Iron Deposition Research Articles

New insights into the mechanisms of iron absorption: Iron dextran uptake in the intestines of weaned pigs through glucose transporter 5 (GLUT5) and divalent metal transporter 1 (DMT1) transporters

The purpose of this study was to gain insight into the mechanism of iron dextran (DexFe) absorption in the intestines. A total of 72 piglets (average BW = 7.12 ± 0.75 kg, male to female ratio = 1:1) weaned at 28 d of age were randomly divided into two treatment groups with six replicates for each group. The experimental diets included the basal diet supplemented with 100 mg/kg iron dextran (DexFe group) and the basal diet supplemented with 100 mg/kg FeSO4•H2O (CON group). The experiment lasted for 28 d. The piglets' intestinal iron transport was measured in vitro using an Ussing chamber. Porcine intestinal epithelial cell line (IPEC-J2) cells were used to develop a monolayer cell model that explored the molecular mechanism of DexFe absorption. Results showed that compared to the CON group, the ADG of pigs in the DexFe group was improved (P = 0.022), while the F/G was decreased (P = 0.015). The serum iron concentration, apparent iron digestibility, and iron deposition in the duodenum, jejunum, and ileum were increased (P < 0.05) by dietary DexFe supplementation. Piglets in the DexFe group had higher serum red blood count, hemoglobin, serum iron content, serum ferritin and transferrin levels and lower total iron binding capacity (P < 0.05). In the Ussing chamber test, the iron absorption rate of the DexFe group was greater (P < 0.001) than the CON group, and there was no significant difference between the DexFe group and the glucose group (P > 0.05). Furthermore, when compared to the CON group, DexFe administration improved (P < 0.05) SLC2A5 gene and glucose transporter 5 (GLUT5) protein expression but had no effect (P > 0.05) on SLC11A2 gene or divalent metal transporter 1 (DMT1) protein expression. Once the GLUT5 protein was suppressed, the iron transport rate and apparent permeability coefficient were decreased (P < 0.05) in IPEC-J2 monolayer cell models. The findings suggest the effectiveness of DexFe application in weaned piglets and revealed for the first time that DexFe absorption in the intestine is closely related to the glucose transporter GLUT5 protein channel.

A billion-year shift in the formation of Earth’s largest ore deposits

Banded iron formations (BIFs) archive the relationship between Earth's lithosphere, hydrosphere, and atmosphere through time. However, constraints on the origin of Earth's largest ore deposits, hosted by BIFs, are limited by the absence of direct geochronology. Without this temporal context, genetic models cannot be correlated with tectono-thermal and atmospheric drivers responsible for BIF upgrading through time. Utilizing in situ iron oxide U-Pb geochronology, we provide a direct timeline of events tracing development of all the giant BIF-hosted hematite deposits of the Hamersley Province (Pilbara Craton, Western Australia). Direct dating demonstrates that the major iron ore deposits in the region formed during 1.4 to 1.1 Ga. This is one billion to hundreds of millions of years later than previous age constraints based upon 1) the presence of hematite ore clasts in conglomerate beds deposited before ~1.84 Ga, and 2) phosphate mineral dating, which placed the onset of iron mineralization in the Province at ~2.2 to 2.0 Ga during the great oxidation event. Dating of the hematite clasts verified the occurrence of a ~2.2 to 2.0 Ga event, reflecting widespread, but now largely eroded iron mineralization occurring when the Pilbara and Kaapvaal cratons were proximal. No existing phosphate mineral dates overlap with obtained hematite dates and therefore cannot be related to hematite crystallization and ore formation. New geochronology conclusively links all major preserved hematite deposits to a far younger (1.4 to 1.1 Ga) formation period, correlated with the amalgamation of Australia following breakup of the Columbia supercontinent.

JWH133 attenuates behavior deficits and iron accumulation in 6-OHDA-induced Parkinson's disease model rats.

Growing evidence indicates that activation of cannabinoid type 2 (CB2) receptors protects dopamine neurons in the pathogenesis of Parkinson's disease (PD). However, the mechanisms underlying neuroprotection mediated by CB2 receptors are still elusive. In this study, we investigated the effects of CB2 receptor activation on 6-hydroxydopamine (6-OHDA)-induced dopamine neuron degeneration and iron accumulation in the substantia nigra (SN) of rats. We found that treatment with JWH133, a selective CB2 receptor agonist, significantly improved the apomorphine (APO)-induced rotational behavior in 6-OHDA-treated rats. The decreased numbers of tyrosine hydroxylase (TH)-positive neurons and reduced TH protein expression in the lesioned SN of rats were effectively restored by JWH133. Moreover, we found that JWH133 inhibited the increase of iron-staining cells in the lesioned SN of rats. To explore the protective mechanisms of activation of CB2 receptors on dopamine neurons, we further observed the effect of JWH133 on 1-methyl-4-phenylpyridinium (MPP+)-treated primary cultured ventral mesencephalon (VM) neurons from rats. We found that JWH133 significantly inhibited the increase of intracellular reactive oxygen species (ROS), the activation of Caspase-3, the decrease of mitochondrial transmembrane potential (ΔΨm), and the decrease of Bcl-2/Bax protein expression caused by MPP+ treatment. JWH133 also inhibited the MPP+-induced upregulation of divalent metal transporter-1 (DMT1) and downregulation of ferroportin 1 (FPN1). Furthermore, JWH133 also suppressed the MPP+-accelerated iron influx in the VM neurons. These results suggest that activation of CB2 receptor suppresses MPP+-induced cellular iron accumulation and prevents neurodegeneration.NEW & NOTEWORTHY Expression of cannabinoid type 2 receptors (CB2Rs) was discovered on dopamine neurons in recent years. The role of CB2R expressed on dopamine neurons in the pathogenesis of Parkinson's disease (PD) has not been fully elucidated. The content of iron accumulation in the brain is closely related to the progress of PD. We verified the inhibitory effect of CB2R on iron deposition in dopamine neurons through experiments, which provided a new idea for the treatment of PD.

Ultraviolet light and riboflavin accelerates red blood cell dysfunction in vitro and in a guinea pig transfusion model.

Quality assessment of modified or processed red blood cell (RBC) components, such as pathogen-reduced RBCs, using only in vitro testing may not always be predictive of in vivo performance. Mouse or rat in vivo models are limited by a lack of applicability to certain aspects of human RBC biology. Here, we used a guinea pig model to study the effects of riboflavin combined with UV light on the integrity of RBCs in vitro and following transfusion in vivo. Guinea pig RBCs were collected from whole blood (WB) treated with varying UV doses (10, 20, 40 or 80 J/mL) in the presence of riboflavin (UVR-RBCs). In vitro tests for UVR-RBCs included hemolysis, osmotic fragility, and cellular morphology by scanning electron microscopy. Guinea pigs transfused with one-day post-treatment UVR-RBCs were evaluated for plasma hemoglobin (Hb), non-transferrin bound iron (NTBI), total iron and Perls-detectable hemosiderin deposition in the spleen and kidney, and renal uptake of Hb. Acute RBC injury was dose dependently accelerated after treatment with UV light in the presence of riboflavin. Aberrant RBC morphology was evident at 20, 40, and 80 J/mL, and membrane lysis with Hb release was prominent at 80 J/mL. Guinea pigs transfused with 40 and 80 J/mL UVR-RBCs showed increased plasma Hb levels, and plasma NTBI was elevated in all UVR-RBC groups (10-80 J/mL). Total iron levels and Perls-hemosiderin staining in spleen and kidney as well as Hb uptake in renal proximal tubules were increased 8 hours post-transfusion with 40 and 80 J/mL UVR-RBCs. UVR-RBCs administered to guinea pigs increased markers of intravascular and extravascular hemolysis in a UV dose-dependent manner. This model may allow for the discrimination of RBC injury during testing of extensively processed RBCs intended for transfusion.

Intermittent hypoxia exacerbates metabolic dysfunction-associated fatty liver disease by aggravating hepatic copper deficiency-induced ferroptosis.

Intermittent hypoxia (IH) is an independent risk factor for metabolic dysfunction-associated fatty liver disease (MAFLD). Copper deficiency can disrupt redox homeostasis, iron, and lipid metabolism. Here, we investigated whether hepatic copper deficiency plays a role in IH-associated MAFLD and explored the underlying mechanism(s). Male C57BL/6 mice were fed a western-type diet with adequate copper (CuA) or marginally deficient copper (CuD) and were exposed separately to room air (RA) or IH. Hepatic histology, plasma biomarkers, copper-iron status, and oxidative stress were assessed. An in vitro HepG2 cell lipotoxicity model and proteomic analysis were used to elucidate the specific targets involved. We observed that there were no differences in hepatic phenotypes between CuA-fed and CuD-fed mice under RA. However, in IH exposure, CuD-fed mice showed more pronounced hepatic steatosis, liver injury, and oxidative stress than CuA-fed mice. IH induced copper accumulation in the brain and heart and exacerbated hepatic copper deficiency and secondary iron deposition. In vitro, CuD-treated cells with IH exposure showed elevated levels of lipid accumulation, oxidative stress, and ferroptosis susceptibility. Proteomic analysis identified 360 upregulated and 359 downregulated differentially expressed proteins between CuA and CuD groups under IH; these proteins were mainly enriched in citrate cycle, oxidative phosphorylation, fatty acid metabolism, the peroxisome proliferator-activated receptor (PPAR)α pathway, and ferroptosis. In IH exposure, CuD significantly upregulated the ferroptosis-promoting factor arachidonyl-CoA synthetase long chain family member (ACSL)4. ACSL4 knockdown markedly eliminated CuD-induced ferroptosis and lipid accumulation in IH exposure. In conculsion, IH can lead to reduced hepatic copper reserves and secondary iron deposition, thereby inducing ferroptosis and subsequent MAFLD progression. Insufficient dietary copper may worsen IH-associated MAFLD.

Ferritin is closely associated with microglia in amyotrophic lateral sclerosis.

Iron deposition is a hallmark of amyotrophic lateral sclerosis (ALS) and has been strongly implicated in its pathogenesis. As a byproduct of cellular oxidative stress, iron dysregulation modifies basal levels of the regulatory iron-binding protein ferritin. Examination of thoracic and lumbar spinal cord tissues found increased ferritin immunostaining in white matter axons that corresponded to areas of increased microgliosis in 8 ALS patients versus 8 normal subjects. Gray matter areas containing the motor neurons also demonstrated increased ferritin and microglia in ALS compared to controls but at lower levels than in the white matter. Motor neurons with or without TDP-43 inclusions did not demonstrate either increased ferritin or associated microglial activation. We also observed an association of ferritin with microglia in cerebral cortical tissue samples of ALS cases and in the spinal cord tissues of transgenic mice expressing the SOD1G93A mutation. Elevated ferritin levels were detected in the insoluble fraction from spinal cord tissues of individuals with ALS. These findings suggest that activated microglia and increased ferritin may play significant roles in ALS progression since they are found closely associated in areas of axonal and cortical degeneration.

Retinal hyperspectral imaging in mouse models of Parkinson’s disease and healthy aging

Retinal hyperspectral imaging (HSI) is a non-invasive in vivo approach that has shown promise in Alzheimer’s disease. Parkinson’s disease is another neurodegenerative disease where brain pathobiology such as alpha-synuclein and iron overaccumulation have been implicated in the retina. However, it remains unknown whether HSI is altered in in vivo models of Parkinson’s disease, whether it differs from healthy aging, and the mechanisms which drive these changes. To address this, we conducted HSI in two mouse models of Parkinson’s disease across different ages; an alpha-synuclein overaccumulation model (hA53T transgenic line M83, A53T) and an iron deposition model (Tau knock out, TauKO). In comparison to wild-type littermates the A53T and TauKO mice both demonstrated increased reflectivity at short wavelengths ~ 450 to 600 nm. In contrast, healthy aging in three background strains exhibited the opposite effect, a decreased reflectance in the short wavelength spectrum. We also demonstrate that the Parkinson’s hyperspectral signature is similar to that from an Alzheimer’s disease model, 5xFAD mice. Multivariate analyses of HSI were significant when plotted against age. Moreover, when alpha-synuclein, iron or retinal nerve fibre layer thickness were added as a cofactor this improved the R2 values of the correlations in certain groups. This study demonstrates an in vivo hyperspectral signature in Parkinson’s disease that is consistent in two mouse models and is distinct from healthy aging. There is also a suggestion that factors including retinal deposition of alpha-synuclein and iron may play a role in driving the Parkinson’s disease hyperspectral profile and retinal nerve fibre layer thickness in advanced aging. These findings suggest that HSI may be a promising translation tool in Parkinson’s disease.

Dexmedetomidine and argon in combination against ferroptosis through tackling TXNIP-mediated oxidative stress in DCD porcine livers

Graft availability from donation after circulatory death (DCD) is significantly limited by ischaemia reperfusion (IR) injury. Effective strategies to mitigate IR injury in DCD grafts are essential to improve graft quality and expand the donor pool. In this study, liver grafts from DCD pigs were preserved in the University of Wisconsin (UW) solution saturated with 0.1 nM dexmedetomidine (Dex) and various concentrations of noble gases Argon (Ar) and/or Xenon (Xe) at 4 °C for 24 or 72 h. The combined 50% Ar and Dex provided maximum protection to liver grafts by reducing morphological damage, apoptosis, necroptosis, ferroptosis, hepatocyte glycogen depletion, reticulin framework collapse, iron deposition, and oxidative stress. In vitro, human liver Hep G2 cells were preserved in the UW solution saturated with 0.1 nM Dex and 50% Ar in combination at 4 °C for 24 h, followed by recovery in medium at 37 °C for up to 48 h to mimic clinical IR injury. This treatment significantly increased the expression of anti-oxidative stress proteins by promoting the translocation of thioredoxin-interacting protein (TXNIP) to mitochondria, thereby inhibiting ferroptosis, increasing plasma membrane integrity, and maintaining cell viability.In summary, The combination of 0.1 nM Dex and 50% Ar may be a promising strategy to reduce ferroptosis and other form cell death, and preserve liver grafts.

Visualizing alpha-synuclein and iron deposition in M83 mouse model of Parkinson's disease in vivo.

Abnormal alpha-synuclein (αSyn) and iron accumulation in the brain play an important role in Parkinson's disease (PD). Herein, we aim to visualize αSyn inclusions and iron deposition in the brains of M83 (A53T) mouse models of PD in vivo. The fluorescent pyrimidoindole derivative THK-565 probe was characterized by means of recombinant fibrils and brains from 10- to 11-month-old M83 mice. Concurrent wide-field fluorescence and volumetric multispectral optoacoustic tomography (vMSOT) imaging were subsequently performed in vivo. Structural and susceptibility weighted imaging (SWI) magnetic resonance imaging (MRI) at 9.4 T as well as scanning transmission x-ray microscopy (STXM) were performed to characterize the iron deposits in the perfused brains. Immunofluorescence and Prussian blue staining were further performed on brain slices to validate the detection of αSyn inclusions and iron deposition. THK-565 showed increased fluorescence upon binding to recombinant αSyn fibrils and αSyn inclusions in post-mortem brain slices from patients with PD and M83 mice. Administration of THK-565 in M83 mice showed higher cerebral retention at 20 and 40 min post-intravenous injection by wide-field fluorescence compared to nontransgenic littermate mice, in congruence with the vMSOT findings. SWI/phase images and Prussian blue indicated the accumulation of iron deposits in the brains of M83 mice, presumably in the Fe3+ form, as evinced by the STXM results. In conclusion, we demonstrated in vivo mapping of αSyn by means of noninvasive epifluorescence and vMSOT imaging and validated the results by targeting the THK-565 label and SWI/STXM identification of iron deposits in M83 mouse brains ex vivo.

Propofol ameliorates cognitive deficits following splenectomy in aged rats by inhibiting ferroptosis via the SIRT1/Nrf2/GPX4 pathway.

The aim of this study was to investigate the mechanism by which propofol reduces postoperative cognitive dysfunction after splenectomy in aged rats. The rats in the model group and propofol group were subjected to splenectomy, and anesthetized with isoflurane and propofol, respectively. Utilizing the western blotting to assess the expression of sirtuin-1 (SIRT1) in the hippocampus. Molecular docking technology was used to predict the binding ability of propofol and SIRT1. Behavioral tests were performed using the Morris water maze, and the hippocampus was isolated for mechanistic investigations. Molecular docking showed that propofol and SIRT1 had a strong binding affinity. The expression of SIRT1 and its related proteins Nrf2, HO-1, NQO1, and GPX4 in the model rats was decreased compared with the sham group. Moreover, the model group exhibited cognitive decline, such as extended escape latency and decreased number of platform crossings. Pathological analysis showed that the number of apoptotic neurons, the levels of oxidative stress and neuroinflammation, the iron deposition, and the expressions of ACSL4 and TFR1 were increased, while the expressions of SLC7A11 and FTH1 were decreased in the hippocampal CA1 region within the model group. These pathological changes in the propofol group were, however, less than those in the model group. Nevertheless, the SIRT1 inhibitor increased these pathological changes compared with the propofol group. Compared with isoflurane, propofol inhibits ferroptosis in the hippocampus of splenectomized rats by causing less downregulation of the SIRT1/Nrf2/GPX4 pathway, thereby reducing the negative impact on cognitive function.

Genesis of the Neoarchean Algoma-type banded iron formation: constraints from Fe isotope and element geochemistry of the Qian’an iron deposit, eastern North China craton

The Neoarchean Qian’an BIF deposit in eastern Hebei, eastern North China Craton has attracted extensive attention of study in the last decades, but the genesis, e.g., Fe sources, metallogenic mechanism, as well as tectonic attributes of the BIFs remains highly disputed. Based on field investigations, microscopic observations and geochemical analysis, this study tries to unravel the source characteristics of ore-forming materials in the Qian’an deposit. The results show that the chemical compositions of the BIF ore samples are mainly composed of TFe2O3 and SiO2, with minor Al2O3 and TiO2. The total trace element contents of the samples are relatively low. The PAAS-normalized REE distribution patterns of the ores show LREE depletion and HREE enrichment, with robust positive anomalies of Eu, Y and La. These characteristics indicate that the BIFs are attributed to dominant chemical precipitation originated from paleo-ocean with obvious volcanic hydrothermal contributions and minor clastic input. Their positive to no Ce anomalies and positive δ56Femagnetite values unveil that the iron was precipitated at low oxygen fugacity. These results, in collaboration with evidence from previous lithological, structural geology, metamorphic P-T paths, geochemistry, geochronology and numerical modeling studies, support a mantle plume model to explain the complicated tectono-thermal processes, and the sources of BIFs in Eastern Hebei, eastern North China Craton.

P-015 Impaired spermatogenesis in colitis: the role of interferon-γ mediated ferroptosis in sertoli cells by colitic CD4+ T cells

Abstract Study question Does colitis have an impact on spermatogenesis and what could be the potential mechanism? Summary answer Colitis causes sertoli cell ferroptosis and disrupts spermatogenesis in mice due to the migration of colitic CD4+ T cells that produce interferon-γ. What is known already In recent years, there has been a significant increase in rheumatic and inflammatory diseases. Epidemiological data reveals that dysregulated immune conditions can directly or indirectly impact male fertility and sexual function in patients of reproductive age. Inflammatory bowel disease (IBD), which encompasses Crohn’s disease and ulcerative colitis, is a chronic, recurring gastrointestinal inflammatory disorder characterized by bloody stools and weight loss. A study from a Swedish national cohort showed that IBD patients had diminished sperm fertility and increased sperm DNA fragmentation compared to healthy individuals. However, the precise mechanisms underlying male fertility problems in IBD remain unclear. Study design, size, duration In this study, C57BL/6 mice were kept under specific pathogen-free conditions. A murine colitis model that simulates human colitis histological features and symptoms was created using Dextran Sulfate Sodium (DSS). To establish the model, 2-2.5% DSS was added to the mice’s drinking water from days 0 to 7, followed by a three-day recovery period. Participants/materials, setting, methods Testis, epididymis and colon sections were stained with hematoxylin and eosin for histological analysis. The localization and phenotype of infiltrated lymphocytes in epididymis and testis were studied by immunostaining and flow cytometry. Sperm functions including motility, viability, and DNA integrity were assessed by standard assays. Iron, malondialdehyde, and reactive oxygen species (ROS) levels were analysed by commercial kit. Main results and the role of chance Colitis was found to impair male fertility in DSS-induced colitic mice, causing testis and epididymis tissue damage along with inflammatory cell infiltration. Colitis altered the immune cell phenotypes in the testis and epididymis. The proportion and absolute cell count of CD4+ T cells and CD19+ B cells increased after colon inflammation. Testicular sertoli cells in colitic mice exhibited ferroptosis, characterized by increased levels of iron deposition, malondialdehyde, and ROS. We assessed sperm parameters from the cauda epididymis of mice. Compared to the control group, there were significant reduction in sperm concentration, motility, viability and DNA integrity in the group with murine colitis induction. Consistently, we observed lower numbers of active pups from the fathers of the colitis group compared to control mice. CD4+ T cells with interferon-γ producing capabilities accumulated in the testes of colitis mice. Leukocyte flow cytometric analysis and parabiotic mouse model further demonstrated that colitis promoted pathogenic CD4+ T cells migration to the testis through circulation. The treatment of anti-CD4 antibody, anti-interferon-γ antibody or ferroptosis inhibitor can attenuate the colitis-associated testis pathologies. Limitations, reasons for caution Our study was conducted exclusively in mice. The pathogenic effect and the corresponding mechanism of colitis on male fertility in humans still needs to be confirmed. Wider implications of the findings Our team identified the mechanism linking dysregulated gut immune cell activity to testicular dysfunction. By identifying specific molecules on colitic immune cells, which allow their infiltration into the testis, may pave the way for a new therapeutic approach potentially improving the prognosis of colitis and related fertility impairments. Trial registration number not applicable

Correlation between plasma biochemical parameters and cardio-hepatic iron deposition in thalassemia major patients

Introduction Major Thalassemia patients suffer from iron overload and organ damage, especially heart and liver damage. Early diagnosis and treatment with a chelator can reduce the complications and mortality of iron overload. Therefore, we aimed to investigate the biochemical and hematological predictors as an alternative and indirect indicator of iron deposition in heart and liver cells in comparison with the MRI T2* method as the gold standard. Material and method MRI T2* was evaluated in the heart and liver tissues of 62 major beta-thalassemia patients undergoing regular transfusion and chelator therapy. Biochemical and hematological factors were also measured, including serum ferritin, serum electrolytes, liver enzymes, hemoglobin, blood glucose, and serum magnesium. The correlation between these factors was assessed using statistical evaluations. Result Serum ferritin had a positive and significant correlation with liver siderosis based on MRI T2* (p-value = .015), and no significant association was observed with cardiac siderosis (p-value = .79). However, there was a significant positive correlation between cardiac iron deposition and fasting blood sugar level (p-value = −.049), and plasma level of liver enzymes (alanine aminotransferase (ALT) (p-value = .001), aspartate aminotransferase (AST ((p-value = .01)). Moreover, there was a significant negative correlation between cardiac iron overload and plasma magnesium level (p-value = .014). According to MRI T2*, there was no significant correlation between cardiac and hepatic iron overload (p value = .36). Conclusion An increase in blood sugar or liver enzymes and a decrease in serum magnesium was associated with an increase in cardiac iron overload based on MRI T2*. Liver iron overload based on MRI T2* had a significant correlation with serum ferritin.

Cobalt enrichment and metallogenic mechanism of the Galinge skarn iron deposit in the Eastern Kunlun metallogenic belt, western China

Skarn iron deposits, as representative examples of Co-rich magmatic-hydrothermal deposits, are attracting increasing attention due to rising cobalt demand worldwide. However, the specific Co enrichment mechanisms and metallogenic processes in skarn deposits remain elusive. This study presents high-precision in situ U–Pb geochronological data for garnet from skarns, major and trace element analyses of sulfarsenides and sulfides, and X-ray mapping in the Galinge deposit. The Galinge skarn iron deposit formed at 237.1 ± 0.3 Ma (garnet U–Pb dating), during which time the region was in the post-collisional stage. During this period, the crust was thickened, causing delamination of the lithospheric mantle, which further led to the upwelling of asthenospheric materials and partial melting of the lower crust. As the resultant mixed magma ascended, it reacted with carbonate strata to form skarn deposits. Cobalt shows two occurrence modes in the Galinge deposit: independent cobalt minerals such as skutterudite and cobaltite, and isomorphic substitution of Co with other metals in ore minerals (arsenopyrite, pyrrhotite, sphalerite, pyrite, magnetite, and chalcopyrite). Our results revealed that arsenopyrite is the most cobalt-enriched ore mineral in the Galinge deposit, with an average Co content of 34,077 ppm. Other minerals generally contain insignificant Co contents of less than 500 ppm, including sphalerite (471 ppm) > pyrite (194 ppm) > pyrrhotite (145 ppm) > alabandite (∼100 ppm) > magnetite (7 ppm) > chalcopyrite (2 ppm). In arsenopyrite, cobalt and nickel replace iron in accordance with the inverse correlation between the concentrations of cobalt and nickel (wt%) and that of iron. In pyrite and chalcopyrite, a portion of the isomorphic cobalt substitutes for Fe or Cu. The weak correlation between Co (ppm) and Cu or Fe (wt%) indicates that only isomorphic cobalt is carried out by substituting Fe or Cu. The negative correlation between Co + Fe and Zn or Mn suggests that cobalt and iron replace Zn or Mn in sphalerite and alabandite. No evidence of element substitution was observed in pyrrhotite. Our study highlights that during the early mineralization stage, cobalt in the magmatic-hydrothermal fluids migrated in the form of CoCl42-. Subsequently, under the influence of an increase in pH, CoCl42- reacts with H3AsO30 to form CoAs3 (skutterudite). With the continuous precipitation of arsenides and sulfarsenides, the As/S (reduced) ratio decreased, leading to the CoAs3 (skutterudite) changing to CoAsS (cobaltite).

Nano-drug-based Targeted Therapy Alleviates Ferroptosis-induced Liver Toxicity

Abstract: Iron is an essential inorganic element for an organism, with several metabolic activities. The glycoproteins ferritin and transferrin, which assist in carrying iron to various body parts, are used to store iron. In terms of iron uptake, storage, and excretion, equilibrium should be preserved. Ferroptosis is an iron-dependent form of cell death with traits like lipid peroxidation buildup and ROS generation. It is distinct from other forms of cell death visually and biochemically. Many cancer cells block ferroptosis by controlling different cell survival pathways. Compared to healthy, normal cells, cancer cells are more dependent on iron. A subgroup of tumor cells known as cancer stem cells has stem-like characteristics. These are in charge of metastasis and recurrence. The liver plays a significant part in the body's detoxifying process and is the primary iron storage organ. Numerous liver disorders are frequently accompanied by excessive iron accumulation. Due to excessive iron deposits, the liver is more vulnerable to oxidative damage, which can occasionally result in liver failure. Chemotherapy, which involves administering several medications to treat cancer, may be hazardous to the body's other cells. The ferroptosis condition and high iron accumulation can potentially impair liver function. A tailored drug delivery method may ameliorate the impact of excessive iron accumulation and favorably correlate with liver damage, consequently enhancing liver function.

The role of Fe(II)-silicate gel in the generation of Archean and Paleoproterozoic chert

Abstract Chert is abundant in Archean and Paleoproterozoic rocks and is commonly densely packed with authigenic Fe(II)-silicate nanoparticles such as greenalite, indicating a close relationship between iron and silica deposition. We investigate the relationship between Fe(II)-silicate minerals and dissolved silica during precipitation, settling, and diagenesis using anoxic synthesis, sorption, and heating experiments. Excess silica is associated with the solid during precipitation, resulting in high molar Si/Fe ratios (&amp;lt;1.52) that exceed that of stoichiometric greenalite (0.67). At pH 8–8.5, silica sorbs to the surface, reaching sorption densities of 0.68 mmol Si per mmol Fe(II)-silicate. Furthermore, excess Si is released upon heating as the Fe(II)-silicate gel crystallizes. We suggest that Fe(II)-silicate minerals acted as an effective Si shuttle between the water column and the sediments in Archean and Paleoproterozoic marine environments, providing sites for the growth of early diagenetic chert, consistent with observations from the sedimentary record. Our results explain the exceptional preservation of greenalite in early chert and indicate that these minerals could provide a robust archive of marine geochemical data.

Alpha-synuclein affects certain iron transporters of BV2 microglia cell through its ferric reductase activity.

Alpha-synuclein (α-syn) is a major component of Lewy bodies, which is a biomarker of Parkinson's disease (PD). It accumulates in substantia nigra pars compacta (SNpc) to form insoluble aggregates and cause neurotoxicity, which is often accompanied by iron deposition. We compared the iron reductase activity between monomeric α-syn (M-α-syn) and oligomeric α-syn (O-α-syn) and investigated the effect of α-syn on iron metabolism of BV2 microglia cells as well. α-syn had ferric reductase activity, and O-α-syn had stronger enzyme activity than M-α-syn. M-α-syn upregulated iron uptake protein, divalent metal transporter1 (DMT1) expression, and iron influx but did not regulate iron release protein ferroportin1 (FPN1) expression and iron efflux. O-α-syn elevated the expression of both DMT1 and FPN1 and thus increased the iron influx and efflux in BV2 microglial cells, but the expressions of iron regulatory protein1 (IRP1) and hypoxia-inducible factor 2α (HIF-2α) had no significant change. Moreover, both M-α-syn and O-α-syn could increase the mRNA expressions of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in BV2 microglia cells. Both types of α-syn can activate microglia, which leads to increased expressions of proinflammatory factors. α-syn can affect DMT1 and FPN1 expressions in BV2 microglia cells, which might be through its ferric reductase activity.NEW & NOTEWORTHY The effects of monomeric α-syn (M-α-syn) and oligomeric α-syn (O-α-syn) on the iron metabolism of BV2 microglia cells were detected by exogenous α-syn treatment. This study provides a strong experimental basis for α-syn involvement in iron metabolism in microglia.

GDF11 OVEREXPRESSION ALLEVIATES SEPSIS-INDUCED LUNG MICROVASCULAR ENDOTHELIAL BARRIER DAMAGE BY ACTIVATING SIRT1/NOX4 SIGNALING TO INHIBIT FERROPTOSIS.

Sepsis is a lethal clinical syndrome, and acute lung injury (ALI) is the earliest and most serious complication. We aimed to explore the role of growth differentiation factor 11 (GDF11) in sepsis-induced dysfunction of lung microvascular endothelial barrier in vivo and in vitro to elucidate its potential mechanism related to sirtuin 1 (SIRT1)/NADPH oxidase 4 (NOX4) signaling. Cecal ligation and puncture (CLP)-induced sepsis mice and lipopolysaccharide (LPS)-induced pulmonary microvascular endothelial cells (PMECs) were used in this study. Histopathological changes in lung tissues were tested by hematoxylin-eosin staining. Lung wet-to-dry weight ratio and inflammatory factors contents in bronchoalveolar lavage fluid were assessed. Evens blue index, trans-epithelial electrical resistance, and expression of zona occludens 1 (ZO-1), occludin-1, and claudin-1 were used to evaluate alveolar barrier integrity. Reactive oxygen species, lipid peroxidation, and ferroptosis markers were analyzed. Iron deposition in the lung tissues was assessed using Prussian blue staining. Intracellular Fe 2+ level was detected using FerroOrange staining. Additionally, expression of GDF11, SIRT1, and NOX4 was estimated with western blot. Then, EX527, a SIRT1 inhibitor, was employed to treat GDF11-overexpressed PMECs with LPS stimulation to clarify the regulatory mechanism. Results showed that GDF11 overexpression attenuated sepsis-induced pathological changes and inflammation and maintained alveolar barrier integrity. Moreover, GDF11 overexpression inhibited ferroptosis, upregulated SIRT1 expression and downregulated NOX4 expression. Additionally, EX527 treatment relieved the impacts of GDF11 overexpression on ferroptosis and destruction of integrity of human pulmonary microvascular endothelial cells exposed to LPS. Taken together, GDF11 overexpression could alleviate sepsis-induced lung microvascular endothelial barrier damage by activating SIRT1/NOX4 signaling to inhibit ferroptosis. Our findings potentially provide new molecular target for clinical therapy of ALI.

Ginsenoside Rg3 attenuates myocardial ischemia/reperfusion-induced ferroptosis via the keap1/Nrf2/GPX4 signaling pathway

BackgroundGinsenoside Rg3 is a component of ginseng that protects against myocardial ischemia/reperfusion (MI/R) injury. Ferroptosis is a new form of cell death characterized by oxidative damage to phospholipids. The purpose of this study was to examine the role and of ginsenoside Rg3 in MI/R and the mechanism.MethodsA mouse model of left anterior descending (LAD) ligation-induced myocardial ischemia/reperfusion (MI/R) injury and oxygen-glucose deprivation/reperfusion (OGD/R) were used as in vitro and in vivo models, respectively. Echocardiographic analysis, 2,3,5-triphenyltetrazolium chloride (TTC) staining and hematoxylin-eosin (H&E) staining were used to assess the cardioprotective effects of ginsenoside Rg3. Western blotting, biochemical analysis, small interfering RNA analysis and molecular docking were performed to examine the underlying mechanism.ResultsGinsenoside Rg3 improved cardiac function and infarct size in mice with MI/R injury. Moreover, ginsenoside Rg3 increased the expression of the ferroptosis-related protein GPX4 and inhibited iron deposition in mice with MI/R injury. Ginsenoside Rg3 also activated the Nrf2 signaling pathway. Ginsenoside Rg3 attenuated myocardial ischemia/reperfusion-induced ferroptosis via the Nrf2 signaling pathway. Notably, ginsenoside Rg3 regulated the keap1/Nrf2 signaling pathway to attenuate OGD/R-induced ferroptosis in H9C2 cells. Taken together, ginsenoside Rg3 attenuated myocardial ischemia/reperfusion-induced ferroptosis via the keap1/Nrf2/GPX4 signaling pathway.ConclusionsOur findings demonstrated that ginsenoside Rg3 ameliorate MI/R-induced ferroptosis via the keap1/Nrf2/GPX4 signaling pathway.

The involvement of IRP2-induced ferroptosis through the p53-SLC7A11-ALOX12 pathway in Parkinson's disease

Disturbance in iron homeostasis has been described in Parkinson's disease (PD), in which iron regulatory protein 2 (IRP2) plays a crucial role. IRP2 deletion resulted in the misregulation of iron metabolism and subsequent neurodegeneration. However, growing evidence showed that the levels of IRP2 were increased in the substantia nigra (SN) in MPTP-induced PD mice. To further clarify the role of increased IRP2 in PD, we developed IRP2-overexpressed mice by microinjecting AAV-Ireb2 in the SN. These mice showed decreased motor ability, abnormal gait and anxiety. Iron deposits induced by increased TFR1 and dopaminergic neuronal loss were observed in the SN. When these mice were treated with MPTP, exacerbated dyskinesia and dopaminergic neuronal loss were observed. In addition, TP53 was post-transcriptionally upregulated by IRP2 binding to the iron regulated element (IRE) in its 3′ untranslated region. This resulted in increased lipid peroxidation levels and induced ferroptosis through the SLC7A11-ALOX12 pathway, which was independent of GPX4. This study revealed that IRP2 homeostasis in the SN was critical for PD progression and clarified the molecular mechanism of ferroptosis caused by IRP2.