Iron supplementation and iron accumulation promote adipocyte thermogenesis through PGC1α-ATGL-mediated lipolysis.

Iron homeostasis is essential for maintaining metabolic health and iron disorder has been linked to chronic metabolic diseases. Increasing thermogenic capacity in adipose tissue has been considered as a potential approach to regulate energy homeostasis. Both Mitochondrial biogenesis and mitochondrial function are iron dependent and essential for adipocyte thermogenic capacity, but the underlying relationships between iron accumulation and adipose thermogenesis is unclear. Firstly, we confirmed that iron homeostasis and the iron regulatory markers (e.g. Tfr1, Hfe) are involved in cold induced thermogenesis in subcutaneous adipose tissues using RNA-seq and bioinformatic analysis. Secondly, an Hfe (Hfe-/-) deficient mouse model, in which tissues become overloaded with iron, was employed. We found iron accumulation caused by Hfe deficiency enhanced mitochondrial respiratory chain expression in subcutaneous white adipose in vivo and resulted in enhanced tissue thermogenesis with upregulation of PGC-1α and ATGL, mitochondrial biogenesis and lipolysis. To investigate the thermogenic capacity in vitro, stromal vascular fraction (SVF) from adipose tissues was isolated, followed with adipogenic differentiation. Primary adipocyte from Hfe-/- mice exhibited higher cellular oxygen consumption, associated with enhanced expression of mitochondrial oxidative respiratory chain protein, while primary adipocytes or SVFs from WT mice supplemented with iron citrate (FAC) exhibited similar effect in thermogenic capacity. Taken together, these findings indicate iron supplementation and iron accumulation (Hfe deficiency) can regulate adipocyte thermogenic capacity, suggesting a potential role for iron homeostasis in adipose tissues.

Genetic Correlation of HBB, HFE and HAMP Genes to Endocrinal Complications in Egyptian Beta Thalassemia Major Patients.

Iron loading is regarded as the primary cause of endocrine abnormalities in thalassemia major patients. Thus, the purpose of the current research was to explore the impact of thalassemia genotypes, hepcidin antimicrobial peptide (HAMP) and hereditary hemochromatosis (HFE) gene variants, and hepcidin expression on serum ferritin and endocrinal complications in thalassemia patients. The study comprised fifty beta-thalassemia cases and fifty age- and sex-matched controls. Genotyping of the Beta-globin gene (HBB), HAMP, and exon 2 of the HFE gene was performed using Sanger sequencing. C282Y (c.845G > A) variant of the HFE gene was determined by PCR-RFLP. Hepcidin mRNA expression was assessed by qRT-PCR. Biochemical and hormonal studies were done for all patients. Hypogonadism and short stature were found in 56% and 20% of the investigated cases, respectively. Molecular studies reported a statistically higher frequency of the HAMP variant c.-582A > G in thalassemic patients than controls. Significant downregulation of hepcidin expression was found in cases compared to healthy subjects that was significantly associated with short stature. Considering the thalassemia alleles, the IVSI.1G > A (ß0) allele was statistically related to hypogonadism. Our results proposed that thalassemia genotypes and downregulated hepcidin expression were the potential risk factors for endocrinopathies in our cases. We also demonstrated an increased incidence of the HAMP promoter variant c.- 582A > G that might have a role in the pathogenesis of iron overload in thalassemic cases. Significant downregulation of hepcidin expression, that contributes to increased iron burden, could be used as a future therapeutic target in these patients.

HFE Mutations in Neurodegenerative Disease as a Model of Hormesis.

Common variants in the iron regulatory protein HFE contribute to systematically increased iron levels, yet the effects in the brain are not fully characterized. It is commonly believed that iron dysregulation is a key contributor to neurodegenerative disease due to iron's ability to catalyze reactive oxygen species production. However, whether HFE variants exacerbate or protect against neurodegeneration has been heavily debated. Some claim that mutated HFE exacerbates oxidative stress and neuroinflammation, thus predisposing carriers to neurodegeneration-linked pathologies. However, H63D HFE has also been shown to slow the progression of multiple neurodegenerative diseases and to protect against environmental toxins that cause neurodegeneration. These conflicting results showcase the need to further understand the contribution of HFE variants to neurodegenerative disease heterogeneity. Data from mouse models consistently demonstrate robust neuroprotection against toxins known to increase the risk of neurodegenerative disease. This may represent an adaptive, or hormetic, response to increased iron, which leaves cells better protected against future stressors. This review describes the current research regarding the contribution of HFE variants to neurodegenerative disease prognosis in the context of a hormetic model. To our knowledge, this is the first time that a hormetic model for neurodegenerative disease has been presented.

Hemochromatosis: Ferroptosis, ROS, Gut Microbiome, and Clinical Challenges with Alcohol as Confounding Variable.

Hemochromatosis represents clinically one of the most important genetic storage diseases of the liver caused by iron overload, which is to be differentiated from hepatic iron overload due to excessive iron release from erythrocytes in patients with genetic hemolytic disorders. This disorder is under recent mechanistic discussion regarding ferroptosis, reactive oxygen species (ROS), the gut microbiome, and alcohol abuse as a risk factor, which are all topics of this review article. Triggered by released intracellular free iron from ferritin via the autophagic process of ferritinophagy, ferroptosis is involved in hemochromatosis as a specific form of iron-dependent regulated cell death. This develops in the course of mitochondrial injury associated with additional iron accumulation, followed by excessive production of ROS and lipid peroxidation. A low fecal iron content during therapeutic iron depletion reduces colonic inflammation and oxidative stress. In clinical terms, iron is an essential trace element required for human health. Humans cannot synthesize iron and must take it up from iron-containing foods and beverages. Under physiological conditions, healthy individuals allow for iron homeostasis by restricting the extent of intestinal iron depending on realistic demand, avoiding uptake of iron in excess. For this condition, the human body has no chance to adequately compensate through removal. In patients with hemochromatosis, the molecular finetuning of intestinal iron uptake is set off due to mutations in the high-FE2+ (HFE) genes that lead to a lack of hepcidin or resistance on the part of ferroportin to hepcidin binding. This is the major mechanism for the increased iron stores in the body. Hepcidin is a liver-derived peptide, which impairs the release of iron from enterocytes and macrophages by interacting with ferroportin. As a result, iron accumulates in various organs including the liver, which is severely injured and causes the clinically important hemochromatosis. This diagnosis is difficult to establish due to uncharacteristic features. Among these are asthenia, joint pain, arthritis, chondrocalcinosis, diabetes mellitus, hypopituitarism, hypogonadotropic hypogonadism, and cardiopathy. Diagnosis is initially suspected by increased serum levels of ferritin, a non-specific parameter also elevated in inflammatory diseases that must be excluded to be on the safer diagnostic side. Diagnosis is facilitated if ferritin is combined with elevated fasting transferrin saturation, genetic testing, and family screening. Various diagnostic attempts were published as algorithms. However, none of these were based on evidence or quantitative results derived from scored key features as opposed to other known complex diseases. Among these are autoimmune hepatitis (AIH) or drug-induced liver injury (DILI). For both diseases, the scored diagnostic algorithms are used in line with artificial intelligence (AI) principles to ascertain the diagnosis. The first-line therapy of hemochromatosis involves regular and life-long phlebotomy to remove iron from the blood, which improves the prognosis and may prevent the development of end-stage liver disease such as cirrhosis and hepatocellular carcinoma. Liver transplantation is rarely performed, confined to acute liver failure. In conclusion, ferroptosis, ROS, the gut microbiome, and concomitant alcohol abuse play a major contributing role in the development and clinical course of genetic hemochromatosis, which requires early diagnosis and therapy initiation through phlebotomy as a first-line treatment.

Evaluation of spatial and temporal dynamics of seawater intrusion in coastal aquifers of southeast India: insights from hydrochemical facies analysis.

This study aims to investigate and understand the temporal and spatial movement of seawater intrusion into the coastal aquifers. Groundwater salinity increase has affected the entire eastern part of the study area and is primarily influenced by direct and reverse ion exchange reactions associated with intrusion and freshwater influx phases, which alternate over monsoons. To gain insights into the spatiotemporal dynamics of the seawater intrusion process, hydrochemical facies analysis utilizing the HFE-Diagram was employed. Additionally, the study considered the major ionic changes during both the monsoons. The HFE-Diagram analysis of hydrochemical facies revealed distinctions in the behaviour of each coastal aquifer concerning seawater intrusion-induced salinization. In PRM 2020, the data shows that approximately 65% of the samples fall under the freshening phase, while the remaining 35% were categorized as intrusion phase. Within the freshening phase, seven different hydrochemical facies were identified, including Na-Cl, Na-MixCl, MixNa-MixCl, Na-MixHCO3/MixSO4, MixNa-MixSO4, Na-HCO3, and MixCa-HCO3. In contrast, the intrusion phase had four facies: MixCaMixHCO3, MixNa-Cl, Ca-Cl, and Na-Cl. Especially, the Na-Cl facies (f1) within the freshening phase attributed for the largest percentage, contributing 30% of the samples. In POM 2021, the distribution of samples shifted slightly, with approximately 72.5% belonging to the freshening phase and 27.5% to the intrusion phase. Within the freshening phase of POM 2021, five hydrochemical facies were identified: Na-Cl, Na-MixCl, Na-MixHCO3/MixSO4, MixNa-MixSO4, and Na-HCO3. The intrusion phase of POM 2021 had three facies: MixNa-Cl, Na-Cl, and MixCa-Cl. Similar to PRM 2020, the Na-Cl facies (f1) remained the most predominant in the freshening phase, comprising 30% of the samples. The relation between total dissolved solids (TDS) and various ionic ratios, such as HCO3-/Cl-, Na+/Cl-, Ca2+/Cl-, Mg2+/Cl-, K+/Cl-, and SO42-/Cl-, clearly demonstrates the presence of seawater influence within the coastal aquifers of the study area.

Iron in immune cell function and host defense.

The control over iron availability is crucial under homeostatic conditions and even more in the case of an infection. This results from diverse properties of iron: first, iron is an important trace element for the host as well as for the pathogen for various cellular and metabolic processes, second, free iron catalyzes Fenton reaction and is therefore producing reactive oxygen species as a part of the host defense machinery, third, iron exhibits important effects on immune cell function and differentiation and fourth almost every immune activation in turn impacts on iron metabolism and spatio-temporal iron distribution. The central importance of iron in the host and microbe interplay and thus for the course of infections led to diverse strategies to restrict iron for invading pathogens. In this review, we focus on how iron restriction to the pathogen is a powerful innate immune defense mechanism of the host called "nutritional immunity". Important proteins in the iron-host-pathogen interplay will be discussed as well as the influence of iron on the efficacy of innate and adaptive immunity. Recently described processes like ferritinophagy and ferroptosis are further covered in respect to their impact on inflammation and infection control and how they impact on our understanding of the interaction of host and pathogen.

On The Nature of FeIV =Oaq in Aqueous Media: A DFT analysis.

FeIV =Oaq is a key intermediate in many advanced oxidation processes and probably in biological systems. It is usually referred to as FeIV =O2+ . The pKa's of FeIV =Oaq as derived by DFT are: pKa1=2.37 M06 L/6-311++G(d,p) (SDD for Fe) and pKa2=7.79 M06 L/6-311++G(d,p) (SDD for Fe). This means that in neutral solutions, FeIV =Oaq is a mixture of (H2 O)4 (OH)FeIV =O+ and (H2 O)2 (OH)2 FeIV =O. The oxidation potential of FeIV =Oaq in an acidic solution, E0 {(H2 O)5 FeIV =O2+ /FeIII (H2 O)6 3+ , pH 0.0} is calculated with and without a second solvation sphere and the recommended value is between 2.86 V (B3LYP/Def2-TZVP, with a second solvation sphere) and 2.23 V (M06 L/Def2-TZVP without a second solvation sphere). This means that FeIV =Oaq is the strongest oxidizing agent formed in systems involving FeVI O4 2- even in neutral media.

Avoiding Regrettable Replacements: Can the Introduction of Novel Functional Groups Move PFAS from Recalcitrant to Reactive?

Per- and polyfluoroalkyl substances (PFASs) are present in a range of commercial and consumer products. These chemicals are often high-performance surfactants or nonstick/water-repellant coatings due to their chemical stability; however, this stability leads to select PFAS being environmentally persistent. To facilitate degradation, new fluorosurfactant building blocks (F7C3-O-CHF-CF2-S-CH2-CH2-OH (FESOH), F3C-O-CHF-CF2-S-CH2-CH2-OH (MeFESOH), F7C3-O-CHF-CF2-O-CH2-CH2-OH (ProFdiEOH), F7C3-O-CHF-CF2-CH2-OH (ProFEOH), and F3C-O-CHF-CF2-O-CH2-CH2-OH (MeFdiEOH)) have been systematically developed with heteroatom linkages such as ethers, thioethers, and polyfluorinated carbons. The room temperature, gas-phase OH oxidation rate constants, and products of these chemicals were monitored in an atmospheric chamber to investigate their fate in the atmosphere. Analysis was performed using online high-resolution chemical ionization mass spectrometry (CIMS) using the iodide reagent ion and via offline UPLC-MS/MS. FESOH and MeFESOH, the thioether congeners, were observed to have the largest rate constants of kFESOH = 2.82 (±0.33) and kMeFESOH = 2.17 (±0.17) (×10-12 cm3 molecules-1 s-1, respectively). First-, second-, and third-generation products of OH oxidation were observed as a function of time, while product quantification yielded ultrashort perfluoropropionic acid (PFPrA) and short polyfluoroether acid species as the terminal products for FESOH and ProFdiEOH. There was evidence for MeFESOH being fully mineralized, demonstrating the potential benign chemical architecture.

Hfe Actions in Kupffer Cells Are Dispensable for Hepatic and Systemic Iron Metabolism.

Mutations in the HFE/Hfe gene cause Hereditary Hemochromatosis (HH), a highly prevalent genetic disorder characterized by elevated iron deposition in multiple tissues. HFE acts in hepatocytes to control hepcidin expression, whereas HFE actions in myeloid cells are required for cell-autonomous and systemic iron regulation in aged mice. To address the role of HFE specifically in liver-resident macrophages, we generated mice with a selective Hfe deficiency in Kupffer cells (HfeClec4fCre). The analysis of the major iron parameters in this novel HfeClec4fCre mouse model led us to the conclusion that HFE actions in Kupffer cells are largely dispensable for cellular, hepatic and systemic iron homeostasis.

Frequency Evaluation of the Interleukin-6 -174G>C Polymorphism and Homeostatic Iron Regulator (HFE) Mutations as Disease Modifiers in Patients Affected by Systemic Lupus Erythematosus and Rheumatoid Arthritis.

Autoimmune diseases are generally characterized by a multifactorial etiology and are often associated with a genetic predisposition. Both iron metabolism and the inflammatory cytokine system have been shown to play a pivotal role in the dysregulation of the immune response in many different autoimmune conditions, rheumatologic diseases included. The purpose of this work was to analyze the frequency of mutations altering the expression of IL-6 or influencing iron metabolism in patients affected by autoimmune diseases such as Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). In this study, 144 patients were enrolled: 77 and 67 patients were affected by RA and SLE, respectively. In these cohorts, the frequency of the IL-6 polymorphism -174G>C located in the IL-6 gene promoter was tested. Moreover, the frequencies of the three HFE gene variations associated with iron overload were analyzed: p.His63Asp, p.Ser65Cys and p.Cys282Tyr. The two mutations p.His63Asp and p.Ser65Cys in the HFE gene did not reach statistical significance in any of the comparisons, regardless of the statistical model, cohorts of patients and control populations analyzed. The frequencies of the p.Cys282Tyr mutation and the IL-6 polymorphism -174G>C were found to be overall significantly decreased in RA and SLE patients when the Dominant model and Allele contrast were adopted with both the Odds Ratio and Chi-square. Although further investigation is needed, the examination of the frequencies of the -174G>C IL-6 promoter polymorphism and HFE mutations may add some valuable information on the interplay linking iron metabolism, inflammation and immunity in autoimmune diseases such as SLE and RA.

Protein Susceptibility to Peroxidation by 4-Hydroxynonenal in Hereditary Hemochromatosis.

Iron overload caused by hereditary hemochromatosis (HH) increases free reactive oxygen species that, in turn, induce lipid peroxidation. Its 4-hydroxynonenal (HNE) by-product is a well-established marker of lipid peroxidation since it reacts with accessible proteins with deleterious consequences. Indeed, elevated levels of HNE are often detected in a wide variety of human diseases related to oxidative stress. Here, we evaluated HNE-modified proteins in the membrane of erythrocytes from HH patients and in organs of Hfe-/- male and female mice, a mouse model of HH. For this purpose, we used one- and two-dimensional gel electrophoresis, immunoblotting and MALDI-TOF/TOF analysis. We identified cytoskeletal membrane proteins and membrane receptors of erythrocytes bound to HNE exclusively in HH patients. Furthermore, kidney and brain of Hfe-/- mice contained more HNE-adducted protein than healthy controls. Our results identified main HNE-modified proteins suggesting that HH favours preferred protein targets for oxidation by HNE.

Using Mendelian Randomization to Study the Role of Iron in Health and Disease.

Iron has been shown to play a dual role in health and disease, with either a protective or harmful effect. Some of the contradictory findings from observational studies may be due to reverse causation, residual confounding, or small sample size. One approach that may overcome these limitations without the high cost of randomized control trials is the use of Mendelian randomization to examine the long-term role of iron in a variety of health outcomes. As there is emerging evidence employing Mendelian randomization as a method of assessing the role of micronutrients in health and disease, this narrative review will highlight recent Mendelian randomization findings examining the role of iron in cardiometabolic disorders, inflammation, neurological disorders, different cancers, and a number of other health-related outcomes.

Managing the Dual Nature of Iron to Preserve Health.

Because of its peculiar redox properties, iron is an essential element in living organisms, being involved in crucial biochemical processes such as oxygen transport, energy production, DNA metabolism, and many others. However, its propensity to accept or donate electrons makes it potentially highly toxic when present in excess and inadequately buffered, as it can generate reactive oxygen species. For this reason, several mechanisms evolved to prevent both iron overload and iron deficiency. At the cellular level, iron regulatory proteins, sensors of intracellular iron levels, and post-transcriptional modifications regulate the expression and translation of genes encoding proteins that modulate the uptake, storage, utilization, and export of iron. At the systemic level, the liver controls body iron levels by producing hepcidin, a peptide hormone that reduces the amount of iron entering the bloodstream by blocking the function of ferroportin, the sole iron exporter in mammals. The regulation of hepcidin occurs through the integration of multiple signals, primarily iron, inflammation and infection, and erythropoiesis. These signals modulate hepcidin levels by accessory proteins such as the hemochromatosis proteins hemojuvelin, HFE, and transferrin receptor 2, the serine protease TMPRSS6, the proinflammatory cytokine IL6, and the erythroid regulator Erythroferrone. The deregulation of the hepcidin/ferroportin axis is the central pathogenic mechanism of diseases characterized by iron overload, such as hemochromatosis and iron-loading anemias, or by iron deficiency, such as IRIDA and anemia of inflammation. Understanding the basic mechanisms involved in the regulation of hepcidin will help in identifying new therapeutic targets to treat these disorders.

Shaping the development and use of Artificial Intelligence: how human factors and ergonomics expertise can become more pertinent.

New developments in Artificial Intelligence (AI) are extensively discussed in public media and scholarly publications. While in many academic disciplines debates on the challenges and opportunities of Artificial Intelligence (AI) and how to best address them have been launched, the human factors and ergonomics (HFE) community has been strangely quiet. I discuss three main areas in which HFE could and should significantly contribute to the socially and economically viable development and use of AI: decisions on automation versus augmentation of human work; alignment of control and accountability for AI outcomes; counteracting power imbalances among AI stakeholders. I then outline actions that the HFE community could undertake to improve their involvement in AI development and use, foremost translating ethical into design principles, strengthening the macro-turn in HFE, broadening the HFE design mindset, and taking advantage of new interdisciplinary research opportunities.Practitioner summary: HFE expertise could and should significantly contribute to the socially and economically viable development and use of AI. Translating ethical into design principles, opening up to broader multi-stakeholder perspectives, and engaging in interdisciplinary collaboration within a design science framework are discussed as measures to achieve that.

Indices of iron homeostasis in asymptomatic subjects with HFE mutations and moderate ferritin elevation during iron removal treatment.

We analysed iron biomarkers and their relationships in 30 subjects with HFE mutations and moderate hyperferritinaemia undergoing iron removal at our blood donation centre. Body mass index (BMI) and liver enzymes were assessed. Serum iron (SI), ferritin, transferrin saturation (TSAT), hepcidin and non-transferrin bound iron (NTBI) were measured serially. Seventeen subjects had p.C282Y/p.C282Y, nine p.C282Y/p.H63D, four p.H63D/p.H63D. Median age (p = 0.582), BMI (p = 0.500) and ferritin (p = 0.089) were comparable. At baseline, 12/17 p.C282Y/p.C282Y and 2/9 p.C282Y/p.H63D had measurable NTBI (p = 0.003). The p.C282Y/p.C282Y had higher TSAT (p < 0.001), lower hepcidin (p = 0.031) and hepcidin/ferritin ratio (p = 0.073). After treatment, iron indices were similar among groups, except TSAT (higher in p.C282Y/p.C282Y; p = 0.06). Strong relationships were observed between ferritin and TSAT (R = 0.71), NTBI and TSAT (R = 0.61), NTBI and SI (R = 0.54) in p.C282Y/p.C282Y. Hepcidin correlated weakly with ferritin in p.C282Y/p.C282Y (R = 0.37) but strongly in p.C282Y/p.H63D (R = 0.66) and p.H63D/p.H63D (R = 0.72), while relationships with TSAT were weak (R = 0.27), moderate (R = 0.55) and strong (R = 0.61), respectively. Low penetrance p.C282Y/p.C282Y phenotype displays hepcidin dysregulation and biochemical risk for iron toxicity.

Patient-reported outcomes and their relation with iron parameters in HFE haemochromatosis during maintenance therapy: A prospective cohort study.

BACKGROUND & AIMS: The standard of care for haemochromatosis is regular phlebotomy in order to maintain low ferritin levels. Many patients report fatigue or joint pain despite serum ferritin within the therapeutic targets. We evaluated Patient-Reported Outcomes, and their relation with iron parameters, in C282Y homozygous patients undergoing maintenance phlebotomy. METHODS: Patients were prospectively enrolled in a French referral care centre. At each phlebotomy, patients completed a numeric fatigue scale, a joint pain questionnaire and SF-36 Mental Component Score (MCS) and Physical Component Score (PCS). Haemoglobin, iron, TS and ferritin were collected concomitantly. RESULTS: About 701 visits were performed in 259 patients. The median fatigue score was 3/10; 171 (66%) patients reported joint pain. Age and worsening of joint pain were associated with fatigue (p < .0001 for both). Female gender (p < .037), age (p < .003), and a decrease of TS (p = .050) were associated with joint pain. Main features associated with PCS <50 were worsening of joint pain and age (p < .001 for both) and TS <20% (p < .02). CONCLUSIONS: Fatigue was independent from iron parameters. The main factor impacting quality of life was joint pain, which was more severe in patients with low TS values. Then, a more precise monitoring of TS should be proposed during haemochromatosis maintenance therapy; while less stringent monitoring of serum ferritin levels could be tested.

Hereditary hemochromatosis: data from a single center Copenhagen cohort.

OBJECTIVES: We aimed to describe a cohort of hereditary hemochromatosis (HH) patients from a single urban center in Copenhagen. METHODS: Retrospectively, data from patients with HH from the years 2009-2020 were collected. RESULTS: A total of 203 patients was recorded. Males constituted 65.0% of the patients. Homozygous HH (HHH)/compound heterozygous HH (CHH) accounted for 69.4%/30.6%. HHH patients had significantly higher ferritin and transferrin saturation (TS) levels at debut than CHH patients. Fifty-five HHH patients (39.0%) had ferritin >1000 ug/L versus 9 (14.5%) in the CHH group (p < .001). Age at debut did not differ between female and male patients. Ferritin (but not TS) levels were significantly higher in male patients. The proportion of patients with ferritin >1000 did not differ between males and females. One-hundred patients (49.3%) had one or more symptoms at the time of diagnosis; arthralgias of the metacarpophalangeal joints and/or ankles (n = 46 (22.7%)), fatigue (n = 67 (33.0%)) and decreased libido (n = 20 (9.9%)). The proportion of patients with symptoms did not differ between HHH and CHH or between male and female patients. Severe organ complications (cardiomyopathy, late onset type 1 diabetes or cirrhosis) were present in 14 patients (6.9%). CONCLUSIONS: We report a high proportion of compound HH, constituting almost one-third of patients. We found that the proportion of patients with symptoms did not differ between HHH and CHH and recommend that CHH should be treated and examined in the same way as HHH.

An exploratory pilot study on the involvement of APOE, HFE, C9ORF72 variants and comorbidities in neurocognitive and physical performance in a group of HIV-infected people.

Cognitive decline of aging is modulated by chronic inflammation and comorbidities. In people with HIV-infection (PWH) it may also be affected by HIV-induced inflammation, lifestyle and long-term effects of antiretroviral therapies (ART). The role of genetics in the susceptibility to HIV-associated neurocognitive disorders (HAND) is not fully understood. Here we explored the possible relations among variants in 3 genes involved in inflammation and neurodegenerative disorders (APOE: ε2/ε3/ε4; HFE: H63D; C9ORF72: hexanucleotide expansions ≥ 9 repeats), cognitive/functional impairment (MiniMental State Examination MMSE, Clock Drawing Test CDT, Short Physical Performance Battery SPPB), comorbidities and HIV-related variables in a cohort of > 50 years old PWH (n = 60) with at least 10 years efficient ART. Patients with diabetes or hypertension showed significantly lower MMSE (p = .031) or SPPB (p = .010) scores, respectively, while no relations between HIV-related variables and cognitive/functional scores were observed. Patients with at least one APOEε3 allele had higher CDT scores (p = .019), APOEε2/ε4 patients showing the lowest scores in all tests. Patients with HFE-H63D variant showed more frequently hypertriglyceridemia (p = .023) and those harboring C9ORF72 expansions > 9 repeats had higher CD4+-cell counts (p = .032) and CD4% (p = .041). Multiple linear regression analysis computed to verify possible associations among cognitive/functional scores and all variables further suggested positive association between higher CDT scores and the presence of at least one APOEε3 allele (2,2; 95% CI [0,03 0,8]; p = .037), independent of other variables, although the model did not reach the statistical significance (p = .14). These data suggest that in PWH on efficient ART cognitive abilities and physical performances may be partly associated with comorbidities and genetic background. However, further analyses are needed to establish whether they could be also dependent and influenced by comorbidities and genetic background.

Effect of homeostatic iron regulator protein gene mutation on Wilson's disease clinical manifestation: original data and literature review.

OBJECTIVE: Wilson's disease (WD) is a hereditary disorder of copper metabolism. The metabolic pathways of copper and iron are interrelated. Our goal was to determine the frequency of the two most common mutations in the coding region of the human iron homeostatic protein gene (HFE) in Europe: C282Y (rs1800562) and H63D (rs1799945) in WD patients, as well as to analyze their relation with WD phenotypic traits. MATERIAL AND METHODS: HFE mutations were studied by PCR RFLP method in 445 WD patients and 102 controls. All patients met the diagnostic criteria of WD 8th International Conference on Wilson Disease and Menkes Disease. RESULTS: HFE C282Y heterozygotes, both women and men, showed WD symptoms earlier than patients with wild-type HFE genotype. HFE 63HD heterozygous men presented symptoms later than HFE 63HH homozygotes, but HFE 63HD women manifested symptoms later than those with HFE 63HH genotype. CONCLUSIONS: HFE genotype seems to be one of the factors modifying Wilson's disease phenotype.

Engineering Peptide Inhibitors of the HFE-Transferrin Receptor 1 Complex.

The protein HFE (homeostatic iron regulator) is a key regulator of iron metabolism, and mutations in HFE underlie the most frequent form of hereditary haemochromatosis (HH-type I). Studies have shown that HFE interacts with transferrin receptor 1 (TFR1), a homodimeric type II transmembrane glycoprotein that is responsible for the cellular uptake of iron via iron-loaded transferrin (holo-transferrin) binding. It has been hypothesised that the HFE/TFR1 interaction serves as a sensor to the level of iron-loaded transferrin in circulation by means of a competition mechanism between HFE and iron-loaded transferrin association with TFR1. To investigate this, a series of peptides based on the helical binding interface between HFE and TFR1 were generated and shown to significantly interfere with the HFE/TFR1 interaction in an in vitro proximity ligation assay. The helical conformation of one of these peptides, corresponding to the α1 and α2 helices of HFE, was stabilised by the introduction of sidechain lactam "staples", but this did not result in an increase in the ability of the peptide to disrupt the HFE/TFR1 interaction. These peptides inhibitors of the protein-protein interaction between HFE and TFR1 are potentially useful tools for the analysis of the functional role of HFE in the regulation of hepcidin expression.