• Chick embryo egg
• Iron
• Pathway
• Regulating gene
• Yolk sac membrane

• Animals
• Iron/metabolism
• Chick Embryo/metabolism
• Transcriptome
• Egg Yolk/metabolism
• Chickens/genetics
• Chickens/metabolism
• Biological Transport
• Avian Proteins/metabolism
• Avian Proteins/genetics
• Gene Expression Profiling/veterinary
• Yolk Sac/metabolism

• Humans
• Diabetes Mellitus, Type 2/complications
• Diabetes Mellitus, Type 2/metabolism
• Diabetes Mellitus, Type 2/blood
• Male
• Female
• Middle Aged
• Iron Overload/complications
• Iron Overload/blood
• Iron Overload/diagnostic imaging
• Hepcidins/blood
• Ferritins/blood
• Biomarkers/blood
• Iron/blood
• Iron/metabolism
• Magnetic Resonance Imaging
• Aged
• Fatty Liver/complications
• Fatty Liver/blood
• China
• Adult
• Liver/metabolism

• 2023RC234 Medical Science and Technology Project of Zhejiang Province
• Medical Science and Technology Project of Zhejiang Province

• Fet3
• Ftr1
• ceruloplasmin
• copper
• ferroportin
• ferroxidase
• hephaestin
• iron
• multicopper oxidase
• yeast

• Ceruloplasmin/metabolism
• Ceruloplasmin/chemistry
• Humans
• Iron/metabolism
• Biological Transport
• Membrane Transport Proteins/metabolism
• Membrane Transport Proteins/chemistry
• Cell Membrane/metabolism
• Animals
• Saccharomyces cerevisiae/metabolism
• Yeasts/metabolism

• Project ECS 0000024 Rome Technopole-NRP Mission 4 Component 2 Investment 1.5
• the European Union-NextGenerationEU
• art. 1, comma 314-337 Legge 232/2016 the Grant Departments of Excellence

• colorectal cancer
• intestinal microbiota
• iron metabolism

• Humans
• Iron/metabolism
• Tumor Microenvironment
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Animals
• Neovascularization, Pathologic/metabolism

• PNRR-MAD-2022-12376791 Ministero della Salute

• Ferroptosis
• HCC
• Iron homeostasis
• Liver fibrosis
• NAFLD
• NASH

• Humans
• Non-alcoholic Fatty Liver Disease/metabolism
• Homeostasis/physiology
• Iron/metabolism
• Ferroptosis/physiology
• Animals

• calcium
• ferroportin
• inflammation
• interleukin 6 (IL-6)
• iron metabolism
• membrane trafficking
• metal homeostasis

• Cation Transport Proteins/metabolism
• Cation Transport Proteins/genetics
• Humans
• Interleukin-6/metabolism
• Interleukin-6/genetics
• Iron/metabolism
• Cell Membrane/metabolism
• Calcium/metabolism
• HEK293 Cells
• Protein Transport
• Animals
• Endothelial Cells/metabolism
• Hepcidins/metabolism
• Hepcidins/genetics
• Ferroportin

• R01 NS102337 NINDS NIH HHS
• R03 NS095063 NINDS NIH HHS

• divalent metal transporter 1 (DMT1)
• ferroportin
• hepcidin
• iron
• oxidative stress

• Fenton reaction
• Fenton-like reaction
• hydroxyl radical
• iron hydroxide
• iron metabolism

• Hydroxyl Radical/chemistry
• Hydrogen Peroxide
• Iron/chemistry
• Hydroxides
• Oxidation-Reduction
• Carrier Proteins

• iron metabolism
• membrane proteins
• structural biology
• transport

• Ceruloplasmin
• Copper
• Ferroxidase
• Hephaestin
• Iron
• Zyklopen

• Animals
• Mice
• Copper/metabolism
• Ceruloplasmin/metabolism
• Mice, Knockout
• Oxidation-Reduction
• Biology
• Mammals/metabolism

• R01 DK074867 NIDDK NIH HHS
• R01 DK109717 NIDDK NIH HHS

• Ferroptosis
• P-glycoprotein
• Refractory epilepsy
• SLC7A11.
• SUDEP

• Iron
• antioxidant enzymes
• chelator agents
• deferasirox
• deferoxamine
• poisoning

• Humans
• Iron/metabolism
• Iron Chelating Agents
• Deferasirox
• Deferiprone
• Deferoxamine
• Reactive Oxygen Species
• Superoxides
• Hydrogen Peroxide
• Pyridones
• Benzoates/therapeutic use
• Triazoles
• DNA

Ferroptosis is a non-necrotic form of regulated cell death (RCD) that is primarily characterized by iron-dependent membrane lipid peroxidation and is regulated by cysteine transport, glutathione synthesis, and glutathione peroxidase 4 function as well as other proteins including ferroptosis suppressor protein 1. It has been found that ferroptosis played an important role in many diseases, such as neurodegenerative diseases and ischemia-reperfusion injury. Spinal cord injury (SCI), especially traumatic SCI, is an urgent problem worldwide due to its high morbidity and mortality, as well as the destruction of functions of the human body. Various RCDs, including ferroptosis, are found in SCI. Different from necrosis, since RCD is a form of cell death regulated by various molecular mechanisms in cells, the study of the role played by RCD in SCI will contribute to a deeper understanding of the pathophysiological process, as well as the treatment and functional recovery. The present review mainly introduces the main mechanism of ferroptosis and its role in SCI, so as to provide a new idea for further exploration.

• ferroptosis
• iron homeostasis
• lipid peroxidation
• regulated cell death
• spinal cord injury

• ceruloplasmin
• ceruloplasmin–transferrin interaction
• iron
• transferrin
• zinc
• zinc-bound ceruloplasmin

• hyperoxia
• osteoblast iron-regulated transporter gene
• osteoblast transferrin receptor gene

• Humans
• Hyperoxia/genetics
• Iron/metabolism
• Osteoblasts
• RNA, Messenger/genetics
• Real-Time Polymerase Chain Reaction
• Receptors, Transferrin/genetics
• Transcription Factors

Giant cell hepatitis in the adult population remains very poorly defined with only 100 case reports published in the literature over the last three decades.

To present our center’s experience in an attempt to learn about the predisposing factors, outcomes and efficacy of proposed therapeutic interventions for giant cell hepatitis.

A retrospective chart review was conducted through the electronic records of the University of Pittsburgh Medical Center. We queried 36726 liver biopsy reports from January 1, 1991 to December 6, 2016. Our search yielded 50 patients who were identified as carrying a definite diagnosis of post-infantile giant cell hepatitis (PIGCH) by pathology. The data collected included demographic information, laboratory data (liver function tests, autoimmune markers) and transplant status. In order to better analyze patient characteristics and outcomes, subjects were separated into a non-transplant (native) liver group and a post-liver transplant (allograft) group.

The incidence of PIGCH was approximately 0.14% of all biopsies queried in the 25-year period. The mean age was 48 years with 66% females. Liver function tests were classified as 38.2% cholestatic, 35.3% hepatocellular and 26.5% mixed. Autoimmune hepatitis was found to be the most prevalent predisposing factor leading to PIGCH constituting 32% of cases. Management consisted mainly of immunosuppression, viral targeted therapy, supportive care and in six cases liver transplantations.

The diagnosis of PIGCH remains clinically challenging and requires a high index of suspicion as well as a thorough history, physical examination, serological workup and liver biopsy. Treatment of the underlying cause can result in clinical stability in a large number of cases.

• Post-infantile giant cell hepatitis
• Liver transplantation
• Autoimmune hepatitis

• Animals
• Biological Transport
• Chromatography
• Female
• Ferritins/blood
• Iron/blood
• Iron/metabolism
• Iron Deficiencies
• Kinetics
• Liver/metabolism
• Molecular Weight
• Phosphorus/blood
• Portal Vein/metabolism
• Reference Standards
• Swine/blood
• Transferrin/metabolism

• R35 GM127021 NIGMS NIH HHS

• pigs
• potato fibre
• trace elements
• zinc glycine chelate
• zinc transporters

• Hepcidin
• iron
• ischemia-reperfusion
• kidney
• sepsis

• amyloid precursor protein (APP)
• ferroportin
• fluorescence resonance energy transfer (FRET)
• hephaestin
• iron efflux
• iron metabolism
• membrane transport
• metal homeostasis

Macrophages are sentinel cells of the innate immune system and have important functions in development, tissue homeostasis, and immunity. These phylogenetically ancient cells also developed a variety of mechanisms to control erythropoiesis and the handling of iron. Red pulp macrophages in the spleen, Kupffer cells in the liver, and central nurse macrophages in the bone marrow ensure a coordinated metabolism of iron to support erythropoiesis. Phagocytosis of senescent red blood cells by macrophages in the spleen and the liver provide a continuous delivery of recycled iron under steady-state conditions and during anemic stress. Central nurse macrophages in the bone marrow utilize this iron and provide a cellular scaffold and niche to promote differentiation of erythroblasts. This review focuses on the role of the distinct macrophage populations that contribute to efficient iron metabolism and highlight important cellular and systemic mechanisms involved in iron-regulating processes.

• Kupffer cell
• central nurse macrophage
• erythroblastic islands
• erythrophagocytosis
• erythropoiesis
• inflammation
• iron metabolism
• macrophage
• red pulp macrophage

• P 27701 Austrian Science Fund FWF
• P 30857 Austrian Science Fund FWF

Iron overload is a hallmark of many neurodegenerative processes such as Alzheimer's, Parkinson's, and Huntington's diseases. Unbound iron accumulated as a consequence of brain aging is highly reactive with water and oxygen and produces reactive oxygen species (ROS) or free radicals. ROS are toxic compounds able to damage cell membranes, DNA, and mitochondria. Which are the mechanisms involved in neuronal iron homeostasis and in neuronal response to iron-induced oxidative stress constitutes a cutting-edge topic in metalloneurobiology. Increasing our knowledge about the underlying mechanisms that operate in iron accumulation and their consequences would shed light on the comprehension of the molecular events that participate in the pathophysiology of the abovementioned neurodegenerative diseases. In this review, current evidences about iron accumulation in the brain, the signaling mechanisms triggered by metal overload, as well as the interaction between amyloid β (Aβ) and iron, will be summarized.

Iron transport across the intestinal epithelium is facilitated by the divalent metal transporter 1 (DMT1) on the brush border membrane (BBM). The fluorescent metal sensor calcein, which is hydrophilic, membrane-impermeable and quenched by chelation with iron, was used to test our hypothesis that intestinal iron absorption is through the endocytic processes and is involved in a pathway where BBM-derived vesicles fuse with basolateral membrane (BLM)-derived vesicles. To monitor the flux of iron via transcytosis, Caco-2 cells were employed as a polarized cell layer in Transwell chambers. When calcein was added to the basal chamber along with apo-transferrin (apo-Tf), calcein rapidly underwent endocytosis and co-localized with apo-Tf. Calcein was quenched by adding an iron-ascorbate complex and then restored by adding 2,2'-dipyridyl into the apical chamber. These results were confirmed by live-cell imaging. When hemin from the apical surface and calcein from the basal chamber were added to the Caco-2 cells, internalization of DMT1 and quenching of calcein were not observed until 2 h later. These results indicated that absorbed hemin required processing before hemin-derived iron was available to BLM-derived vesicles. These studies suggest that iron is transported in Caco-2 cells by transcytosis with apical-derived vesicles that are fused to BLM-derived vesicles.

• Caco-2
• calcein
• hemin
• iron absorption
• iron transport

In vertebrates, there is an intimate relationship between copper and iron homeostasis. Copper deficiency, which leads to a defect in ceruloplasmin enzymatic activity, has a strong effect on iron homeostasis resulting in cellular iron retention. Much is known about the mechanisms underlying cellular iron retention under “normal” conditions, however, less is known about the effect of copper deficiency during inflammation.

We show that copper deficiency and the inflammatory cytokine interleukin-6 have different effects on the expression of proteins involved in iron and copper metabolism such as the soluble and glycosylphosphtidylinositol anchored forms of ceruloplasmin, hepcidin, ferroportin1, transferrin receptor1, divalent metal transporter1 and H-ferritin subunit. We demonstrate, using the human HepG2 cell line, that in addition to ceruloplasmin isoforms, copper deficiency affects other proteins, some posttranslationally and some at the transcriptional level. The addition of interleukin-6, moreover, has different effects on expression of ferroportin1 and ceruloplasmin, in which ferroportin1 is decreased while ceruloplasmin is increased. These effects are stronger when a copper chelating agent and IL-6 are used simultaneously.

These results suggest that copper chelation has effects not only on ceruloplasmin but also on other proteins involved in iron metabolism, sometimes at the mRNA level and, in inflammatory conditions, the functions of ferroportin and ceruloplasmin may be independent.

• Ceruloplasmin
• Copper deficiency
• Inflammation
• Iron metabolism

Iron is an essential element for human development. It is a major requirement for cellular processes such as oxygen transport, energy metabolism, neurotransmitter synthesis, and myelin synthesis. Despite its crucial role in these processes, iron in the ferric form can also produce toxic reactive oxygen species. The duality of iron’s function highlights the importance of maintaining a strict balance of iron levels in the body. As a result, organisms have developed elegant mechanisms of iron uptake, transport, and storage. This review will focus on the mechanisms that have evolved at physiological barriers, such as the intestine, the placenta, and the blood–brain barrier (BBB), where iron must be transported. Much has been written about the processes for iron transport across the intestine and the placenta, but less is known about iron transport mechanisms at the BBB. In this review, we compare the established pathways at the intestine and the placenta as well as describe what is currently known about iron transport at the BBB and how brain iron uptake correlates with processes at these other physiological barriers.

• Blood–brain barrier
• Gut
• HFE
• Iron transport
• Placenta

• Animals
• Biological Transport
• Blood-Brain Barrier/metabolism
• Humans
• Iron/metabolism

• R01 NS077678 NINDS NIH HHS
• National Institutes of Health

• Exosomes
• Intercellular communication
• Metal homeostasis
• Microvesicles
• Neurodegeneration

• Hemochromatosis
• Hepcidin
• Iron
• Iron deficiency
• Post-transcriptional regulation

• Alpha-1 antitrypsin deficiency
• Citrin deficiency
• HFE-associated hemochromatosis
• Inborn errors of metabolism
• Wilson disease

• Adult
• Calcium-Binding Proteins/deficiency
• Child
• Hemochromatosis/diagnosis
• Hemochromatosis/genetics
• Hemochromatosis/physiopathology
• Hemochromatosis/therapy
• Hemochromatosis Protein
• Hepatolenticular Degeneration/diagnosis
• Hepatolenticular Degeneration/genetics
• Hepatolenticular Degeneration/physiopathology
• Histocompatibility Antigens Class I/genetics
• Humans
• Liver Diseases/diagnosis
• Liver Diseases/physiopathology
• Membrane Proteins/genetics
• Metabolism, Inborn Errors/diagnosis
• Metabolism, Inborn Errors/genetics
• Metabolism, Inborn Errors/physiopathology
• Metabolism, Inborn Errors/therapy
• Organic Anion Transporters/deficiency
• alpha 1-Antitrypsin Deficiency/diagnosis
• alpha 1-Antitrypsin Deficiency/genetics
• alpha 1-Antitrypsin Deficiency/physiopathology
• alpha 1-Antitrypsin Deficiency/therapy

• divalent metal-ion transporter 1
• duodenum
• ferroportin 1
• hepcidin
• hephaestin

• ceruloplasmin, hephaestin
• copper-transporting ATPase1
• divalent metal-ion transporter 1
• ferroportin 1
• intestine
• liver

• Biopsy
• Heart/physiopathology
• Heart Failure/etiology
• Heart Failure/mortality
• Heart Failure/physiopathology
• Hemochromatosis/complications
• Hemochromatosis/physiopathology
• Hemochromatosis/therapy
• Humans
• Iron/metabolism
• Iron Chelating Agents/therapeutic use
• Liver/pathology
• Phlebotomy
• Survival Rate
• Treatment Outcome

• Anemia
• human iron requirement
• iron bioavailability
• iron deficiency
• iron metabolism

• Iron
• Iron Metabolism
• Metalloproteins
• Metals
• Protein Metal Ion Interaction
• α2-Macroglobulin

Multi-copper oxidases (MCOs) are a small group of enzymes that oxidize their substrate with the concomitant reduction of dioxygen to two water molecules. Generally, multi-copper oxidases are promiscuous with regards to their reducing substrates and are capable of performing various functions in different species. To date, three multi-copper oxidases have been detected in humans—ceruloplasmin, hephaestin and zyklopen. Each of these enzymes has a high specificity towards iron with the resulting ferroxidase activity being associated with ferroportin, the only known iron exporter protein in humans. Ferroportin exports iron as Fe²⁺, but transferrin, the major iron transporter protein of blood, can bind only Fe³⁺ effectively. Iron oxidation in enterocytes is mediated mainly by hephaestin thus allowing dietary iron to enter the bloodstream. Zyklopen is involved in iron efflux from placental trophoblasts during iron transfer from mother to fetus. Release of iron from the liver relies on ferroportin and the ferroxidase activity of ceruloplasmin which is found in blood in a soluble form. Ceruloplasmin, hephaestin and zyklopen show distinctive expression patterns and have unique mechanisms for regulating their expression. These features of human multi-copper ferroxidases can serve as a basis for the precise control of iron efflux in different tissues. In this manuscript, we review the biochemical and biological properties of the three human MCOs and discuss their potential roles in human iron homeostasis.

Iron is an essential nutrient for almost every living organism because it is required in a number of biological processes that serve to maintain life. In humans, recycling of senescent erythrocytes provides most of the daily requirement of iron. In addition, we need to absorb another 1–2 mg Fe from the diet each day to compensate for losses due to epithelial sloughing, perspiration, and bleeding. Iron absorption in the intestine is mainly regulated on the enterocyte level by effectors in the diet and systemic regulators accessing the enterocyte through the basal lamina. Recently, a complex meshwork of interactions between several trace metals and regulatory proteins was revealed. This review focuses on advances in our understanding of Cu, Zn, and Ca in the regulation of iron absorption. Ascorbate as an important player is also considered.

As is the case in all areas of gastroenterology and hepatology, in 2009 and 2010 there were many advances in our knowledge and understanding of small intestinal diseases. Over 1000 publications were reviewed, and the important advances in basic science as well as clinical applications were considered. In Part II we review six topics: absorption, short bowel syndrome, smooth muscle function and intestinal motility, tumors, diagnostic imaging, and cystic fibrosis.

• Absorption
• Cystic fibrosis
• Diagnostic imaging
• Intestinal motility
• Short bowel syndrome
• Smooth muscle function
• Tumors

• ferroportin
• iron
• hepcidin
• genetics

• belgrade (b/b) rats
• iron absorption
• divalent metal transporter and ferroportin