–87. doi: 10.1016/j.cotox.2020.01.005. Fulltekst i vitenarkiv Vis sammendrag

  Methylmercury (MeHg) is a globally relevant environmentalneurotoxic pollutant. Recent evidence from the Faroe Islandsand Seychelles cohort studies suggest that maternal exposureto MeHg via consumption of contaminated fish and seafoodresults in transplacental exposure of the fetus to MeHg, seri-ously affecting fetal neurodevelopment. In birth cohorts, withmercury exposure below the existing tolerable weekly intake(1.3mg/kg b.w., European Food Safety Authority) MeHgexposure associations to adverse neurodevelopmental effectshave been observed. However, there are inconsistencies be-tween studies, attributing confounding factors as the primarysource of data variability. We summarize current knowledge ofMeHg-mediated effects during nervous system development.Major molecular targets are thiols and selenols and, inparticular, selenoenzymes, resulting in exacerbated oxidativestress–related damage. Generation of reactive oxygen spe-cies (ROS) is an underlying trigger for apoptosis. Low levels ofMeHg can induce apoptotic death in cerebellar neurons, andMeHg can induce endoplasmic reticulum stress, disrupt cal-cium homeostasis, and cause mitochondrial disruption. At acellular level, the effects of MeHg exposure involve thedysfunction of a myriad of neurodevelopment and neuro-behavioral functions.

• Alehagen, Urban; Aaseth, Jan; Alexander, Jan; Brismar, Kerstin & Larsson, Anders (2020). Selenium and coesnzyme q10 supplementation improves renal function in elderly deficient in selenium: Observational results and results from a subgroup analysis of a prospective randomised double-blind placebo-controlled trial. Nutrients. 12(12), s. 1–18. doi: 10.3390/nu12123780. Fulltekst i vitenarkiv Vis sammendrag

  A low selenium intake is found in European countries, and is associated with increased cardiovascular mortality. There is an association between selenium level and the severity of kidney disease. An association between inflammation and selenium intake is also reported. The coenzyme Q10 level is decreased in kidney disease. The aim of this study was to examine a possible association between selenium and renal function in an elderly population low in selenium and coenzyme Q10, and the impact of intervention with selenium and coenzyme Q10 on the renal function. The association between selenium status and creatinine was studied in 589 elderly persons. In 215 of these (mean age 71 years) a randomised double-blind placebo-controlled prospective trial with selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/day) (n = 117) or placebo (n = 98) was conducted. Renal function was determined using measures of glomerular function at the start and after 48 months. The follow-up time was 5.1 years. All individuals were low on selenium (mean 67 μg/L (SD 16.8)). The changes in renal function were evaluated by measurement of creatinine, cystatin-C, and the use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) algorithm, and by the use of T-tests, repeated measures of variance and ANCOVA analyses. An association between low selenium status and impaired renal function was observed. Intervention causes a significantly lower serum creatinine, and cystatin-C concentration in the active treatment group compared with those on placebo (p = 0.0002 and p = 0.001 resp.). The evaluation with CKD-EPI based on both creatinine and cystatin-C showed a corresponding significant difference (p < 0.0001). All validations showed corresponding significant differences. In individuals with a deficiency of selenium and coenzyme Q10, low selenium status is related to impaired renal function, and thus supplementation with selenium and coenzyme Q10 results in significantly improved renal function as seen from creatinine and cystatin-C and through the CKD-EPI algorithm. The explanation could be related to positive effects on inflammation and oxidative stress as a result of the supplementation. Keywords: renal function; micronutrients; supplementation; elderly; cardiovascular mortality; selenium; coenzyme Q10 1. Introduction

• Alexander, Jan; Tinkov, Alexey A.; Strand, Tor A; Alehagen, Urban; Skalny, Anatoly V. & Aaseth, Jan (2020). Early nutritional interventions with zinc, selenium and vitamin D for raising anti-viral resistance against progressive COVID-19. Nutrients. 12(8), s. 1–12. doi: 10.3390/nu12082358. Fulltekst i vitenarkiv Vis sammendrag

  Objectives: The novel coronavirus infection (COVID-19) conveys a serious threat globally to health and economy because of a lack of vaccines and specific treatments. A common factor for conditions that predispose for serious progress is a low-grade inflammation, e.g., as seen in metabolic syndrome, diabetes, and heart failure, to which micronutrient deficiencies may contribute. The aim of the present article was to explore the usefulness of early micronutrient intervention, with focus on zinc, selenium, and vitamin D, to relieve escalation of COVID-19. Methods: We conducted an online search for articles published in the period 2010-2020 on zinc, selenium, and vitamin D, and corona and related virus infections. Results: There were a few studies providing direct evidence on associations between zinc, selenium, and vitamin D, and COVID-19. Adequate supply of zinc, selenium, and vitamin D is essential for resistance to other viral infections, immune function, and reduced inflammation. Hence, it is suggested that nutrition intervention securing an adequate status might protect against the novel coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome - coronavirus-2) and mitigate the course of COVID-19. Conclusion: We recommended initiation of adequate supplementation in high-risk areas and/or soon after the time of suspected infection with SARS-CoV-2. Subjects in high-risk groups should have high priority as regards this nutritive adjuvant therapy, which should be started prior to administration of specific and supportive medical measures. Keywords: COVID-19; coenzyme Q10; corona virus; micronutrients; nutritional; selenium; therapy; vitamin A; vitamin D; zinc.

• Bjørklund, Geir; Peana, Massimaliano; Dadar, Maryam; Chirumbolo, Salvatore; Aaseth, Jan & Martins, Natália (2020). Mercury-induced autoimmunity: Drifting from micro to macro concerns on autoimmune disorders. Clinical Immunology. ISSN 1521-6616. 213:108352, s. 1–7. doi: 10.1016/j.clim.2020.108352. Fulltekst i vitenarkiv Vis sammendrag

  Mercury (Hg) is widely recognized as a neurotoxic metal, besides it can also act as a proinflammatory agent and immunostimulant, depending on individual exposure and susceptibility. Mercury exposure may arise from internal body pathways, such as via dental amalgams, preservatives in drugs and vaccines, and seafood consumption, or even from external pathways, i.e., occupational exposure, environmental pollution, and handling of metallic items and cosmetics containing Hg. In susceptible individuals, chronic low Hg exposure may trigger local and systemic inflammation, even exacerbating the already existing autoimmune response in patients with autoimmunity. Mercury exposure can trigger dysfunction of the autoimmune responses and aggravate immunotoxic effects associated with elevated serum autoantibodies titers. The purpose of the present review is to provide a critical overview of the many issues associated with Hg exposure and autoimmunity. In addition, the paper focuses on individual susceptibility and other health effects of Hg.

• Aaseth, Jan; Nurchi, Valeria Marina & Andersen, Ole (2019). Medical therapy of patients contaminated with radioactive cesium or iodine. Biomolecules. 9:856(12), s. 1–10. doi: 10.3390/biom9120856. Fulltekst i vitenarkiv Vis sammendrag

  Follow-up studies after the Chernobyl and Fukushima accidents have shown that 137Cs and 131I made up the major amount of harmful contaminants in the atmospheric dispersion and fallout. Other potential sources for such radionuclide exposure may be terrorist attacks, e.g., via contamination of drinking water reservoirs. A primary purpose of radionuclide mobilization is to minimize the radiation dose. Rapid initiation of treatment of poisoned patients is imperative after a contaminating event. Internal contamination with radioactive material can expose patients to prolonged radiation, thus leading to short- and long-term clinical consequences. After the patient’s emergency conditions are addressed, the treating physicians and assisting experts should assess the amount of radioactive material that has been internalized. This evaluation should include estimation of the radiation dose that is delivered and the specific radionuclides inside the body. These complex assessments warrant the reliance on a multidisciplinary approach that incorporates regional experts in radiation medicine and emergencies. Regional hospitals should have elaborated strategies for the handling of radiation emergencies. If radioactive cesium is a significant pollutant, Prussian blue is the approved antidote for internal detoxification. Upon risks of radioiodine exposure, prophylactic or immediate treatment with potassium iodide tablets is recommended. Chelators developed from calcium salts have been studied for gastrointestinal trapping and enhanced mobilization after strontium exposure.

• Aaseth, Jan; Roer, Grethe Emilie; Lien, Lars & Bjørklund, Geir (2019). Is there a relationship between PTSD and complicated obesity? A review of the literature. Biomedicine & Pharmacotherapy. ISSN 0753-3322. 117. doi: 10.1016/j.biopha.2019.108834. Fulltekst i vitenarkiv Vis sammendrag

  Recent research strongly supports the hypothesis that posttraumatic stress disorder (PTSD) can be accompanied by obesity and related metabolic disturbances. The mechanisms of these associations are however still not well defined, although disturbed functions in the sympathetic-adrenergic nervous system together with the disturbed release of hormones via the endocrine HPA (hypothalamic-pituitary-adrenal) axis apparently play a role. Leptin resistance and ghrelin excesses might contribute to a disturbed hypothalamic function, and also disturb other cerebral functions, leading to dysfunctional reward signaling and uncontrolled appetite combined with a tendency to alcohol abuse. Secondarily, cortisol stimulation will contribute to the development of central obesity which is known to facilitate the development of metabolic syndrome, including slightly increased levels of inflammatory biomarkers such as C-reactive protein and fibrinogen. While previous therapeutic strategies have focused on early psychotherapeutic interventions in PTSD, the present review emphasizes the importance of better therapeutic approaches regarding the somatic correlates of the syndrome. Strict regulation of dietary meals and food composition with minimal intake of sweets and saturated fat, as well as alcohol avoidance, can provide a basic therapeutic framework. A cognitive psychotherapeutic approach with graduated desensitization toward trigging factors, combined with pharmacotherapy, is discussed in the present review.

• Bjørklund, Geir; Aaseth, Jan; Dadar, Maryam & Chirumbolo, Salvatore (2019). Molecular Targets in Alzheimer’s Disease. Molecular Neurobiology. ISSN 0893-7648. doi: 10.1007/s12035-019-1563-9. Fulltekst i vitenarkiv Vis sammendrag

  Alzheimer’s disease (AD) is known as a devastating neurodegenerative disorder in aged subjects, which is related to multiple heterogeneous genetic factors. The two basic pathological aspects of AD are related to amyloid beta (Aβ) peptides and tau proteins. Some researchers have demonstrated plaques and tangles as apparently primary lesions. Also, experimental data propose that these two lesions are intimately related. In the present review, we highlight some molecular mechanisms linking tau and Aβ toxicities involving oxidative stress, aging, Aβ turnover, the contribution of thiol groups, and the role mitochondrial activities in the AD pathogenesis. Understanding the interplay of these mechanisms as parts of common pathophysiological pathways could reveal molecular targets to control or even treat AD.

• Dehghanifiroozabadi, Mohammad; Noferesti, Parisa; Amirabadizadeh, Alireza; Nakhaee, Samaneh; Aaseth, Jan & Noorbakhsh, Farshid [Vis alle 7 forfattere av denne artikkelen] (2019). Blood lead levels and multiple sclerosis: A case-control study. Multiple Sclerosis and Related Disorders. ISSN 2211-0348. 27, s. 151–155. doi: 10.1016/j.msard.2018.10.010. Fulltekst i vitenarkiv Vis sammendrag

  Background Multiple sclerosis (MS) is a debilitating disease of the central nervous system, with disseminating demyelination of nerve fibers and spinal cord. Exposure to heavy metals seems to be associated with a higher incidence of MS. Few studies have assessed the correlation of the incidence of MS with heavy metal concentrations. The present study aimed to assess the relationship between blood lead levels and MS. Methods This case-control study was conducted on 29 MS patients and 29 healthy control persons. The controls were age, gender and occupation matched at the time of blood sampling. Blood lead levels were measured using the atomic absorption spectrometry method. Data were analyzed using Student t-test, Mann-Whitney U, and multiple logistic regression, using a significance level of p ˂ 0.05. Results According to the result of this study, the mean blood lead level (BLL) was 75.6 ± 9.35and33.8 ± 28.8 µg/L in patients with MS and control group, respectively. Median blood lead levels were significantly higher in MS patients (38 µg/L, range: 27–67), compared to the controls (30 µg/L, range: 11–49) (p = 0.03). The risk of MS increased 1.17 times per one µg/L increment of blood lead level, using the multiple logistic regression analysis on the present results. Conclusion In conclusion, based on our results, BLL was higher in MS patients, compared with healthy individuals. The risk of MS increased 1.17 times per one µg/L increment of blood lead level.

• Bjørklund, Geir; Aaseth, Jan; Crisponi, Guido; Rahman, Md. Mostafizur & Chirumbolo, Salvatore (2019). Insights on alpha lipoic and dihydrolipoic acids as promising scavengers of oxidative stress and possible chelators in mercury toxicology. Journal of Inorganic Biochemistry. ISSN 0162-0134. 195, s. 111–119. doi: 10.1016/j.jinorgbio.2019.03.019. Fulltekst i vitenarkiv Vis sammendrag

  Alpha lipoic acid (α-LA) and its reduced form dihydrolipoic acid (DHLA) have been historically considered as excellent anti-oxidants and oxidative stress scavengers. Upon oxidation with reactive oxygen species (ROS) and pro-oxidants, α-LA may be reconstituted from DHLA and other reduced forms. Oxidative stress is one of the fundamental causes of functional degeneration, autophagy and apoptosis leading to cytotoxicity and loss of cell survival, often due to exposure to xenobiotics, pollutants, heavy metals, and other environmental and endogenous toxicants. α-LA and DHLA can react with these molecules to strengthen the primary antioxidant defense system during cell injury. The compound α-LA is suggested for heavy metal detoxification, in particular for supporting the mercury (Hg) detoxifying process. Mercury is one of the major environmental toxicant, particularly noxious even upon limited exposure. Oxidative stress pathways have been identified as a key upstream event for Hg-induced toxicity in humans and animals. However, very few existing drugs to date can successfully prevent or reduce Hg toxicity. Although several thiol-based chelators, such as British Anti-Lewisite (2,3-dimercaptopropanol, BAL), meso-2,3-dimercaptosuccinic acid (DMSA), and sodium 2,3-dimercapto-1-propanesulfonate (DMPS), have shown promise for ameliorating Hg intoxication. In this review, the potential role of α-LA and DHLA in scavenging toxic metals and other xenobiotics is discussed, focusing especially on the mechanisms of actions of α-LA and DHLA as potential antioxidants towards Hg-induced toxicity.

• Bjørklund, Geir; Pivina, Lyudmila; Dadar, Maryam; Semenova, Yuliya; Chirumbolo, Salvatore & Aaseth, Jan (2019). Long-Term Accumulation of Metals in the Skeleton as Related to Osteoporotic Derangements. Current Medicinal Chemistry. ISSN 0929-8673. doi: 10.2174/0929867326666190722153305. Fulltekst i vitenarkiv Vis sammendrag

  The concentrations of metals in the environment are still not within the recommended limits as set by the regulatory authorities in various countries because of human activities. They can enter the food chain and bioaccumulate in soft and hard tissues/organs, often with a long half-life of the metal in the body. Metal exposure has a negative impact on bone health and may result in osteoporosis and increased fracture risk depending on concentration and duration of metal exposure and metal species. Bones are a long-term repository for lead and some other metals, and may approximately contain 90% of the total body burden in birds and mammals. The present review focuses on the most common metals found in contaminated areas (mercury, cadmium, lead, nickel, chromium, iron, and aluminum) and their effects on bone tissue, considering the possibility of the long-term bone accumulation, and also some differences that might exist between different age groups in the whole population.

• Bjørklund, Geir; Chirumbolo, Salvatore; Dadar, Maryam; Pivina, Lyudmila; Lindh, Ulf & Butnariu, Monica [Vis alle 7 forfattere av denne artikkelen] (2019). Mercury exposure and its effects on fertility and pregnancy outcome. Basic & Clinical Pharmacology & Toxicology. ISSN 1742-7835. 125(4), s. 317–327. doi: 10.1111/bcpt.13264. Fulltekst i vitenarkiv Vis sammendrag

  Mercury (Hg), a highly toxic environmental pollutant, shows harmfulness which still represents a big concern for human health, including hazards to fertility and pregnancy outcome. Research has shown that Hg could induce impairments in the reproductive function, cellular deformation of the Leydig cells and the seminiferous tubules, and testicular degeneration as well as abnormal menstrual cycles. Some studies investigated spontaneous abortion and complicated fertility outcome due to occupational Hg exposure. Moreover, there is a relation between inhaled Hg vapour and reproductive outcome. This MiniReview evaluates the hypothesis that exposure to Hg may increase the risk of reduced fertility, spontaneous abortion and congenital deficits or abnormalities.

• Bjørklund, Geir; Pivina, Lyudmila; Dadar, Maryam; Semenova, Yuliya; Chirumbolo, Salvatore & Aaseth, Jan (2019). Mercury Exposure, Epigenetic Alterations, and Brain Tumorigenesis: A Possible Relationship? Current Medicinal Chemistry. ISSN 0929-8673. 26(1). doi: 10.2174/0929867326666190930150159. Fulltekst i vitenarkiv Vis sammendrag

  The risk assessment of mercury (Hg), in both wildlife and humans, represents an increasing challenge. Increased production of reactive oxygen species (ROS) is a known Hg-induced toxic effect, which can be accentuated by other environmental pollutants and by complex interactions between environmental and genetic factors. Some epidemiological and experimental studies have investigated a possible correlation between brain tumors and heavy metals. Epigenetic modifications in brain tumors include aberrant activation of genes, hypomethylation of specific genes, changes in various histones, and CpG hypermethylation. Also, Hg can decrease the bioavailability of selenium and induce the generation of reactive oxygen that plays important roles in different pathological processes. Modification of homeostasis of metals can induce excess ROS and cause lipid peroxidation, alteration of proteins, and DNA damage. In this review, we highlight the possible relationship between Hg exposure, epigenetic alterations, and brain tumors.

• Alehagen, Urban; Johansson, Peter; Aaseth, Jan; Alexander, Jan; Surowiec, Izabella & Lundstedt-Enkel, Katrin [Vis alle 7 forfattere av denne artikkelen] (2019). Significant changes in metabolic profiles after intervention with selenium and coenzyme q10 in an elderly population. Biomolecules. 9(10). doi: 10.3390/biom9100553. Fulltekst i vitenarkiv Vis sammendrag

  Selenium and coenzyme Q10 (SeQ10) are important for normal cellular function. Low selenium intake leads to increased cardiovascular mortality. Intervention with these substances with healthy elderly persons over a period of four years in a double-blind, randomised placebo-controlled prospective study showed reduced cardiovascular mortality, increased cardiac function, and a lower level of NT-proBNP. Therefore, we wanted to evaluate changes in biochemical pathways as a result of the intervention with SeQ10 using metabolic profiling. From a population of 443 healthy elderly individuals that were given 200 µg selenium and 200 mg coenzyme Q10, or placebo daily for four years, we selected nine males on active intervention and nine males on placebo for metabolic profiling in the main study. To confirm the results, two validation studies (study 1 n = 60 males, study 2 n = 37 males) were conducted. Principal component analyses were used on clinical and demographic data to select representative sets of samples for analysis and to divide the samples into batches for analysis. Gas chromatography time-of-flight mass spectrometry-based metabolomics was applied. The metabolite data were evaluated using univariate and multivariate approaches, mainly T-tests and orthogonal projections to latent structures (OPLS) analyses. Out of 95 identified metabolites, 19 were significantly decreased due to the intervention after 18 months of intervention. Significant changes could be seen in the pentose phosphate, the mevalonate, the beta-oxidation and the xanthine oxidase pathways. The intervention also resulted in changes in the urea cycle, and increases in the levels of the precursors to neurotransmitters of the brain. This adds information to previous published results reporting decreased oxidative stress and inflammation. This is the first-time metabolic profiling has been applied to elucidate the mechanisms behind an intervention with SeQ10. The study is small and should be regarded as hypothesis-generating; however, the results are interesting and, therefore, further research in the area is needed. This study was registered at Clinicaltrials.gov, with the identifier NCT01443780.

• Tinkov, Alexey A.; Skalnaya, Margarita G.; Aaseth, Jan; Ajsuvakova, Olga P.; Aschner, Michael & Skalny, Anatoly V. (2019). Aluminium levels in hair and urine are associated with overweight and obesity in a non-occupationally exposed population. Journal of Trace Elements in Medicine and Biology. ISSN 0946-672X. 56, s. 139–145. doi: 10.1016/j.jtemb.2019.08.005. Fulltekst i vitenarkiv Vis sammendrag

  Background Data on the association between aluminium (Al) exposure and obesity and/or metabolic syndrome are insufficient. The objective of the present study was to investigate the association between hair and urine Al levels and obesity. Methods A total of 206 lean and 205 obese non-occupationally exposed subjects (30–50 y.o.) were enrolled in the study. Hair and urine Al levels were assessed with ICP-MS. Laboratory quality control was performed using the certified reference materials of human hair, plasma, and urine. Results Hair and urinary Al levels in obese subjects were significantly higher by 31% and 46% compared to the control levels, respectively. The presence of hypertension (41% cases), atherosclerosis (8%), type 2 diabetes mellitus (10%), and non-alcoholic fatty liver disease (NAFLD) (53%) in obese patients were not associated with Al levels in the studied subjects. An overall multiple regression model established urinary Al levels (β = 0.395; p < 0.001), hypertension (β = 0.331; p < 0.001) and NAFLD (β = 0.257; p = 0.003) were significantly and directly associated with BMI. Hair Al levels were found to be border-line significantly related to BMI after adjustment for several confounders (β = −0.205; p = 0.054). Conclusions Aluminium body burden is associated with increased body weight, although the causal relationship between Al exposure and obesity is not clear. Both clinical and experimental studies are required to further investigate the impact of Al exposure on metabolic parameters in obesity and especially direct effects of Al in adipose tissue.

• Alehagen, Urban; Alexander, Jan; Aaseth, Jan & Larsson, Anders (2019). Decrease in inflammatory biomarker concentration by intervention with selenium and coenzyme Q10: a subanalysis of osteopontin, osteoprotergerin, TNFr1, TNFr2 and TWEAK. Journal of Inflammation. 16(5), s. 1–9. doi: 10.1186/s12950-019-0210-6. Fulltekst i vitenarkiv Vis sammendrag

  Background Inflammation is central to the pathogenesis of many diseases. Supplementation with selenium and coenzyme Q10 has been shown to reduce cardiovascular mortality, and increase cardiac function in elderly persons with a low intake of selenium. There are indications that one of the mechanisms of this positive effect is a decrease in inflammation. Methods Osteopontin, osteoprotegerin, sTNF receptor 1, sTNF receptor 2 and the tumor necrosis factor-like weak inducer of apoptosis called TWEAK, were determined in plasma after 6 months and 42 months in 219 community-living elderly persons, of whom 119 received supplements of selenium (200 μg/day) and coenzyme Q10 (200 mg/day), and 101 received a placebo. Repeated measures of variance were used to evaluate the levels, and the results were validated through ANCOVA analyses with adjustments for important covariates. Results Significantly lower concentrations of four of the five biomarkers for inflammation were observed as a result of the intervention with the supplements. Only TWEAK did not show significant differences. Conclusion In this sub-analysis of the intervention with selenium and coenzyme Q10 or placebo in an elderly community-living population, biomarkers for inflammation were evaluated. A significantly lower concentration in four of the five biomarkers tested could be demonstrated as a result of the supplementation, indicating a robust effect on the inflammatory system. The decrease in inflammation could be one of the mechanisms behind the positive clinical results on reduced cardiovascular morbidity and mortality reported earlier as a result of the intervention. The study is small and should be regarded as hypothesis-generating, but nonetheless adds important data about mechanisms presently known to increase the risk of clinical effects such as reduced cardiovascular mortality, increased cardiac function and better health-related quality of life scoring, as previously demonstrated in the active treatment group . Trial registration The intervention study was registered at Clinicaltrials.gov, and has the identifier NCT01443780 and registered on 09/30/2011.

• Bjørklund, Geir; Tinkov, Alexey A.; Dadar, Maryam; Rahman, Md Mostafizur; Chirumbolo, Salvatore & Skalny, Anatoly V. [Vis alle 10 forfattere av denne artikkelen] (2019). Insights into the potential role of mercury in Alzheimer's disease. Journal of Molecular Neuroscience. ISSN 0895-8696. 67(4), s. 511–533. doi: 10.1007/s12031-019-01274-3. Fulltekst i vitenarkiv Vis sammendrag

  Mercury (Hg), which is a non-essential element, is considered a highly toxic pollutant for biological systems even when present at trace levels. Elevated Hg exposure with the growing release of atmospheric pollutant Hg and rising accumulations of mono-methylmercury (highly neurotoxic) in seafood products have increased its toxic potential for humans. This review aims to highlight the potential relationship between Hg exposure and Alzheimer’s disease (AD), based on the existing literature in the field. Recent reports have hypothesized that Hg exposure could increase the potential risk of developing AD. Also, AD is known as a complex neurological disorder with increased amounts of both extracellular neuritic plaques and intracellular neurofibrillary tangles, which may also be related to lifestyle and genetic variables. Research reports on AD and relationships between Hg and AD indicate that neurotransmitters such as serotonin, acetylcholine, dopamine, norepinephrine, and glutamate are dysregulated in patients with AD. Many researchers have suggested that AD patients should be evaluated for Hg exposure and toxicity. Some authors suggest further exploration of the Hg concentrations in AD patients. Dysfunctional signaling pathways in AD and Hg exposure appear to be interlinked with some driving factors such as arachidonic acid, homocysteine, dehydroepiandrosterone (DHEA) sulfate, hydrogen peroxide, glucosamine glycans, glutathione, acetyl-L carnitine, melatonin, and HDL. This evidence suggests the need for a better understanding of the relationship between AD and Hg exposure, and potential mechanisms underlying the effects of Hg exposure on regional brain functions. Also, further studies evaluating brain functions are needed to explore the long-term effects of subclinical and untreated Hg toxicity on the brain function of AD patients.

• Bjørklund, Geir; Dadar, Maryam; Chirumbolo, Salvatore & Aaseth, Jan (2019). The role of xenobiotics and trace metals in Parkinson's disease. Molecular Neurobiology. ISSN 0893-7648. s. 1–13. doi: 10.1007/s12035-019-01832-1. Fulltekst i vitenarkiv Vis sammendrag

  Research on the etiopathogenesis of Parkinson’s disease (PD) has in the very recent years earned many insightful cues about the involvement of xenobiotics and metal pollutants in the onset and exacerbation of this neurodegenerative disorder. Furthermore, particularly for metal pollutants, the hypothesis about the role exerted by impaired mitochondrial function is gaining a leading causative role. In this review, we outline the role of environmental pollution in the pathogenesis of PD, as the prolonged exposure to xenobiotics may account for the majority of PD reported cases, expanding the debate also about some suggested therapeutic approaches.

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• Aaseth, Jan & Roer, Grethe Emilie (2024). Slank og friskere uten sukker. Indiemoon. ISBN 9788294111145. 122 s. Fulltekst i vitenarkiv

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• Aaseth, Jan; Rootwelt, Helge; Retterstøl, Kjetil; Hestad, Knut & Farup, Per Grønaas (2022). Reply to Paredes et al. Comment on “Aaseth et al. Circulating Lipoproteins in Subjects with Morbid Obesity Undergoing Bariatric Surgery with Gastric Bypass or Sleeve Gastrectomy. Nutrients 2022, 14, 2381”. Nutrients. 15(1). doi: 10.3390/nu15010053. Fulltekst i vitenarkiv
• Roer, Grethe Emilie; Lien, Lars; Bolstad, Ingeborg; Aaseth, Jan & Abebe, Dawit Shawel (2022). The impact of PTSD on risk of cardiometabolic diseases and the moderating effect of socioeconomic status, alcohol use disorder and depression: A National Patient Cohort study in Norway. Fulltekst i vitenarkiv
• Aaseth, Jan Olav; Rootwelt, Helge; Retterstøl, Kjetil; Hestad, Knut & Farup, Per Grønaas (2022). Reply to Paredes et al. Comment on "Aaseth et al. Circulating Lipoproteins in Subjects with Morbid Obesity Undergoing Bariatric Surgery with Gastric Bypass or Sleeve Gastrectomy. Nutrients 2022, 14, 2381". Nutrients. 15(1). doi: 10.3390/nu15010053. Fulltekst i vitenarkiv Vis sammendrag

  Hereby, we thank Silvia Paredes et al. [...].

• Aaseth, Jan (2022). Toxic and Essential Metals in Human Health and Disease 2021. Biomolecules. 12(10). doi: 10.3390/biom12101375. Fulltekst i vitenarkiv
• Skalny, Anatoly V.; Lima, Thania Rios Rossi; Ke, Tao; Zhou, Ji-Chang; Bornhorst, Julia & Alekseenko, Svetlana I. [Vis alle 12 forfattere av denne artikkelen] (2021). Corrigendum to “Toxic metal exposure as a possible risk factor for COVID-19 and other respiratory infectious diseases” [Food Chem. Toxicol. 146 111809]. Food and Chemical Toxicology (FCT). ISSN 0278-6915. 149. doi: 10.1016/j.fct.2021.111999. Fulltekst i vitenarkiv
• Bernhoft, Aksel; Falk, Michaela; Aaseth, Jan & Alexander, Jan (2020). Riktig kosthold kan være viktig mot koronaviruset. Harvest Magazine. Fulltekst i vitenarkiv
• Bjørklund, Geir; Aaseth, Jan; Dadar, Maryam; Butnariu, Monica & Chirumbolo, Salvatore (2019). Exposure to Environmental Organic Mercury and Impairments in Human Fertility. Journal of Reproduction & Infertility (JRI). ISSN 2228-5482. Fulltekst i vitenarkiv
• Alexander, Jan; Alehagen, Urban; Larsson, Anders & Aaseth, Jan (2019). Selenium in clinical medicine and medical biochemistry. Klinisk Biokemi i Norden. ISSN 1101-2013. 31(3), s. 12–19. Fulltekst i vitenarkiv

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