Iron is a critical metal for several vital biological processes. Most of the body’s iron is bound to hemoglobin in erythrocytes. Iron from senescent red blood cells is recycled by macrophages in the spleen, liver and bone marrow. Dietary iron is taken up by the divalent metal transporter 1 (DMT1) in enterocytes and transported to portal blood via ferroportin (FPN), where it is bound to transferrin and taken up by hepatocytes, macrophages and bone marrow cells via transferrin receptor 1 (TfR1). While most of the physiologically active iron is bound hemoglobin, the major storage of most iron occurs in the liver in a ferritin-bound fashion. In response to an increased iron load, hepatocytes secrete the peptide hormone hepcidin, which binds to and induces internalization and degradation of the iron transporter FPN, thus controlling the amount of iron released from the cells into the blood. This review summarizes the key mechanisms and players involved in cellular and systemic iron regulation.

AimsThe deacetylase sirtuin 1 (Sirt1) exerts beneficial effects on lipid metabolism, but its roles in plasma LDL-cholesterol regulation and atherosclerosis are controversial. Thus, we applied the pharmacological Sirt1 activator SRT3025 in a mouse model of atherosclerosis and in hepatocyte culture.Methods and resultsApolipoprotein E-deficient (Apoe−/−) mice were fed a high-cholesterol diet (1.25% w/w) supplemented with SRT3025 (3.18 g kg−1 diet) for 12 weeks. In vitro, the drug activated wild-type Sirt1 protein, but not the activation-resistant Sirt1 mutant; in vivo, it increased deacetylation of hepatic p65 and skeletal muscle Foxo1. SRT3025 treatment decreased plasma levels of LDL-cholesterol and total cholesterol and reduced atherosclerosis. Drug treatment did not change mRNA expression of hepatic LDL receptor (Ldlr) and proprotein convertase subtilisin/kexin type 9 (Pcsk9), but increased their protein expression indicating post-translational effects. Consistent with hepatocyte Ldlr and Pcsk9 accumulation, we found reduced plasma levels of Pcsk9 after pharmacological Sirt1 activation. In vitro administration of SRT3025 to cultured AML12 hepatocytes attenuated Pcsk9 secretion and its binding to Ldlr, thereby reducing Pcsk9-mediated Ldlr degradation and increasing Ldlr expression and LDL uptake. Co-administration of exogenous Pcsk9 with SRT3025 blunted these effects. Sirt1 activation with SRT3025 in Ldlr−/− mice reduced neither plasma Pcsk9, nor LDL-cholesterol levels, nor atherosclerosis.ConclusionWe identify reduction in Pcsk9 secretion as a novel effect of Sirt1 activity and uncover Ldlr as a prerequisite for Sirt1-mediated atheroprotection in mice. Pharmacological activation of Sirt1 appears promising to be tested in patients for its effects on plasma Pcsk9, LDL-cholesterol, and atherosclerosis.

Our data demonstrated lithium-mimetic effects of ebselen in different experimental models of 5-HT receptor function, probably mediated by IMPase inhibition. This evidence of lithium-like neuropharmacological effects of ebselen adds further support for the clinical testing of ebselen in mood disorders, including as an antidepressant augmenting agent.

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Objective To provide an assessment of the quality of the most frequently used self-reported, generic patient-reported outcome measures (PROMs) that measure health-related quality of life (HRQoL) in children against the good research practices recommended by ISPOR task force for the pediatric population. Method Literature search was conducted on OvidSP database to identify the generic pediatric PROMs used in published clinical studies. The quality of PROMs used in more than ten clinical studies were descriptively evaluated against the ISPOR task force’s good research practices. Results Six PROMs were evaluated, namely Pediatric Quality-of-Life inventory 4.0 (PedsQL), Child Health Questionnaire (CHQ), KIDSCREEN, KINDL, DISABKIDS and Child Health and Illness Profile (CHIP). All PROMs, except KIDSCREEN, had versions for different age ranges. Domains of physical, social, emotional health and school activities were common across all the instruments, while domains of family activities, parent relations, independence, and self-esteem were not present in all. Children’s input was sought during the development process of PROMs. Likert scales were used in all the instruments, supplemented with faces (smileys) in instruments for children under 8 years. KIDSCREEN and DISABKIDS were developed in a European collaboration project considering the cross-cultural impact during development. Conclusion The comparison of the instruments highlights differences in the versions for different pediatric age groups. None of the PROMs fulfill all the good research practices recommended by the ISPOR task force. Further research is needed to define which age-appropriate domains are important for older children and adolescents.