Ferroptosis contributing to cardiomyocyte injury induced by silica nanoparticles via miR-125b-2-3p/HO-1 signaling.

BACKGROUND: Amorphous silica nanoparticles (SiNPs) have been gradually proven to threaten cardiac health, but pathogenesis has not been fully elucidated. Ferroptosis is a newly defined form of programmed cell death that is implicated in myocardial diseases. Nevertheless, its role in the adverse cardiac effects of SiNPs has not been described. RESULTS: We first reported the induction of cardiomyocyte ferroptosis by SiNPs in both in vivo and in vitro. The sub-chronic exposure to SiNPs through intratracheal instillation aroused myocardial injury, characterized by significant inflammatory infiltration and collagen hyperplasia, accompanied by elevated CK-MB and cTnT activities in serum. Meanwhile, the activation of myocardial ferroptosis by SiNPs was certified by the extensive iron overload, declined FTH1 and FTL, and lipid peroxidation. The correlation analysis among detected indexes hinted ferroptosis was responsible for the SiNPs-aroused myocardial injury. Further, in vitro tests, SiNPs triggered iron overload and lipid peroxidation in cardiomyocytes. Concomitantly, altered expressions of TfR, DMT1, FTH1, and FTL indicated dysregulated iron metabolism of cardiomyocytes upon SiNP stimuli. Also, shrinking mitochondria with ridge fracture and ruptured outer membrane were noticed. To note, the ferroptosis inhibitor Ferrostatin-1 could effectively alleviate SiNPs-induced iron overload, lipid peroxidation, and myocardial cytotoxicity. More importantly, the mechanistic investigations revealed miR-125b-2-3p-targeted HO-1 as a key player in the induction of ferroptosis by SiNPs, probably through regulating the intracellular iron metabolism to mediate iron overload and ensuing lipid peroxidation. CONCLUSIONS: Our findings firstly underscored the fact that ferroptosis mediated by miR-125b-2-3p/HO-1 signaling was a contributor to SiNPs-induced myocardial injury, which could be of importance to elucidate the toxicity and provide new insights into the future safety applications of SiNPs-related nano products.

Investigation the mechanism of iron overload-induced colonic inflammation following ferric citrate exposure.

Iron overload occurs due to excessive iron intake compared to the body's demand, leading to iron deposition and impairment of multiple organ functions. Our previous study demonstrated that chronic oral administration of ferric citrate (FC) caused colonic inflammatory injury. However, the precise mechanism underlying this inflammatory response remains unclear. The current study aims to investigate the mechanism by which iron overload induced by FC exposure leads to colonic inflammation. To accomplish this, mice were orally exposed to three different concentrations of FC (71 mg/kg/bw (L), 143 mg/kg/bw (M) and 286 mg/kg/bw (H)) for continuous 16 weeks, with the control group receiving ultrapure water (C). Exposure to FC caused disturbances in the excretory system, altered colonic flora alpha diversity, and enriched pathogenic bacteria, such as Mucispirillum, Helicobacter, Desulfovibrio, and Shigella. These changes led to structural disorders of the colonic flora and an inflammatory response phenotype characterized by inflammatory cells infiltration, atrophy of intestinal glands, and irregular thickening of the intestinal wall. Mechanistic studies revealed that FC-exposure activated the NF-κB signaling pathway by up-regulating TLR4, MyD88, and NF-κB mRNA levels and protein expression. This activation resulted in increased production of pro-inflammatory cytokines, further contributing to the colonic inflammation. Additionally, in vitro experiments in SW480 cells confirmed the activation of NF-κB signaling pathway by FC exposure, consistent with the in vivo findings. The significance of this study lies in its elucidation of the mechanism by which iron overload caused by FC exposure leads to colonic inflammation. By identifying the role of pathogenic bacteria and the NF-κB signaling pathway, this study could potentially offer a crucial theoretical foundation for the research on iron overload, as well as provide valuable insights for clinical iron supplementation.

Cold-inducible RNA binding protein alleviates iron overload-induced neural ferroptosis under perinatal hypoxia insult.

Cold-inducible RNA binding protein (CIRBP), a stress response protein, protects cells from mild hypothermia or hypoxia by stabilizing specific mRNAs and promoting their translation. Neurons subjected to hypobaric hypoxia insult trigger various cell death programs. One of these is ferroptosis, a novel non-apoptotic form of programmed cell death, which is characterized by excessive iron ion accumulation and lipid peroxidation. Here, we establish that CIRBP can regulate neuronal ferroptosis both in vivo and in vitro. We observe that hypoxia leads to neuronal death via intracellular ferrous iron overload and impaired antioxidant systems, accompanied by suppressed CIRBP expression. Genetic enrichment of CIRBP in hippocampal neurons CIRBPTg mice bred with Emx1-Cre mice attenuates hypoxia-induced cognitive deficits and neuronal degeneration. Mechanistically, CIRBP alleviates neuronal ferroptosis and intracellular ferrous ion accumulation by binding to the mitochondrial ferritin (FTMT) 3'UTR to stabilize mRNA and promote its translation. Our novel study shows the critical role of CIRBP in the progression of ferroptosis, and provides promising therapeutic target for hypoxia-induced neurological diseases.

Iron overload causes macrophages to produce a pro-inflammatory phenotype in the synovium of hemophiliac arthritis via the acetyl-p53 pathway.

AIM: Haemophiliac arthritis (HA) is caused by spontaneous intra-articular hemorrhage and repeated intra-articular hematomas, leading to iron overload, which, in turn, induces M1 macrophage polarisation and inflammatory cytokine secretion, resulting in synovitis. Here, we explored the mechanism by which iron overload in HA induces the polarisation of M1 macrophages, providing a new approach for the treatment of HA synovitis. METHODS: The synovium from the knee joints of normal amputees and patients with HA was collected. Pathological changes in the synovial tissues were analysed using hematoxylin and eosin staining. Iron tissue deposition was evaluated using the iron assay kit and Prussia Blue staining, while macrophage phenotype was determined using immunofluorescence. The levels of pro-inflammatory cytokines and p53 acetylation were determine using western blotting. An in vitro iron overload model was established by inducing THP-1 macrophages with ferric ammonium citrate, and the involvement of acetylated p53 in M1 macrophage polarisation was investigated. RESULTS: Compared to control samples, the iron content in the synovium of patients with HA was significantly increased. The protein levels of M1 macrophage markers, pro-inflammatory cytokines, and acetylated p53, were also significantly elevated in the synovial tissues of patients with HA. Similar results were observed in the in vitro iron overload model. Furthermore, the inhibition of p53 acetylation in vitro reversed these iron overload-induced effects. CONCLUSION: In patients with HA, iron overload induced synovial p53 acetylation, leading to macrophage polarisation toward the M1 phenotype and increased inflammatory cytokine secretion, resulting in synovitis. HIGHLIGHTS: Synovial iron overload is associated with changes in P53 acetylation in hemophiliac arthritis (HA). Acetylated p53, a known regulator of macrophage polarization, is highly expressed in HA synovium, suggesting a potential role in M1 polarization. HA synovial macrophages predominantly polarize into the pro-inflammatory M1 phenotype, secreting elevated levels of pro-inflammatory cytokines.

Research on the clinical factors of cardiac iron deposition in children with beta-thalassemia major.

Magnetic resonance imaging (MRI) T2* is the gold standard for detecting iron deposition in cardiac tissue, but the technique has limitations and cannot be fully performed in paediatric thalassemia patients. The aim of this study was to analyse clinical data to identify other predictors of cardiac iron deposition. A retrospective analysis was performed on 370 children with ß-TM. According to the cardiac MRI results, patients were allocated to a cardiac deposition group and noncardiac deposition group. Multivariate analysis revealed that genotype and corrected QT interval were associated with cardiac iron deposition, indicating that the-ß0/ß0 genotype conferred greater susceptibility to cardiac iron deposition. Receiver operating characteristic curve (ROC) analysis was performed, and the area under the curve (AUC) of genotype was 0.651. The AUC for the corrected QT interval was 0.711, at a cut-off value of 418.5 ms. ROC analysis of the combined genotype and corrected QT interval showed an AUC of 0.762 with 81.3% sensitivity and 64.7% specificity. Compared to patients with the ß+/ß+ and ß0ß+ genotypes, ß0ß0 children with ß-TM were more likely to have cardiac iron deposition.  Conclusion: The genotype and QTc interval can be used to predict cardiac iron deposition in children with ß-TM who are unable to undergo MRI T2 testing.

Relationship between bone marrow iron load and liver iron concentration in dialysis-associated haemosiderosis.

BACKGROUND: Iron overload due to the excessive use of parenteral iron in haemodialysis is now an increasingly recognised clinical issue. Before erythropoiesis-stimulating agents (ESA) were introduced, a specific feature of patients treated by dialysis and having iron overload was that iron levels in the bone marrow were paradoxically low in most of them, despite severe hepatosplenic siderosis. Whether or not this paradox persists in the actual ESA era was unknown until recently, when an autopsy study in 21 patients treated by haemodialysis revealed similarities between liver and bone marrow iron content. The aim of this study was to further explore these recent findings in a cohort of alive patients on dialysis and to analyse the determinants of iron bone marrow. METHODS: Liver iron concentration (LIC) and vertebral T2∗ (a surrogate marker of bone marrow iron) were analysed retrospectively in 152 alive patients on dialysis (38.8% female) of whom 47.4% had iron overload by quantitative magnetic resonance imaging (MRI). FINDINGS: Vertebral T2∗ differed significantly between patients classified according to liver iron content at MRI: those with mild or moderate and severe liver iron overload had increased vertebral iron content at R2∗ relaxometry MRI (mild: vertebral T2∗ = 9.9 ms (4-24.8); moderate and severe: vertebral T2∗ = 8.5 ms (4.9-22.8)) when compared to patients with normal LIC (vertebral T2∗ = 13.2 ms (6.6-30.5) (p < 0.0001 Kruskal-Wallis test)). INTERPRETATION: The paradoxical discrepancy between bone marrow and liver iron-storage compartments observed in the pre-ESA era has disappeared today, as shown by a recent autopsy study and the present study in a cohort of alive patients treated by dialysis. FUNDING: None.

Heterogeneous ferroptosis susceptibility of macrophages caused by focal iron overload exacerbates rheumatoid arthritis.

Focal iron overload is frequently observed in patients with rheumatoid arthritis (RA), yet its functional significance remains elusive. Herein, we report that iron deposition in lesion aggravates arthritis by inducing macrophage ferroptosis. We show that excessive iron in synovial fluid positively correlates with RA disease severity as does lipid hyperoxidation of focal monocyte/macrophages. Further study reveals high susceptibility to iron induced ferroptosis of the anti-inflammatory macrophages M2, while pro-inflammatory M1 are less affected. Distinct glutathione peroxidase 4 (GPX4) degradation depending on p62/SQSTM1 in the two cell types make great contribution mechanically. Of note, ferroptosis inhibitor liproxstatin-1 (LPX-1) can alleviate the progression of K/BxN serum-transfer induced arthritis (STIA) mice accompanied with increasing M2 macrophages proportion. We thus propose that the heterogeneous ferroptosis susceptibility of macrophage subtypes as well as consequent inflammation and immune disorders are potential biomarkers and therapeutic targets in RA.

Vanillin serves as a potential substitute for chemical chelator desferal in iron-overloaded mice.

PURPOSE: Iron toxicity occurs under iron-overloaded settings, such as a high iron diet and blood transfusion, and damages important organs. Vanillin has been proven to have potential iron chelation capability. Given the negative effects of commonly used iron chelators like deferoxamine (DFO), we sought to examine the iron chelation potency of vanillin and evaluate its potential effect in the treatment of iron overload-related disorders. METHODS: 42 male NMRI mice were prepared for this purpose, and except for the negative control group, iron overload conditions were generated in them by injecting iron. Then normal saline (as a control), vanillin, and DFO (n = 7) were subsequently given to iron-overloaded mice. In the following, the activity of antioxidant enzymes catalase and superoxide dismutase were measured in the blood serum, brain, kidney, spleen, lung, and liver tissues of mice. Furthermore, the level of lipid peroxidation was determined by measuring the amount of malondialdehyde. Also, Perl's and H&E staining were used to examine the physiopathology changes of tissues. FINDINGS: Vanillin, a natural antioxidant compound, outperformed deferoxamine, a chemical iron chelator. Along with a decrease in iron content, the activity of catalase and superoxide dismutase enhanced in the iron-overloaded groups that were treated with vanillin. The level of lipid peroxidation was also declined in the iron-overloaded mice receiving vanillin. CONCLUSION: Vanillin can be used as a suitable substitute for chemical chelators with fewer side effects and equivalent efficiency. We encourage the use of this compound as a natural iron chelator following performing additional safety and efficacy studies.

Endometrial stromal cell autophagy-dependent ferroptosis caused by iron overload in ovarian endometriosis is inhibited by the ATF4-xCT pathway.

Ferroptosis is an iron-dependent programmed cell death process characterized by the accumulation of lethal oxidative damage. Localized iron overload is a unique clinical phenomenon in ovarian endometriosis (EM). However, the role and mechanism of ferroptosis in the course of ovarian EM remain unclear. Traditionally, autophagy promotes cell survival. However, a growing body of research suggests that autophagy promotes ferroptosis under certain conditions. This study aimed to clarify the status of ferroptosis in ovarian EM and explore the mechanism(s) by which iron overload causes ferroptosis and ectopic endometrial resistance to ferroptosis in human. The results showed increased levels of iron and reactive oxygen species in ectopic endometrial stromal cells (ESCs). Some ferroptosis and autophagy proteins in the ectopic tissues differed from those in the eutopic endometrium. In vitro, iron overload caused decreased cellular activity, increased lipid peroxidation levels, and mitochondrial morphological changes, whereas ferroptosis inhibitors alleviated these phenomena, illustrating activated ferroptosis. Iron overload increased autophagy, and ferroptosis caused by iron overload was inhibited by autophagy inhibitors, indicating that ferroptosis caused by iron overload was autophagy-dependent. We also confirmed the effect of iron overload and autophagy on lesion growth in vivo by constructing a mouse EM model; the results were consistent with those of the in vitro experiments of human tissue and endometrial stomal cells. However, ectopic lesions in patients can resist ferroptosis caused by iron overload, which can promote cystine/glutamate transporter hyperexpression by highly expressing activating transcription factor 4 (ATF4). In summary, local iron overload in ovarian EM can activate autophagy-related ferroptosis in ESCs, and ectopic lesions grow in a high-iron environment via ATF4-xCT while resisting ferroptosis. The effects of iron overload on other cells in the EM environment require further study. This study deepens our understanding of the role of ferroptosis in ovarian EM.

Magnetic resonance imaging assessment of the changes of cardiac and hepatic iron load in thalassemia patients before and after hematopoietic stem cell transplantation.

To investigate the value of T2* technique on 3.0 T magnetic resonance imaging (MRI) in evaluating the changes of cardiac and hepatic iron load before and after hematopoietic stem cell transplantation (HSCT) in patients with thalassemia (TM), the 141 TM patients were divided into 6 group for subgroup analysis: 6, 12, 18, 24 and > 24 months group, according to the postoperative interval. The T2* values of heart and liver (H-T2*, L-T2*) were quantified in TM patients before and after HSCT using 3.0 T MRI T2* technology, and the corresponding serum ferritin (SF) was collected at the same time, and the changes of the three before and after HSCT were compared. The overall H-T2* (P = 0.001) and L-T2* (P = 0.041) of patients after HSCT were higher than those before HSCT (mean relative changes = 19.63%, 7.19%). The H-T2* (P < 0.001) and L-T2* (P < 0.001) > 24 months after HSCT were significantly higher than those before HSCT (mean relative changes = 69.19%, 93.73%). The SF of 6 months (P < 0.001), 12 months (P = 0.008), 18 months (P = 0.002) and > 24 months (P = 0.001) were significantly higher than those before HSCT (mean relative changes = 57.93%, 73.84%, 128.51%, 85.47%). There was no significant improvement in cardiac and liver iron content in TM patients within 24 months after HSCT, while the reduction of cardiac and liver iron content in patients is obvious when > 24 months after HSCT.

Pattern and clinical correlates of renal iron deposition in adult beta-thalassemia major patients.

We evaluated pattern and clinical correlates of renal T2* measurements in adult ß-thalassemia major (ß-TM) patients. Ninety ß-TM patients (48 females, 38.15 ± 7.94 years), consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia network, underwent T2* magnetic resonance imaging (MRI) for quantification of iron overload (IO) in kidneys, liver, pancreas, and heart. Ten (11.1%) patients showed renal IO (T2* < 31 ms). Global kidney T2* values did not show a correlation with gender, age, splenectomy, regular transfusions or chelation starting age, pre-transfusion hemoglobin, and serum ferritin levels. Global kidney T2* values showed an inverse correlation with MRI liver iron concentration (LIC) values (R = - 0.349; p = 0.001) and a positive correlation with global pancreas T2* values (R = 0.212; p = 0.045). Frequency of renal IO was significantly higher in patients with cardiac IO than in patients without cardiac IO (50.0% vs. 6.3%; p = 0.001). A significant inverse association was detected between global kidneys T2* values and lactate dehydrogenase (LDH) (R = - 0.529; p < 0.0001). In multivariate regression analysis, MRI LIC and LDH were the strongest predictors of global kidney T2* values. A MRI LIC > 4.83 mg/g dw predicted the presence of renal IO (sensitivity = 90.0%; specificity = 61.2%). Global kidney T2* values were inversely correlated with uric acid (R = - 0.269; p = 0.025). In conclusion, in adult ß-TM patients, renal iron deposition is not common and is linked to both hemolysis and total body iron overload.

High Serum Ferritin Levels among Blood Transfused Thalassemic Patients Admitted to the Department of Paediatrics in a Tertiary Care Centre: A Descriptive Cross-Sectional Study.

Introduction: Raised serum ferritin levels often indicate iron overload, but they are not specific as the levels are elevated in inflammatory disorders, liver diseases, alcohol excess, or malignancy. If regular transfusions are required for the patient with thalassemia, this doubles the rate of iron accumulation leading to earlier massive iron overload and iron-related damage. The aim of this study aimed to find out the prevalence of high serum ferritin levels among blood-transfused thalassemic patients admitted to the Department of Paediatrics in a tertiary care centre. Methods: A descriptive cross-sectional study was conducted at a tertiary care centre from 1 March 2022 to 31 December 2022. Ethical approval was taken from the Institutional Review Committee (Reference number: 078/79-017/HG). Children who were confirmed by haemoglobin electrophoresis on regular blood transfusion were included in the study. Those who did not gave consent were excluded from the study. Convenience sampling method was used. Point estimate and 90% Confidence Interval were calculated. Results: Out of 53 cases, the prevalence of high serum ferritin level was seen in 46 (88.79%) (80.30-97.28, 95% Confidence Interval). Among 46, 34 (73.91%) had serum ferritin levels of more than 1000 to 2500 ng/ml whereas 12 (26.09%) had more than 25000 ng/ml. Conclusions: The prevalence of high serum ferritin levels among blood transfused thalassemic patients admitted to the Department of Paediatrics in a tertiary care centre was found to be higher than in other studies done in similar settings. Keywords: blood transfusion; ferritin; thalassemia.

Heme oxygenase 1 alleviates nonalcoholic steatohepatitis by suppressing hepatic ferroptosis.

BACKGROUND: Heme oxygenase 1 (HO-1) has an influential but insufficiently investigated effect on ferroptosis, which is a novel form of programmed cell death and may play an effect on nonalcoholic steatohepatitis (NASH). However, the understanding of the mechanism is limited. Herein, our study aimed to explore the mechanism and role of HO-1 in NASH ferroptosis. METHODS: Hepatocyte conditional HO-1 knockout (HO-1HEPKO) C57BL/6J mice were established and fed a high-fat diet (HFD). Additionally, wild-type mice were fed either a normal diet or a HFD. Hepatic steatosis, inflammation, fibrosis, lipid peroxidation, and iron overload were assessed. AML12 and HepG2 cells were used to investigate the underlying mechanisms in vitro. Finally, liver sections from NASH patients were used to clinically validate the histopathology of ferroptosis. RESULTS: In mice, HFD caused lipid accumulation, inflammation, fibrosis, and lipid peroxidation, which were aggravated by HO-1HEPKO. In line with the in vivo results, HO-1 knockdown upregulated reactive oxygen species accumulation, lipid peroxidation, and iron overload in AML12 and HepG2 cells. Additionally, HO-1 knockdown reduced the GSH and SOD levels, which was in contrast to HO-1 overexpression in vitro. Furthermore, the present study revealed that the NF-κB signaling pathway was associated with ferroptosis in NASH models. Likewise, these findings were consistent with the liver histopathology results of NASH patients. CONCLUSION: The current study showed that HO-1 could alleviate NASH progression by mediating ferroptosis.

Oxidative stress induces lysosomal membrane permeabilization and ceramide accumulation in retinal pigment epithelial cells.

Oxidative stress has been implicated in the pathogenesis of age-related macular degeneration, the leading cause of blindness in older adults, with retinal pigment epithelium (RPE) cells playing a key role. To better understand the cytotoxic mechanisms underlying oxidative stress, we used cell culture and mouse models of iron overload, as iron can catalyze reactive oxygen species formation in the RPE. Iron-loading of cultured induced pluripotent stem cell-derived RPE cells increased lysosomal abundance, impaired proteolysis and reduced the activity of a subset of lysosomal enzymes, including lysosomal acid lipase (LIPA) and acid sphingomyelinase (SMPD1). In a liver-specific Hepc (Hamp) knockout murine model of systemic iron overload, RPE cells accumulated lipid peroxidation adducts and lysosomes, developed progressive hypertrophy and underwent cell death. Proteomic and lipidomic analyses revealed accumulation of lysosomal proteins, ceramide biosynthetic enzymes and ceramides. The proteolytic enzyme cathepsin D (CTSD) had impaired maturation. A large proportion of lysosomes were galectin-3 (Lgals3) positive, suggesting cytotoxic lysosomal membrane permeabilization. Collectively, these results demonstrate that iron overload induces lysosomal accumulation and impairs lysosomal function, likely due to iron-induced lipid peroxides that can inhibit lysosomal enzymes.

Dynamic chromatin accessibility during nutritional iron overload reveals a BMP6-independent induction of cell cycle genes.

Iron is essential to organism physiology as it participates in numerous biological processes including oxygen transport, respiration, and erythropoiesis. Although iron is critical to physiology, excess iron is toxic to cells and tissues due to generation of reactive oxygen species. Therefore, well-kept iron homeostasis is a mainstay of proper cell and organ function. Iron overload disorders, caused by nutritional or genetic factors, contribute to many pathologies such as diabetes, non-alcoholic steatohepatitis and hepatocellular carcinoma. The liver is not only vulnerable to the effects of iron overload, it is also the major organ controlling iron homeostasis. During iron overload, Bone Morphogenic Protein (BMP) levels increase and initiate a hepatic response aimed at lowering iron levels. The transcriptional effects of iron overload are not well-characterized and the underlining enhancer regulation is uncharted. Here, we profiled the liver's transcriptome and chromatin accessibility following nutritional iron overload. We found marked changes in gene expression and enhancer accessibility following iron overload. Surprisingly, 16% of genes induced following iron overload participate in propagating the cell cycle. Induction of cell cycle genes was independent of BMP. Genome-wide enhancer landscape profiling revealed hundreds of enhancers with altered activity following iron overload. Characterization of transcription factor motifs and footprints in iron-regulated enhancers showed a role for the Activator Protein 1 (AP-1) transcription factor in promoting cell cycle-related transcription. In summary, we found that the transcriptional program at play during iron overload is bifurcated in which BMP signaling controls iron homeostasis genes while an AP-1-driven program controls cell cycle genes.

Digital Hepatic Iron Content: An Artificial Intelligence Model for Spatially Resolved Histologic Iron Quantitative Analysis in Liver Samples.

Currently, the precise evaluation of tissue hepatic iron content (HIC) requires laboratory testing using tissue-destructive methods based on colorimetry or spectrophotometry. To maximize the use of routine histologic stains in this context, we developed an artificial intelligence (AI) model for the recognition and spatially resolved measurement of iron in liver samples. Our AI model was developed using a cloud-based, supervised deep learning platform (Aiforia Technologies). Using digitized Pearl Prussian blue iron stain whole slide images representing the full spectrum of changes seen in hepatic iron overload, our training set consisted of 59 cases, and our validation set consisted of 19 cases. The study group consisted of 98 liver samples from 5 different laboratories, for which tissue quantitative analysis using inductively coupled plasma mass spectrometry was available, collected between 2012 and 2022. The correlation between the AI model % iron area and HIC was Rs = 0.93 for needle core biopsy samples (n = 73) and Rs = 0.86 for all samples (n = 98). The digital hepatic iron index (HII) was highly correlated with HII > 1 (area under the curve [AUC] = 0.93) and HII > 1.9 (AUC = 0.94). The percentage area of iron within hepatocytes (vs Kupffer cells and portal tract iron) identified patients with any hereditary hemochromatosis-related mutations (either homozygous or heterozygous) (AUC = 0.65, P = .01) with at least similar accuracy than HIC, HII, and any histologic iron score. The correlation between the Deugnier and Turlin score and the AI model % iron area for all patients was Rs = 0.87 for total score, Rs = 0.82 for hepatocyte iron score, and Rs = 0.84 for Kupffer cell iron score. Iron quantitative analysis using our AI model was highly correlated with both detailed histologic scoring systems and tissue quantitative analysis using inductively coupled plasma mass spectrometry and offers advantages (related to the spatial resolution of iron analysis and the nontissue-destructive nature of the test) over standard quantitative methods.

Acetylated Oligopeptide and N-acetyl cysteine Protected Against Oxidative Stress, Inflammation, Testicular-Blood Barrier Damage, and Testicular Cell Death in Iron-Overload Rat Model.

Multiple organs, including the testes, are damaged by iron overload. It has been shown that N-acetyl cysteine (NAC) influences oxidative stress in iron overload. The present study aimed to evaluate the roles of acetylated peptide (AOP) and NAC in the inhibition of iron-overload induced-testicular damage. At the beginning of the experiment, NAC (150 mg /kg) was given for a week to all 40 rats. Then, four groups were formed by dividing the animals (10 rats/group). Group I included healthy control rats. Group II (iron overload) was given intraperitoneal iron dextran (60 mg/kg/day) 5 days a week for 4 weeks. Group III (NAC) was given NAC orally at a dose of 150 mg/kg/day for 4 weeks in addition to iron dextran. Group IV (AOP) was given AOP orally at a dose of 150 mg/kg/day for 4 weeks besides iron dextran. When the experiment time was over, testosterone serum level, testicular B cell lymphoma-2 (BCL-2) and protein kinase B (PKB) protein levels, nuclear factor kappa-B (NF-κB), and Beclin1 mRNA expression levels, and malondialdehyde (MDA), and reduced glutathione (GSH) were determined by ELISA, quantitative reverse transcription-PCR, and chemical methods. Finally, histopathological examinations and immunohistochemical detection of claudin-1 and CD68 were performed. The iron overload group exhibited decreased testosterone, BCL-2, PKB, claudin-1, and GSH and increased MDA, NF-κB, Beclin1, and CD68, while both NAC and AOP treatments protected against the biochemical and histopathological disturbances occurring in the iron overload model. We concluded that NAC and AOP can protect against testes damage by iron overload via their antioxidant, anti-inflammatory, antiapoptotic, and ant-autophagic properties. The NAC and AOP may be used as preventative measures against iron overload-induced testicular damage.

Iron, ferroptosis, and ischemic stroke.

Over 30 million people suffer from the consequences of ischemic stroke. The precise molecular mechanism of neuronal damage during ischemic stroke remains unclear; therefore, the effective treatment of post-ischemic stroke remains a critical challenge. Recently, iron has emerged as a crucial factor in post-reperfusion injuries, participating in cell peroxidation, excitotoxicity, and a distinctive cell death pathway, namely, ferroptosis. Since iron is tightly regulated in the brain and important for brain functions, the imbalance of its metabolism, including its overload and deficiency, has been shown to impact ischemic stroke outcomes. This review summarizes the current understanding of pathological events associated with iron in ischemic stroke and discusses relevant drug development.

Sudden Onset Iron Overload Cardiomyopathy After Liver Transplantation.

Iron overload cardiomyopathy has been described in patients who develop acute heart failure after liver transplantation but few reports of this are available. We present a case of a patient with end-stage liver disease who underwent a deceased donor liver transplantation and developed acute onset systolic heart failure with reduced left ventricular ejection fraction. A cardiac magnetic resonance image demonstrated late gadolinium enhancement with diffuse enhancement globally and T1 mapping with severely decreased pre-contrast T1 values suggesting iron overload cardiomyopathy. The patient was treated with iron chelating therapy as well as heart failure guideline-directed medical therapy with subsequent improvement in cardiac function on follow-up magnetic resonance images. Despite our patient's diagnosis of iron overload cardiomyopathy, her iron studies showed normal serum iron and ferritin levels and no evidence of hepatic iron deposition in the transplanted liver.

Iron in blood cells: Function, relation to disease, and potential for magnetic separation.

Iron in blood cells has several physiological functions like transporting oxygen to cells and maintaining iron homeostasis. Iron is primarily contained in red blood cells (RBCs), but monocytes also store iron as these cells are responsible for the recycling of senescent RBCs. Iron also serves an important role related to the function of different leukocytes. In inflammation, iron homeostasis is dependent on cytokines derived from T cells and macrophages. Fluctuations of iron content in the body lead to different diseases. Iron deficiency, which is also known as anemia, hampers different physiological processes in the human body. On the other hand, genetic or acquired hemochromatosis ultimately results in iron overload and leads to the failure of different vital organs. Different diagnoses and treatments are developed for these kinds of disorders, but the majority are costly and suffer from side effects. To address this issue, magnetophoresis could be an attractive technology for the diagnosis (and in some cases treatment) of these pathologies due to the paramagnetic character of the cells containing iron. In this review, we discuss the main functions of iron in blood cells and iron-related diseases in humans and highlight the potential of magnetophoresis for diagnosing and treating some of these disorders.