Dysregulation Of Iron Metabolism Research Articles

Iron Metabolism and Ferroptosis in Early Brain Injury after Subarachnoid Haemorrhage.

At present, it appears that the prognosis for subarachnoid haemorrhage (SAH), which has a high death and disability rate, cannot be greatly improved by medication or other treatment. Recent research suggests that different types of cell death are implicated in early brain injury (EBI) after SAH, and this has been recognised as a major factor impacting the prognosis of SAH. Ferroptosis, which is a recently identified imbalance of iron metabolism and programmed cell death triggered by phospholipid peroxidation, has been shown to be involved in EBI after SAH and is thought to have a significant impact on EBI. The decomposition of cleaved haemoglobin during SAH involves the release of enormous amounts of free iron, resulting in iron metabolism disorders. Potential therapeutic targets for the signalling pathways of iron metabolism disorders and ferroptosis after SAH are constantly being discovered. To serve as a guide for research into other possible therapeutic targets, this paper will briefly describe the mechanisms of dysregulated iron metabolism and ferroptosis in the pathogenesis of SAH and highlight how they are involved in the development and promotion of EBI in SAH.

A Plant Model of α-Synucleinopathy: Expression of α-Synuclein A53T Variant in Hairy Root Cultures Leads to Proteostatic Stress and Dysregulation of Iron Metabolism

Synucleinopathies, typified by Parkinson’s disease (PD), entail the accumulation of α-synuclein (αSyn) aggregates in nerve cells. Various αSyn mutants, including the αSyn A53T variant linked to early-onset PD, increase the propensity for αSyn aggregate formation. In addition to disrupting protein homeostasis and inducing proteostatic stress, the aggregation of αSyn in PD is associated with an imbalance in iron metabolism, which increases the generation of reactive oxygen species and causes oxidative stress. This study explored the impact of αSyn A53T expression in transgenic hairy roots of four medicinal plants (Lobelia cardinalis, Artemisia annua, Salvia miltiorrhiza, and Polygonum multiflorum). In all tested plants, αSyn A53T expression triggered proteotoxic stress and perturbed iron homeostasis, mirroring the molecular profile observed in human and animal nerve cells. In addition to the common eukaryotic defense mechanisms against proteostatic and oxidative stresses, a plant stress response generally includes the biosynthesis of a diverse set of protective secondary metabolites. Therefore, the hairy root cultures expressing αSyn A53T offer a platform for identifying secondary metabolites that can ameliorate the effects of αSyn, thereby aiding in the development of possible PD treatments and/or treatments of synucleinopathies.

Ferritin Levels on Hospital Admission Predict Hypoxic-Ischemic Encephalopathy in Patients After Out-of-Hospital Cardiac Arrest: A Prospective Observational Single-Center Study.

Out-of-hospital cardiac arrest (OHCA) is a major health concern in Western societies. Poor outcome after OHCA is determined by the extent of hypoxic-ischemic encephalopathy (HIE). Dysregulation of iron metabolism has prognostic relevance in patients with ischemic stroke and sepsis. The aim of this study was to determine whether serum iron parameters help to estimate outcomes after OHCA. In this prospective single-center study, 70 adult OHCA patients were analyzed. Serum ferritin, iron, transferrin (TRF), and TRF saturation (TRFS) were measured in blood samples drawn on day 0 (admission), day 2, day 4, and 6 months after the return of spontaneous circulation (ROSC). The association of 4 iron parameters with in-hospital mortality, neurological outcome (cerebral performance category [CPC]), and HIE was investigated by receiver operating characteristics and multivariate regression analyses. OHCA subjects displayed significantly increased serum ferritin levels on day 0 and lowered iron, TRF, and TRFS on days 2 and 4 after ROSC, as compared to concentrations measured at a 6-month follow-up. Iron parameters were not associated with in-hospital mortality or neurological outcomes according to the CPC. Ferritin on admission was an independent predictor of features of HIE on cranial computed tomography and death due to HIE. OHCA is associated with alterations in iron metabolism that persist for several days after ROSC. Ferritin on admission can help to predict HIE.

Updates on clinical and laboratory aspects of hereditary dyserythropoietic anemias.

Hereditary dyserythropoietic anemias, or congenital dyserythropoietic anemias (CDAs), are rare disorders disrupting normal erythroid lineage development, resulting in ineffective erythropoiesis and monolinear cytopenia. CDAs include three main types (I, II, III), transcription-factor-related forms, and syndromic forms. The widespread use of next-generation sequencing in the last decade has unveiled novel causative genes and unexpected genotype-phenotype correlations. The discovery of the genetic defects underlying the CDAs not only facilitates accurate diagnosis but also enhances understanding of CDA pathophysiology. Notable advancements include identifying a hepatic-specific role of the SEC23B loss-of-function in iron metabolism dysregulation in CDA II, deepening CDIN1 dysfunction during erythroid differentiation, and uncovering a recessive CDA III form associated with RACGAP1 variants. Current treatments primarily rely on supportive measures tailored to disease severity and clinical features. Comparative studies with pyruvate kinase deficiency have illuminated new therapeutic avenues by elucidating iron dyshomeostasis and dyserythropoiesis mechanisms. We herein discuss recent progress in diagnostic methodologies, novel gene discoveries, and enhanced comprehension of CDA pathogenesis and molecular genetics.

Exploring the Impact of Preoperative Sleep Fragmentation on Cognitive Function in Mice: The Role of Microglial Activation and Iron Metabolism

Background. Perioperative neurocognitive disorders (PND) are a significant concern, particularly for aged individuals. Sleep fragmentation (SF), a common condition in older adults, is considered a risk factor for PND. The present study explored the impact of SF on cognitive function and its association with microglial activation and iron metabolism. Methods. Adult and aged C57BL/6J mice were subjected to tibial fracture surgery (TFS) and varying durations of SF. Cognitive function was assessed using the Morris water maze and fear conditioning experiments. Microglial activation was evaluated by measuring CD68 protein expression and inflammatory cytokine levels. Iron metabolism and ferroptosis-related proteins were also examined. Results. SF significantly impacted spatial memory and conditioned fear responses in mice, with aged mice showing greater susceptibility. Microglial activation, indicated by changes in CD68 protein expression and inflammatory cytokine levels, was observed in mice exposed to SF. Alterations in iron metabolism, as evidenced by changes in hippocampal iron content and expression of ferroptosis-related proteins, were also observed in these mice. Conclusion. SF can lead to significant cognitive impairment, particularly in aged mice, likely mediated through microglial activation and dysregulated iron metabolism. These findings provide novel insights into the pathogenesis of PND and suggest potential targets for intervention. Significance. This study illuminates the complex interactions between SF, microglial activation, and cognitive function. It highlights the importance of sleep quality for cognitive health in older adults and points to potential therapeutic strategies for preventing PND, including targeting microglial activation and iron metabolism.

Research progress of ferroptosis and inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a non-specific chronic inflammatory disorder of the gastrointestinal tract, imposing significant burdens on both society and individuals. As a new type of regulated cell death (RCD), ferroptosis is different from classic RCDs such as apoptosis and necrosis in cell morphology, biochemistry and genetics. The main molecular mechanisms of ferroptosis include dysregulation of iron metabolism, impaired antioxidant capacity, mitochondrial dysfunction, accumulation of lipid-associated super-oxides, and membrane disruption. In recent years, increasing evidence has shown that ferroptosis is involved in the pathophysiology of inflammatory bowel disease. However, the exact roles and underlying molecular mechanisms have not been fully elucidated. This article reviews the mechanism of ferroptosis in the occurrence and development of inflammatory bowel disease, in order to provide new ideas for the pathophysiological research of inflammatory bowel disease. Additionally, we discuss potential strategies for the prevention and treatment of inflammatory bowel disease by targeting ferroptosis.

Calcium and IL-6 regulate the anterograde trafficking and plasma membrane residence of the iron exporter ferroportin to modulate iron efflux

Iron is an essential element for proper cell functioning, but unbalanced levels can cause cell death. Iron metabolism is controlled at the blood-tissue barriers provided by microvascular endothelial cells. Dysregulated iron metabolism at these barriers is a factor in both neurodegenerative and cardiovascular diseases. Mammalian iron efflux is mediated by the iron efflux transporter ferroportin (Fpn). Inflammation is a factor in many diseases and correlates with increased tissue iron accumulation. Evidence suggests treatment with interleukin 6 (IL-6) increases intracellular calcium levels and calcium is known to play an important role in protein trafficking. We have shown that calcium increases plasma membrane localization of the iron uptake proteins ZIP8 and ZIP14, but if and how calcium modulates Fpn trafficking is unknown. In this article, we examined the effects of IL-6 and calcium on Fpn localization to the plasma membrane. In HEK cells expressing a doxycycline-inducible GFP-tagged Fpn, calcium increased Fpn-GFP membrane presence by 2 h, while IL-6 increased membrane-localized Fpn-GFP by 3 h. Calcium pretreatment increased Fpn-GFP mediated 55Fe efflux from cells. Endoplasmic reticulum calcium stores were shown to be important for Fpn-GFP localization and iron efflux. Use of calmodulin pathway inhibitors showed that calcium signaling is important for IL-6-induced Fpn relocalization. Studies in brain microvascular endothelial cells in transwell culture demonstrated an initial increase in 55Fe flux with IL-6 that is reduced by 6h coinciding with upregulation of hepcidin. Overall, this research details one pathway by which inflammatory signaling mediated by calcium can regulate iron metabolism, likely contributing to inflammatory disease mechanisms.

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

BackgroundAmorphous 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.ResultsWe 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.ConclusionsOur 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.Graphical

Abstract 5937: KS20226, a first-in-class IRP2 inhibitor, preferentially induces reprogramming of iron metabolism and suppresses tumor growth in colorectal cancer

Abstract Background: Iron homeostasis plays a role in redox activity, mitochondrial function, and cell cycle regulation. Specifically, the dysregulation of iron metabolism is implicated in malignant transformation and cancer progression. Iron regulatory protein 2 (IRP2) is crucial for maintaining balance within iron levels and primarily controls genes associated with iron utilization. Our discovery of KS20226, a first-in-class IRP2 inhibitor, reveals remarkable potential as an effective anti-cancer drug candidate. We have elucidated the mechanisms underlying the therapeutic effects of KS20226, thereby highlighting the feasibility of targeting IRP2 in colorectal cancer (CRC). Methods: The proliferation inhibitory activity of KS20226 was assessed the CCK-8 and 3D Spheroid models. To investigate mitochondrial function, we conducted measurement of oxidative phosphorylation (OCR) and glycoPER. Furthermore, gene expression analysis was performed through RNA sequencing (RNA-seq) using the Illumina HiSeq 2500 system platform (Macrogen Inc.). Differential expressed gene (DEG) analysis was carried out using the R package DESeq2, and pathway enrichment analysis was analyzed using GSEA (v_4.2.3.). For the observation of autophagic morphology, we utilized transmission electron microscopy (TEM), immunofluorescence staining targeting the autophagy marker LC3B, and immunoblotting. Results: KS20226 exhibited a remarkable growth inhibitory effect in 10 different CRC cell lines, with GI50 values ranging from 1 to 10 μM. KS20226 suppressed IRP2 expression and the corresponding occupancy of the iron-responsive elements of ferritin H and transferrin receptor 1, resulting in iron deprivation, and efficiently controlled CRC growth. Pharmacologic inhibition of IRP2 induced reprogramming of mitochondrial respiration, reducing reliance on oxidative phosphorylation. The observed mitochondrial dysfunction induced by KS20226 was correlated with pathway analysis, revealing a decrease in the gene-set for HALLMARK_OXIDATIVE_PHOSPHORYLATION (NES = -1.38, p-value = 0.008) and an increase in the gene-set for POSITIVE_REGULATION_OF_AUTOPHAGY (NES=1.43, p-value=0.016). Immunoblotting demonstrated that KS20226 activated the phosphorylation of AMPK, ULK, and Beclin1 cascade, leading to the autophagic cell death of the CRC cells. Conclusions: The reliance of cancer cells on iron metabolism to drive proliferation has led to the development of therapeutic strategies targeting the inhibition of IRP2. KS20226, a first-in-class IPR2 inhibitor, exhibits distinct therapeutic properties, such as perturbation of mitochondrial iron metabolism and induction of autophagic cell death. Our findings represent important progress toward exploiting IRP2-mediated abnormal iron metabolism in cancer, an unexplored area of research with substantial unmet needs. Citation Format: Jieon Hwang, Areum Park, Chinwoo Kim, Chang Gon Kim, Jaesung Kwak, Byungil Kim, Hyunjin Shin, Minhee Ku, Jaemoon Yang, Ayoung Baek, Jiwon Choi, Hocheol Lim, Kyoung Tai No, Xianghua Zhao, Uyeong Choi, Tae Il Kim, Kyu-Sung Jeong, Hyuk Lee, Sang Joon Shin. KS20226, a first-in-class IRP2 inhibitor, preferentially induces reprogramming of iron metabolism and suppresses tumor growth in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5937.

Iron metabolism and ferroptosis in nonalcoholic fatty liver disease: what is our next step?

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with increasing prevalence worldwide. NAFLD could develop from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), NASH-related fibrosis, cirrhosis, and even hepatocellular carcinoma. However, the mechanism of NAFLD development has not yet been fully defined. Recently, emerging evidence shows that the dysregulated iron metabolism marked by elevated serum ferritin, and ferroptosis are involved in the NAFLD. Understanding iron metabolism and ferroptosis can shed light on the mechanisms of NAFLD development. Here, we summarized studies on iron metabolism and the ferroptosis process involved in NAFLD development to highlight potential medications and therapies for treating NAFLD.

Essential tremor is associated with reduced serum ceruloplasmin levels.

Essential tremor (ET), a prevalent movement disorder, has an elusive pathogenesis. A reduction in ceruloplasmin (Cp) levels can be found in some patients with ET. In addition, some studies have suggested an association between ET and neurodegeneration. As a ferroxidase, Cp is critical for iron metabolism, protecting against oxidative stress and neurodegeneration. Iron metabolism dysregulation, linked to ferroptosis, has implications in neurodegenerative diseases. Yet, research on Cp and ET remains limited. This study aims to elucidate the relationship between ET and serum Cp levels. We collected demographic and clinical data from 62 patients with ET satisfying the diagnostic criteria and compared these to data from 100 healthy controls. The median Cp levels in ET patients were 21.5 (18.8, 23.9) mg/dL, significantly lower than those in controls (23.1 [(20.7, 25.7) mg/dL; P = 0.006]). A reduction in Cp levels emerged as a risk factor for ET incidence (odds ratio (OR) = 0.873, 95% confidence interval (CI), 0.795, 0.959; P = 0.005). The area under the receiver operating characteristic (ROC) curve for serum Cp levels to predict the onset of ET was 0.629 (95% CI, 0.537-0.720; P = 0.006), and the optimal cut-off value for Cp levels was 19.5mg/dL with a sensitivity of 91% and a specificity of 33.9%. Our analysis suggests that reduced Cp levels are associated with ET. We speculate that reduced Cp levels may be involved in the pathogenesis of ET, which requires further studies.

Ferroptosis and EMT resistance in cancer: a comprehensive review of the interplay.

Ferroptosis differs from traditional cell death mechanisms like apoptosis, necrosis, and autophagy, primarily due to its reliance on iron metabolism and the loss of glutathione peroxidase activity, leading to lipid peroxidation and cell death. The dysregulation of iron metabolism is a hallmark of various cancers, contributing to tumor progression, metastasis, and notably, drug resistance. The acquisition of mesenchymal characteristics by epithelial cells is known as Epithelial-Mesenchymal Transition (EMT), a biological process intricately linked to cancer development, promoting traits such as invasiveness, metastasis, and resistance to therapeutic interventions. EMT plays a pivotal role in cancer progression and contributes significantly to the complex dynamics of carcinogenesis. Research findings indicate that mesenchymal cancer cells exhibit greater susceptibility to ferroptosis compared to their epithelial counterparts. The induction of ferroptosis becomes more effective in eliminating drug-resistant cancer cells during the process of EMT. The interplay between ferroptosis and EMT, a process where epithelial cells transform into mobile mesenchymal cells, is crucial in understanding cancer progression. EMT is associated with increased cancer metastasis and drug resistance. The review delves into how ferroptosis and EMT influence each other, highlighting the role of key proteins like GPX4, which protects against lipid peroxidation, and its inhibition can induce ferroptosis. Conversely, increased GPX4 expression is linked to heightened resistance to ferroptosis in cancer cells. Moreover, the review discusses the implications of EMT-induced transcription factors such as Snail, Zeb1, and Twist in modulating the sensitivity of tumor cells to ferroptosis, thereby affecting drug resistance and cancer treatment outcomes. Targeting the ferroptosis pathway offers a promising therapeutic strategy, particularly for tumors resistant to conventional treatments. The induction of ferroptosis in these cells could potentially overcome drug resistance. However, translating these findings into clinical practice presents challenges, including understanding the precise mechanisms of ferroptosis induction, identifying predictive biomarkers, and optimizing combination therapies. The review underscores the need for further research to unravel the complex interactions between ferroptosis, EMT, and drug resistance in cancer. This could lead to the development of more effective, targeted cancer treatments, particularly for drug-resistant tumors, offering new hope in cancer therapeutics.

Ferroptosis-Based Therapeutic Strategies toward Precision Medicine for Cancer.

Ferroptosis is a type of iron-dependent programmed cell death characterized by the dysregulation of iron metabolism and the accumulation of lipid peroxides. This nonapoptotic mode of cell death is implicated in various physiological and pathological processes. Recent findings have underscored its potential as an innovative strategy for cancer treatment, particularly against recalcitrant malignancies that are resistant to conventional therapies. This article focuses on ferroptosis-based therapeutic strategies for precision cancer treatment, covering the molecular mechanisms of ferroptosis, four major types of ferroptosis inducers and their inhibitory effects on diverse carcinomas, the detection of ferroptosis by fluorescent probes, and their implementation in image-guided therapy. These state-of-the-art tactics have manifested enhanced selectivity and efficacy against malignant carcinomas. Given that the administration of ferroptosis in cancer therapy is still at a burgeoning stage, some major challenges and future perspectives are discussed for the clinical translation of ferroptosis into precision cancer treatment.

Correlation between iron metabolism indicators and programmed death ligand 1 expression in advanced non-small cell lung cancer.

The dysregulation of iron metabolism is closely linked to the onset and progression of lung cancer. This study aimed to explore the association between iron metabolism indicators (serum iron, transferrin, ferritin) and the expression level of programmed death factor ligand 1 in primary lesions of advanced non-small cell lung cancer. A cohort of 62 patients, including 42 men and 20 women, was recruited from October 2022 to July 2023, all diagnosed with advanced non-small cell lung cancer, confirmed through radiographic imaging and histopathological analysis. Comprehensive clinical data (such as gender, age, familial lung cancer history, smoking history, pathological classification, clinical stage, etc.) and concentrations of fasting serum iron, transferrin, and ferritin were collected. Patients were categorized into PD-L1 negative (<1% expression) and programmed death ligand 1 (PD-L1) positive (≥1% expression) groups based on PD-L1 expression levels in tumor tissues. Subsequently, the correlation between levels of serum iron, transferrin, ferritin, and PD-L1 expression in advanced non-small cell lung cancer were examined. Patients in the PD-L1 positive group exhibited lower levels of peripheral serum iron and transferrin compared to those in the PD-L1 negative group (P<0.05). For patients exhibiting positive PD-L1 expression, a negative correlation was observed between PD-L1 expression and both serum iron and transferrin levels (r = -0.465, P=0.003; r = -0.447, P=0.005), and a positive correlation was noted between PD-L1 expression and ferritin levels (r=0.393, P=0.015). We conclude that in In patients with advanced non-small cell lung cancer, serum iron and transferrin levels can serve as partial predictors of PD-L1 expression; among those positive for PD-L1, a significant association exists between indicators of iron metabolism and PD-L1 expression.

Butyrate Prevents the Pathogenic Anemia-Inflammation Circuit by Facilitating Macrophage Iron Export.

Most patients with inflammatory bowel disease (IBD) develop anemia, which is attributed to the dysregulation of iron metabolism. Reciprocally, impaired iron homeostasis also aggravates inflammation. How this iron-mediated, pathogenic anemia-inflammation crosstalk is regulated in the gut remains elusive. Herein, it is for the first time revealed that anemic IBD patients exhibit impaired production of short-chain fatty acids (SCFAs), particularly butyrate. Butyrate supplementation restores iron metabolism in multiple anemia models. Mechanistically, butyrate upregulates ferroportin (FPN) expression in macrophages by reducing the enrichment of histone deacetylase (HDAC) at the Slc40a1 promoter, thereby facilitating iron export. By preventing iron sequestration, butyrate not only mitigates colitis-induced anemia but also reduces TNF-α production in macrophages. Consistently, macrophage-conditional FPN knockout mice exhibit more severe anemia and inflammation. Finally, it is revealed that macrophage iron overload impairs the therapeutic effectiveness of anti-TNF-α antibodies in colitis, which can be reversed by butyrate supplementation. Hence, this study uncovers the pivotal role of butyrate in preventing the pathogenic circuit between anemia and inflammation.

Iron homeostasis and post-hemorrhagic hydrocephalus: a review.

Iron physiology is regulated by a complex interplay of extracellular transport systems, coordinated transcriptional responses, and iron efflux mechanisms. Dysregulation of iron metabolism can result in defects in myelination, neurotransmitter synthesis, and neuronal maturation. In neonates, germinal matrix-intraventricular hemorrhage (GMH-IVH) causes iron overload as a result of blood breakdown in the ventricles and brain parenchyma which can lead to post-hemorrhagic hydrocephalus (PHH). However, the precise mechanisms by which GMH-IVH results in PHH remain elusive. Understanding the molecular determinants of iron homeostasis in the developing brain may lead to improved therapies. This manuscript reviews the various roles iron has in brain development, characterizes our understanding of iron transport in the developing brain, and describes potential mechanisms by which iron overload may cause PHH and brain injury. We also review novel preclinical treatments for IVH that specifically target iron. Understanding iron handling within the brain and central nervous system may provide a basis for preventative, targeted treatments for iron-mediated pathogenesis of GMH-IVH and PHH.

Dysfunctional iron metabolism in pressure injuries is related to aberrant CD163 and Homx-1 signal transduction.

Dysregulation of iron metabolism has been associated with impaired chronic wound healing. However, changes in iron metabolism have yet to be reported in pressure injuries, a type of chronic wound. In this study, we aimed to investigate changes in iron metabolism and associated regulatory mechanisms in pressure injuries. We collected tissue biopsies and data from 20 consenting stage IV-pressure injuries patients and 5 non-pressure injuries patients hospitalised at the Affiliated Hospital of Qingdao University between March 2021 and June 2021. In addition, we measured the iron content by inductively coupled plasma mass spectrometry and Prussian blue staining in deep tissue pressure injury mouse models. An Enzyme-linked immune sorbent assay measured the expression of ferritin, ferroportin-1 and transferrin. Immunofluorescence staining, high-throughput transcriptome sequencing, Western blot and RT-qPCR further analysed the fundamental mechanisms regulating iron metabolism. In this study, we observed numerous inflammatory cells infiltrating the marginal tissues of stage IV pressure injury patients and in deep tissue pressure injury models. The expression levels of pro-inflammatory factors, such as inducible nitric oxide synthase and interleukin-6, were significantly increased (p < 0.05). The iron level was proportional to the degree of progression, with the most significant change appearing on the third day in deep tissue pressure injury models (p < 0.05). Enzyme-linked immune sorbent assay results suggested abnormal gene expression was related to iron metabolism, including a substantial increase in ferritin and a significant decrease in the expression of ferroportin-1 (p < 0.05). In addition, immunofluorescence staining and Western blot showed that the expression of macrophage membrane receptor CD163 was abnormally elevated (p < 0.05). Both high-throughput transcriptome sequencing and qRT-PCR results suggested aberrant expression of the CD163/Homx-1-mediated signalling pathway. Dysfunctional iron metabolism was suggested to be related to the aberrant CD163/Homx-1 signalling pathway in deep tissue pressure injury models.

Iron Dys-Homeostasis Contributed to Liver Gvhd after Allogeneic Hematopoietic Stem Cell Transplantation

Graft-versus-host disease (GVHD), which results from immunological attack to recipient organs or tissues (such as the skin, liver and gut) by donor allogeneic T cells, limits the success of allogeneic hematopoietic stem cell transplantation (allo-HSCT). A correlation of high serum ferritin levels with increased mortality after allo-HSCT has been suggested by several analyses. While the role of iron dys-homeostasis in the risk of GVHD remains unclear. Whether iron dys-homeostasis contributes to the development of GVHD or iron dys-homeostasis is only a result of severe GVHD remains unknown. To assess the status of iron metabolism during GVHD following allo-HSCT, we established aGVHD mouse model by transplantation of T cell-depleted bone marrow (TCD BM) with or without splenic T cells from C57BL/6 (B6) mice to BALB/c mice after being lethally irradiated. By 28 days post-transplantation, when aGVHD stable developed, the serum iron level was significantly higher in aGVHD group compared with control. Meanwhile, ferrous-ion load in aGVHD-involved liver was also increased, while the total iron load did not differ significantly in aGVHD-involved liver compared with control. The ferrous-ion load as well as the total iron load in intestine, lung and spleen were comparable between aGVHD group and control group. To further determine the dysregulation of iron metabolism during liver aGVHD, we detected the expression levels of pivotal iron regulatory genes in liver and duodenum. The expression levels of transferrin receptor 1 ( Tfr1) and divalent metal transporter 1 ( Dmt1) were significantly upregulated in aGVHD-involved liver, which contributed to ferrous-ion overload in the liver aGVHD. Besides, Ferroportin 1 was down-regulated in aGVHD-involved duodenum, which is the result of the upregulated hepcidin ( Hamp1) in liver. Our data suggested that the increased serum iron in aGVHD was not related to iron absorption by duodenum, but may be associated with ineffectively use of iron, which was caused by the impaired marrow function after myeloablative conditioning. To explore whether ferrous-ion overload in liver would lead to induction of reactive oxygen species (ROS) via the Fenton reaction, and eventually results in liver damage during aGVHD, we detected the activity of superoxide dismutase (SOD) and the load of thiol and lipid peroxidation product, malondialdehyde (MDA). The activity of SOD and thiol load both decreased significantly in aGVHD-involved liver, while the serum MDA level increased in aGVHD group, indicating that iron dys-homeostasis may aggravate liver GVHD damage by induction of lipid peroxidation injury. Finally, to explore how iron overload affect GVHD, we fed recipient mice with high-iron diet and low-iron diet since three weeks before transplantation, respectively. The survival rates and GVHD score were significantly worse in high-iron diet group compared with normal-iron diet group. Interestingly, low-iron diet didn't show survival benefit compared with the normal-iron diet. This suggests that excessive iron deficiency is not beneficial for preventing and treating GVHD. Thus, we applied apo-transferrin (apo-Tf) administration to receipt mice, which can render the poorly soluble non-transferrin bonding iron (NTBI) into a soluble transferrin-bound form, and prevent iron from being rapidly uptake by the liver. The administration of apo-Tf alleviated the organ damage during aGVHD, and reduced the infiltration of CD4 +IFN-γ +T cells, CD4 +IL17 +T cells and CD8 +IL17 +T cells in target organs such as intestine, liver and lung. These data suggested that ferrous-ion overload leads to the increase of NTBI, which aggravate GVHD tissue damage. Our findings reveal a novel mechanism of iron dys-homeostasis during the development of liver aGVHD, which may reveal promising therapeutic targeting in the prevention and treatment of liver aGVHD.

Mitochondrial iron dyshomeostasis and its potential as a therapeutic target for Parkinson's disease

Abnormal iron accumulation has been implicated in the etiology of Parkinson's disease (PD). Understanding how iron damages dopaminergic neurons in the substantia nigra (SN) of PD is particularly important for developing targeted neurotherapeutic strategies for the disease. However, it is still not fully understood how excess iron contributes to the neurodegeneration of dopaminergic neurons in PD. There has been increased attention on mitochondrial iron dyshomeostasis, iron-induced mitochondrial dysfunction and ferroptosis in PD. Therefore, this review begins with a brief introduction to describe cellular iron metabolism and the dysregulation of iron metabolism in PD. Then we provide an update on how iron is delivered to mitochondria and induces the damage of dopaminergic neurons in PD. In addition, we also summarize new research progress on iron-dependent ferroptosis in PD and mitochondria-localized proteins involved in ferroptosis. This will provide new insight into potential therapeutic strategies targeting mitochondrial iron dysfunction.

Haptoglobin gene polymorphism and iron profile in sickle cell disease patients with inflammation in Yaounde, Cameroon.

Major sickle cell syndromes are the most common hemoglobinopathy in the world. The sickle cell patients are subjected to several factors causing inflammation, and the genetic identification of each individual allows to focus the possibility of allelic variations influence of a specific gene and then the polymorphism. This study aims at determining the distribution of HP gene (OMIM#140100) and their involvement on hematological parameters and the iron profile in the sickle cell patients presenting an inflammation condition during major sickle cell syndromes in Cameroun. A case-control analytical study has been conducted over a period of 6 months. Cases consisting of sickle cell patients in a situation of inflammation and control of non-inflamed sickle cell patients. The patients presenting major sickle cell syndromes, interned and/or followed at the Hematology Department of the Regional Hospital of Bafoussam and the Central Hospital of Yaoundé have been recruited. HP genotyping was carried out at the Laboratory for Public Health Research Biotechnologies (LAPHER-Biotech) in Yaoundé using allele-specific PCR. Also, inflammatory, hematological parameters and martial assessment were explored by standard methods. Statistical analysis of the data was performed using the statistical tool R version 4.1.1. The comparison of proportions of alleles was made with the chi-square test, and the Wilcoxon test was used to compare the median between different groups using the statistical tool R version 4.1.1. We analyzed the samples of 149 patients. The HP polymorphism describes a significant frequency of the "1F" allele (69.8%) followed by the "2" allele (46.31%). In addition, 80 patients (53.69%), 48 (32.21%), and 21 (14.09%) presented the genotype HP 1-1, HP 2-1, and HP 2-2, respectively. And eighty-one percent (81%) patients with genotype HP 2-2 showed a significant higher relative frequency of thrombocytosis compared with the genotype HP 1-1 and HP 2-1, respectively (51.2% and 68.8%, p = 0.087). The proportion of inflammation in the HP 2-2 group was higher (57.1%) compared with the other groups (respectively 42.5% and 35.4% in the HP 1-1 and HP 2-1 groups). Furthermore, the median CRP was significantly higher in the HP 2-2 group compared with the other groups (p = 0.039). Moreover, the entire population of the HP 2-2 group showed an elevation of ferritin and IL6 unlike the HP 1-1 and HP 2-1 groups. This study demonstrates a higher frequency of genotype HP 1-1 followed by the HP 2-2 genotype in patients with major sickle cell syndromes. However, a larger proportion of patients with genotype HP 2-2 are associated with hematological profile disorders, inflammation, and dysregulation of iron metabolism. Then, the haptoglobin polymorphism contributes to the severity of major sickle cell syndromes.