Mechanistic Insights into Ferroptotic Cell Death in Pancreatic Islets.

Ferroptosis was recently identified as a non-apoptotic, iron-dependent cell death mechanism that is involved in various pathologic conditions. There is first evidence for its significance also in the context of islet isolation and transplantation. Transplantation of pancreatic human islets is a viable treatment strategy for patients with complicated diabetes mellitus type 1 (T1D) that suffer from severe hypoglycemia. A major determinant for functional outcome is the initial islet mass transplanted. Efficient islet isolation procedures and measures to minimize islet loss are therefore of high relevance. To this end, better understanding and subsequent targeted inhibition of cell death during islet isolation and transplantation is an effective approach. In this study, we aimed to elucidate the mechanism of ferroptosis in pancreatic islets. Using a rodent model, isolated islets were characterized relating to the effects of experimental induction (RSL3) and inhibition (Fer1) of ferroptotic pathways. Besides viability, survival, and function, the study focused on characteristic ferroptosis-associated intracellular changes such as MDA level, iron concentration and the expression of ACSL4. The study demonstrates that pharmaceutical induction of ferroptosis by RSL3 causes enhancement of oxidative stress and leads to an increase of intracellular iron, zinc and MDA concentration, as well as the expression of ACSL4 protein. Consequently, a massive reduction of islet function, viability, and survival was found. Fer1 has the potential to inhibit and attenuate these cellular changes and thereby protect the islets from cell death.

Glutathione and the intracellular labile heme pool.

One candidate for the cytosolic labile iron pool is iron(II)glutathione. There is also a widely held opinion that an equivalent cytosolic labile heme pool exists and that this pool is important for the intracellular transfer of heme. Here we describe a study designed to characterise conjugates that form between heme and glutathione. In contrast to hydrated iron(II), heme reacts with glutathione, under aerobic conditions, to form the stable hematin-glutathione complex, which contains iron(III). Thus, glutathione is clearly not the cytosolic ligand for heme, indeed we demonstrate that the rate of heme degradation is enhanced in the presence of glutathione. We suggest that the concentration of heme in the cytosol is extremely low and that intracellular heme transfer occurs via intracellular membrane structures. Should any heme inadvertently escape into the cytosol, it would be rapidly conjugated to glutathione thereby protecting the cell from the toxic effects of heme.

The Role of GSH in Intracellular Iron Trafficking.

Evidence is reviewed for the role of glutathione in providing a ligand for the cytosolic iron pool. The possibility of histidine and carnosine forming ternary complexes with iron(II)glutathione is discussed and the physiological significance of these interactions considered. The role of carnosine in muscle, brain, and kidney physiology is far from established and evidence is presented that the iron(II)-binding capability of carnosine relates to this role.

Association between vegetarian and vegan diets and depression: A systematic review.

Recent evidence suggests that vegetarian and vegan diets may increase the risk and symptoms of depression, a mental health condition affecting 350 million people globally. We aimed to systematically review the literature on the associations between vegetarian and/or vegan diets and the risk or symptoms of depression using evidence from both observational and intervention studies. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, with pre-specification of all methods. A systematic search for relevant papers was performed on Medline and Embase, Web of Science and the Cochrane Library for cohort, case-control, cross-sectional studies or randomised controlled trials examining associations between a vegetarian or vegan diet and depression in adults. Three independent reviewers extracted data and assessed risk of bias using the National Heart, Lung, and Blood Institute of the National Institutes of Health for Quality Assessment of Observational Cohort and Cross-Sectional Studies and Controlled Studies. Evidence was tabulated according to the type of diet analysed as vegetarian, vegan or both and narratively synthesised. A total of 23 studies (18 cross-sectional, three prospective cohort and two randomised controlled trials) with 25 study outcomes were eligible for inclusion in this review. Conflicting evidence was found on the association between vegetarian or vegan diets and depression. Eleven (44%) of the outcomes indicated that vegetarian and vegan diets were associated with higher rates of depression, while seven (28%) outcomes revealed beneficial effects of the diets on depression. Seven (28%) outcomes found no association between vegetarian and vegan diets and depression, although two of these studies found a higher risk of depression in some groups. The quality of evidence was rated as good for four of the studies with the remaining 19 studies rated as fair. The evidence on the effect of vegetarian and vegan diets on depression is contradictory, possibly due to the heterogeneity of the studies analysed. Further research, including longitudinal and intervention studies, is required to resolve this observation.

Association of Serum Hepcidin Levels with Aerobic and Resistance Exercise: A Systematic Review.

BACKGROUND: Prevalence of iron deficiency is commonly reported among athletic population groups. It impairs physical performance due to insufficient oxygen delivery to target organs and low energy production. This is due to the high demand of exercise on oxygen delivery for systemic metabolism by the erythrocytes in the blood. Hepcidin, the key regulator of iron homeostasis, decreases to facilitate iron efflux into the circulation during enhanced erythropoiesis. However, acute anaemia of exercise is caused by increased hepcidin expression that is induced by stress and inflammatory signal. The study aimed to systematically review changes in serum hepcidin levels during resistance and aerobic exercise programmes. METHODS: A systemic literature search from 2010 to April 2020 across seven databases comprised of Cochrane library, PubMed, Web of Science, Scopus, Embase, MEDLINE, and OpenGrey. The primary outcome was increased or decreased serum hepcidin from baseline after the exercise activity. Risks of bias were evaluated by using the National Institutes of Health (NIH) for quality assessment of before and after different exercise programmes. RESULTS: Overall, twenty-three studies met the inclusion criteria. Out of the 23 studies, 16 studies reported significantly exercise-induced serum hepcidin elevation. Of the 17 studies that evaluated serum interleukin (IL)-6 levels, 14 studies showed significant exercise-induced serum IL-6 elevation. Changes in exercise-induced serum hepcidin and IL-6 levels were similar in both resistance and endurance exercise. Significant correlations were observed between post-exercise hepcidin and baseline ferritin levels (r = 0.69, p < 0.05) and between post-exercise hepcidin and post-exercise IL-6 (r = 0.625, p < 0.05). CONCLUSION: Resistance and endurance training showed significant increase in serum hepcidin and IL-6 levels in response to exercise. Baseline ferritin and post-exercise IL-6 elevation are key determining factors in the augmentation of hepcidin response to exercise.

Brain iron concentrations in the pathophysiology of children with attention deficit/hyperactivity disorder: a systematic review.

CONTEXT: Attention deficit/hyperactivity disorder (ADHD) is a neurological disorder associated with iron dysregulation in children. Although previous focus was on examining systemic iron status, brain iron content may be a more reliable biomarker of the disorder. OBJECTIVE: This systematic review examines whether children with ADHD have lower serum as well as brain iron concentrations, compared with healthy control subjects (HCS). DATA SOURCES: A systematic literature search was conducted in Medline via PubMed, the Cochrane Library, Web of Science, Embase. and Ovid for papers published between 2000 and June 7, 2019. DATA EXTRACTION: Studies were included if the mean difference of iron concentration, measured as serum iron, serum ferritin, or brain iron, between children with ADHD and HCS was an outcome measure. DATA ANALYSIS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Risks of bias within and between studies were assessed using the quality assessment tools of the National Institutes of Health. Of 599 records screened, 20 case-control studies met the inclusion criteria. In 10 of 18 studies in which serum ferritin concentration was assessed, and 2 of 10 studies that assessed serum iron, a significant difference between children with ADHD and HCS was observed. Results of systemic iron levels were inconsistent. In 3 studies in which brain iron concentration was assessed, a statistically significant, lower thalamic iron concentration was found in children with ADHD than in HCS. CONCLUSION: The evidence, though limited, reveals that brain iron rather than systemic iron levels may be more associated with the pathophysiology of ADHD in children. Larger, longitudinal, magnetic resonance imaging studies are needed to examine any correlations of iron deficiency in specific brain regions and symptoms of ADHD.