Showing papers by "Isabella Zanella published in 2016"

Iron and Neurodegeneration: Is Ferritinophagy the Link?

Abstract: Mounting evidence indicates that the lysosome-autophagy pathway plays a critical role in iron release from ferritin, the main iron storage cellular protein, hence in the distribution of iron to the cells. The recent identification of nuclear receptor co-activator 4 as the receptor for ferritin delivery to selective autophagy sheds further light on the understanding of the mechanisms underlying this pathway. The emerging view is that iron release from ferritin through the lysosomes is a general mechanism in normal and tumour cells of different tissue origins, but it has not yet been investigated in brain cells. Defects in the lysosome-autophagy pathway are often involved in the pathogenesis of neurodegenerative disorders, and brain iron homeostasis disruption is a hallmark of many of these diseases. However, in most cases, it has not been established whether iron dysregulation is directly involved in the pathogenesis of the diseases or if it is a secondary effect derived from other pathogenic mechanisms. The recent evidence of the crucial involvement of autophagy in cellular iron handling offers new perspectives about the role of iron in neurodegeneration, suggesting that autophagy dysregulation could cause iron dyshomeostasis. In this review, we recapitulate our current knowledge on the routes through which iron is released from ferritin, focusing on the most recent advances. We summarise the current evidence concerning lysosome-autophagy pathway dysfunctions and those of iron metabolism and discuss their potential interconnections in several neurodegenerative disorders, such as Alzheimer’s, Parkinson’s and Huntington’s diseases; amyotrophic lateral sclerosis; and frontotemporal lobar dementia.

Iron in Frontotemporal Lobar Degeneration: A New Subcortical Pathological Pathway?

Abstract: Introduction: Brain iron homeostasis dysregulation has been widely related to neurodegeneration. In particular, human haemochromatosis protein (HFE) is involved i

The strange case of the [13N]NH3: validation of the production process for human use.

Abstract: OBJECTIVE PET radiopharmaceuticals are often injected in patients before all quality controls are performed and before sterility results are available. We propose a process validation to produce very safe and pure [N]NH3 for human use. METHODS [N]NH3 was produced in the cyclotron target. Online purification was performed by anionic exchange resin. All the production steps were subjected to a sterility test. Some additional controls were added to those required by the monograph. RESULTS The radiochemical yield of the syntheses was 26.3 and 61.5% corrected for decay, with a radiochemical purity of 100%. In addition to quality controls requested by the European Pharmacopeia monograph, we carefully analyzed the product for the presence of possible contaminants. Some elements, mainly metals, were found in very low amounts at concentrations in the range of ppb. The radionuclidic purity was verified. The achievement of the parameters of osmolality, by addition of saline solution to the preparation, made the analysis of chemical purity difficult and worsened the measurement of radiochemical purity by high performance liquid chromatography. Only pH control is necessary before administration to patients and therefore a safe production process was set up to prevent microbiological contamination. All phases were carefully standardized, starting from in-target production of [N]NH3, to final splitting in the syringes. Sterility tests showed no bacterial growth, indicating the safety of the production process. CONCLUSION All our syntheses followed the monograph indications and were optimal to obtain PET imaging of a patient's myocardium.

Could 18F-FDG PET Be a Diagnostic Tool for Hemochromatosis?

Abstract: H ereditary hemochromatosis (HH) is a genetically determined disorder characterized by iron overload. The patients present elevated serum ferritin, high serum iron, and transferrin saturation greater than 45%. If untreated, the pathology evolves to diabetes, heart failure, arthritis, bronze pigmentation of the skin, and liver cirrhosis, which could degenerate in hepatocellular carcinoma. Hereditary hemochromatosis was described in 4 typologies more than 10 years ago. Type 1 is characterized by mutations in the HFE gene and is the most common genetic disorder with mild severity. The classical variations, which constitute the more frequent genetic background, are either the homozygous mutation p.C282Y or the compound heterozygous mutations C282Y/H63D. Type 2 is the more severe form of the disorder with the onset in the first to third decade of life and is defined as juvenile hemochromatosis. It is characterized by rare mutations in the HAMP (type 2A) or in the HJV (type 2B) genes. Type 3 has early onset and an intermediate severity and is related to rare mutations in the TFR2 gene. Type IV is also named ferroportin disease because it has some peculiarities in clinical manifestations and is determined by rare mutations in the SLC40A1 gene. The penetrance of the more common HH form (type 1) is incomplete among individuals with genetic predisposition, and variability in the severity of clinical manifestations is often described. Furthermore, not all hemochromatosis cases are classifiable as described above or are explained by mutations in the mentioned genes. The studies of the HH molecular mechanisms mainly demonstrated the deregulation of the systemic expression of hepcidin or the lack of effect on its receptor ferroportin. The variability of clinical manifestations, which were the object of numerous studies in the past decade, is likely explained by both environmental and genetic factors. F-FDG PET is a diagnostic imaging applied in oncology, cardiology, and neurology. The liver and brain have elevated glucose metabolism, and therefore both these organs are characterized by physiologically high F-FDG uptake. Inflammation is a pathological condition that augments