Increased Iron Accumulation Research Articles

Inhibition of CISD2 enhances sensitivity to doxorubicin in diffuse large B-cell lymphoma by regulating ferroptosis and ferritinophagy.

CDGSH iron-sulfur domain 2 (CISD2), an iron-sulfur protein with a [2Fe-2S] cluster, plays a pivotal role in the progression of various cancers, including Diffuse Large B-cell Lymphoma (DLBCL). However, the mechanisms by which CISD2 regulates the occurrence and development of DLBCL remain to be fully elucidated. The potential role of CISD2 as a predictive marker in DLBCL patients treated with the R-CHOP regimen was investigated through bioinformatics analysis and clinical cohort studies. DLBCL cell lines (SUDHL-4 and HBL-1) were employed in this research. Adenoviral (AV) plasmids were used to either silence or overexpress CISD2 in these DLBCL cell lines. Additionally, the induction of ferroptosis in DLBCL cell lines was assessed. Various parameters, including cell proliferation, intracellular free iron levels, lipid peroxides, reactive oxygen species (ROS), and mitochondrial membrane potential (MMP), were measured. Furthermore, the expression of proteins associated with ferroptosis and ferritinophagy was analyzed. Drug-resistant DLBCL cell lines were developed by gradually increasing doxorubicin (DOX) concentration over 6months. The biological role of CISD2 in these drug-resistant DLBCL cell lines was subsequently assessed. Elevated CISD2 levels were found to be associated with decreased sensitivity of DLBCL patients to the R-CHOP regimen, as indicated by bioinformatics and clinical cohort analysis. Silencing CISD2 significantly reduced cell proliferation, increased iron accumulation, depleted glutathione (GSH), and elevated malondialdehyde (MDA) levels, alongside the accumulation of ROS and increased MMP. Additionally, BECN1 and NCOA4 expressions were upregulated, while p62, FTH1, and GPX4 expressions were downregulated. Conversely, overexpression of CISD2 reversed these effects. Treatment of DLBCL cell lines with Erastin led to decreased CISD2 levels. Notably, in drug-resistant DLBCL cell lines, CISD2 knockdown promoted ferroptosis and ferritinophagy, restoring sensitivity to DOX and enhancing the efficacy of Erastin treatment. Our findings suggest that CISD2 may play a role in the drug resistance observed in DLBCL patients. Inhibition of CISD2 could enhance ferroptosis and ferritinophagy, potentially improving the sensitivity of DLBCL cells to DOX treatment.

Sophora alopecuroide - Taraxacum decoction (STD) inhibits non-small cell lung cancer via inducing ferroptosis and modulating tumor immune microenvironment

The Sophora alopecuroide - Taraxacum Decoction (STD) is a traditional Chinese herbal formulation that has demonstrated significant potential in combating tumors. Despite its apparent effectiveness, the specific mechanisms through which STD exerts its anti-tumor properties remain largely unexplored and are yet to be fully understood. In our study, we provided evidence that STD effectively inhibits cellular growth and movement, as well as halting the cell cycle at the G2/M checkpoint. Furthermore, our pharmacological network analysis indicated that STD might induce cell death through a process known as ferroptosis. This hypothesis was substantiated by observing important biochemical changes associated with ferroptosis, including a decrease in glutathione (GSH) levels, an increase in iron accumulation, and elevated levels of reactive oxygen species (ROS) and lipid peroxidation. Additionally, we noted a significant rise in the expression of pro-ferroptosis genes such as Keap1, Nrf2, and HO-1, further supporting our findings. Significantly, and in line with the in vitro results, STD also showed a strong ability to inhibit tumor growth by inducing ferroptosis in a subcutaneous tumor model. Additionally, STD treatment changed the tumor immune microenvironment (TIME), as seen by an increase in CD107a+ CD8 and NK cells within the tumor. These findings demonstrate that STD induces ferroptosis and alters TIME to combat tumors, suggesting that STD may be a viable alternative treatment for patients with NSCLC.

Lifestyle, biological, and genetic factors related to brain iron accumulation across adulthood

Iron is necessary for many neurobiological mechanisms, but its overaccumulation can be harmful. Factors triggering age-related brain iron accumulation remain largely unknown and longitudinal data are insufficient. We examined associations between brain iron load and accumulation and, blood markers of iron metabolism, cardiovascular health, lifestyle factors (smoking, alcohol use, physical activity, diet), and ApoE status using longitudinal data from the IronAge study (n = 208, age = 20–79, mean follow-up time = 2.75 years). Iron in cortex and basal ganglia was estimated with magnetic resonance imaging using quantitative susceptibility mapping (QSM). Our results showed that (1) higher peripheral iron levels (i.e., composite score of blood iron markers) were related to greater iron load in the basal ganglia; (2) healthier diet was related to higher iron levels in the cortex and basal ganglia, although for the latter the association was significant only in younger adults (age = 20–39); (3) worsening cardiovascular health was related to increased iron accumulation; (4) younger ApoE ε4 carriers accumulated more iron in basal ganglia than younger non-carriers. Our results demonstrate that modifiable factors, including lifestyle, cardiovascular, and physiological ones, are linked to age-related brain iron content and accumulation, contributing novel information on potential targets for interventions in preventing brain iron-overload.

Asiatic acid induces lung cancer toxicity by triggering SRC-mediated ferroptosis

Ferroptosis is a recently discovered form of regulated cell death that shows promise as a novel approach for inducing tumor cell death in cancer treatment, with significant research potential. Asiatic acid (AA), a key component of the traditional Chinese medicine Centella asiatica, has been identified as having potential therapeutic benefits for various diseases, particularly cancer. Non-small cell lung cancer (NSCLC) is a challenging and prevalent form of cancer to treat. In our study, we utilized network pharmacology, molecular docking, and experimental methods to investigate the potential of AA in treating NSCLC and to elucidate its role in inhibiting cancer through the ferroptosis pathway. Through network pharmacology analysis, we identified that AA targets the core NSCLC protein SRC through the ferroptosis pathway. Our experiments demonstrated that treatment with AA led to increased iron accumulation, mitochondrial membrane potential, and expression of ferroptosis markers glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), and acyl-CoA synthetase long chain family member 4 (ACSL4) in NSCLC cells, confirming the induction of ferroptosis. In conclusion, AA has the potential to target SRC and induce NSCLC cell death through the ferroptosis pathway, offering a promising approach for cancer treatment.

Host response to Aplysia Abyssovirus 1 in nervous system and gill

The California sea hare (Aplysia californica) is a model for age associated cognitive decline. Recent researched identified a novel nidovirus, Aplysia Abyssovirus 1, with broad tropism enriched in the Aplysia nervous system. This virus is ubiquitous in wild and maricultured, young and old animals without obvious pathology. Here we re-evaluated gene expression data from several previous studies to investigate differential expression in the nervous system and gill in response to virus and aging as well as the mutational spectrum observed in the viral sequences obtained from these datasets. Viral load and age were highly correlated, indicating persistent infection. Upregulated genes in response to virus were enriched for immune genes and signatures of ER and proteostatic stress, while downregulated genes were enriched for mitochondrial metabolism. Differential expression with respect to age suggested increased iron accumulation and decreased glycolysis, fatty acid metabolism, and proteasome function. Interaction of gene expression trends associated with viral infection and aging suggest that viral infection likely plays a role in aging in the Aplysia nervous system. Mutation analysis of viral RNA identified signatures suggesting ADAR and AID/APOBEC like deaminase act as part of Aplysia anti-viral defense.

SUGP2 p.(Arg639Gln) variant is involved in the pathogenesis of hemochromatosis via the CIRBP/BMPER signaling pathway.

Pathogenic variants in HFE and non-HFE genes have been identified in hemochromatosis in different patient populations, but there are still a certain number of patients with unexplained primary iron overload. We recently identified in Chinese patients a recurrent p.(Arg639Gln) variant in SURP and G-patch domain containing 2 (SUGP2), a potential mRNA splicing-related factor. However, the target gene of SUGP2 and affected iron-regulating pathway remains unknown. We aimed to investigate the pathogenicity and underlying mechanism of this variant in hemochromatosis. RNA-seq analysis revealed that SUGP2 knockdown caused abnormal alternative splicing of CIRBP pre-mRNA, resulting in an increased normal splicing form of CIRBP V1, which in turn increasedthe expression of BMPER by enhancing its mRNA stability and translation. Furthermore, RNA-protein pull-down and RNA immunoprecipitation assays revealed that SUGP2 inhibited splicing of CIRBP pre-mRNA by a splice site variant at CIRBP c.492 and was more susceptible to CIRBP c.492 C/C genotype. Cells transfected with SUGP2 p.(Arg639Gln) vector showed up-regulation of CIRBP V1 and BMPER expression and down-regulation of pSMAD1/5 and HAMP expression. CRISPR-Cas9 mediated SUGP2 p.(Arg622Gln) knock-in mice showed increased iron accumulation in the liver, higher total serum iron, and decreased serum hepcidin level. A total of 10 of 54 patients with hemochromatosis (18.5%) harbored the SUGP2 p.(Arg639Gln) variant and carried CIRBP c.492 C/C genotype, and had increased BMPER expression in the liver. Altogether, the SUGP2 p.(Arg639Gln) variant down-regulates hepcidin expression through the SUGP2/CIRBP/BMPER axis, which may represent a novel pathogenic factor for hemochromatosis.

Iron Supplementation of Pregnant Sows to Prevent Iron Deficiency Anemia in Piglets: A Procedure of Questionable Effectiveness.

In pigs, iron deficiency anemia (IDA) is a common disorder that occurs during the early postnatal period, leading to the stunted growth and increased mortality of piglets. The main cause of IDA is low iron stores in the liver of newborn piglets; these stores constitute the main source of iron needed to satisfy the erythropoietic requirements of the piglets in their first weeks of life. Insufficient iron stores in piglets are usually due to the inadequate placental iron transfer from the sow to the fetuses. Therefore, iron supplementation in pregnant sows has been implemented to enhance placental iron transfer and increase iron accumulation in the liver of the fetuses. Over the years, several oral and parenteral approaches have been attempted to supplement sows with various iron preparations, and consequently, to improve piglets' red blood cell indices. However, there is debate with regard to the effectiveness of iron supplementation in pregnant sows for preventing IDA in newborn piglets. Importantly, this procedure should be carried out with caution to avoid iron over-supplementation, which can lead to iron toxicity. This article aims to critically review and evaluate the use of iron supplementation in pregnant sows as a procedure for preventing IDA in piglets.

Investigating the toxic mechanism of iron oxide nanoparticles-induced oxidative stress in tadpole (Duttaphrynus melanostictus): A combined biochemical and molecular study

Metal oxide nanomaterials have toxicity towards aquatic organisms, especially microbes and invertebrates, but little is known about their impact on amphibians. We conducted a study on Duttaphrynus melanostictus (D. melanostictus) tadpoles to explore the chronic toxicity effects of iron oxide nanoparticles (IONPs) and the underlying mechanisms of IONPs-induced oxidative stress. IONPs exposure led to increased iron accumulation in the blood, liver, and kidneys of tadpoles, significantly affecting blood parameters and morphology. Higher IONPs concentrations (10 and 50 mg L−1) triggered reactive oxygen species generation, resulting in lipid peroxidation, oxidative stress, and pronounced toxicity in tadpoles. The activity levels of antioxidant enzymes/proteins (SOD, CAT, albumin, and lysozyme) decreased after IONPs exposure, and immunological measures in the blood serum were significantly reduced compared to the control group. Molecular docking analysis revealed that IONPs primarily attached to the surface of SOD/CAT/albumin/lysozyme through hydrogen bonding and hydrophobic forces. Overall, this study emphasizes the ability of IONPs to induce oxidative damage by decreasing immunological profiles such as ACH50 (34.58 ± 2.74 U mL−1), lysozyme (6.94 ± 0.82 U mL−1), total Ig (5.00 ± 0.35 g dL−1), total protein (1.20 ± 0.17 g dL−1), albumin (0.52 ± 0.01 g dL−1) and globulin (0.96 ± 0.01 g dL−1) and sheds light on their potential toxic effects on tadpoles.

Ovaries of estrogen receptor 1-deficient mice show iron overload and signs of aging.

Estrogens are crucial regulators of ovarian function, mediating their signaling through binding to estrogen receptors. The disruption of the estrogen receptor 1 (Esr1) provokes infertility associated with a hemorrhagic, cystic phenotype similar to that seen in diseased or aged ovaries. Our previous study indicated the possibility of altered iron metabolism in Esr1-deficient ovaries showing massive expression of lipocalin 2, a regulator of iron homeostasis. Therefore, we examined the consequences of depleting Esr1 in mouse ovaries, focusing on iron metabolism. For that reason, we compared ovaries of adult Esr1-deficient animals and age-matched wild type littermates. We found increased iron accumulation in Esr1-deficient animals by using laser ablation inductively coupled plasma mass spectrometry. Western blot analysis and RT-qPCR confirmed that iron overload alters iron transport, storage and regulation. In addition, trivalent iron deposits in form of hemosiderin were detected in Esr1-deficient ovarian stroma. The depletion of Esr1 was further associated with an aberrant immune cell landscape characterized by the appearance of macrophage-derived multinucleated giant cells (MNGCs) and increased quantities of macrophages, particularly M2-like macrophages. Similar to reproductively aged animals, MNGCs in Esr1-deficient ovaries were characterized by iron accumulation and strong autofluorescence. Finally, deletion of Esr1 led to a significant increase in ovarian mast cells, involved in iron-mediated foam cell formation. Given that these findings are characteristics of ovarian aging, our data suggest that Esr1 deficiency triggers mechanisms similar to those associated with aging.

A ROS-responsive loaded desferoxamine (DFO) hydrogel system for traumatic brain injury therapy

Traumatic brain injury (TBI) produces excess iron, and increased iron accumulation in the brain leads to lipid peroxidation and reactive oxygen species (ROSs), which can exacerbate secondary damage and lead to disability and death. Therefore, inhibition of iron overload and oxidative stress has a significant role in the treatment of TBI. Functionalized hydrogels with iron overload inhibiting ability and of oxidative stress inhibiting ability will greatly contribute to the repair of TBI. Herein, an injectable, post-traumatic microenvironment-responsive, ROS-responsive hydrogel encapsulated with deferrioxamine mesylate (DFO) was developed. The hydrogel is rapidly formed via dynamic covalent bonding between phenylboronic acid grafted hyaluronic acid (HA-PBA) and polyvinyl alcohol (PVA), and phenylboronate bonds are used to respond to and reduce ROS levels in damaged brain tissue to promote neuronal recovery. The release of DFO from HA-PBA/PVA hydrogels in response to ROS further promotes neuronal regeneration and recovery by relieving iron overload and thus eradicating ROS. In the Feeney model of Sprague Dawley rats, HA-PBA/PVA/DFO hydrogel treatment significantly improved the behavior of TBI rats and reduced the area of brain contusion in rats. In addition, HA-PBA/PVA/DFO hydrogel significantly reduced iron overload to reduce ROS and could effectively promote post-traumatic neuronal recovery. Its effects were also explored, and notably, HA-PBA/PVA/DFO hydrogel can reduce iron overload as well as ROS, thus protecting neurons from death. Thus, this injectable, biocompatible and ROS-responsive drug-loaded hydrogel has great potential for the treatment of TBI. This work suggests a novel method for the treatment of secondary brain injury by inhibiting iron overload and the oxidative stress response after TBI.

Resveratrol protects against doxorubicin-induced cardiotoxicity by attenuating ferroptosis through modulating the MAPK signaling pathway

Doxorubicin (Dox) is a widely used antitumor agent with dose-dependent and cumulative cardiotoxic effects. Resveratrol (Res) is a natural non-flavonoid polyphenol that can potentially provide cardiovascular benefits. We aimed to estimate the protective effect of Res on Dox-induced cardiotoxicity (DIC) and explore whether it was related to attenuating ferroptosis. We established DIC models in C57BL/6 J mice, H9C2 cardiomyoblasts, and neonatal rat cardiomyocytes (NRCMs). We further treated H9C2 cells with RSL3, a ferroptosis agonist, to investigate whether Res exerted protective effects through inhibiting ferroptosis. Ferrostatin-1 (Fer-1) was applied to suppress ferroptosis. Dox treatment caused cardiac dysfunction and resulted in apparent ferroptotic damage in cardiac tissue, involving increased iron accumulation, glutathione depletion, increased expression of ferroptosis-related proteins, and decreased expression of glutathione peroxidase 4, which were alleviated by Fer-1 and Res administration. These findings were also confirmed in Dox-treated H9C2 cells and NRCMs, with Fer-1 and Res effectively attenuating Dox-induced cytotoxicity and ferroptosis. Furthermore, Res protected H9C2 cells from RSL3-induced ferroptotic cell death, and the protective effect was similar to that of Fer-1. Both Dox and RSL3 treatment increased the phosphorylation levels of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinases; however, these changes were hindered by Res. This study demonstrates that Res effectively alleviates DIC by suppressing ferroptosis possibly through modulating the MAPK signaling pathway. Our results highlight that targeting ferroptosis can be a potential cardioprotective strategy for DIC.

Ginsenoside Rg3 promotes hepatic stellate cell ferroptosis by epigenetically regulating ACSL4 to suppress liver fibrosis progression

BackgroundGinsenoside Rg3 (G-Rg3), extracted from Panax notoginseng, possesses hepatoprotective properties. Hepatic stellate cells (HSCs) activation is responsible for liver fibrosis. Recent studies have reported the suppressive effects of G-Rg3 on HSC activation and proliferation. Ferroptosis is a novel iron regulated cell death. ACSL4, a key indicator of ferroptosis, is commonly methylated in various diseases. PurposeHowever, the role of ACSL4 methylation-mediated HSC ferroptosis in G-Rg3 inhibition of hepatic fibrosis needs to be explored. MethodsEffects of G-Rg3 on inhibiting fibrosis were evaluated in vivo and in vitro. The impact of G-Rg3 on HSC ferroptosis was assessed in vitro. Furthermore, the expression of ACSL4, ACSL4 methylation and microRNA-6945–3p (miR-6945–3p) levels were determined. ResultsG-Rg3 significantly alleviated CCl4-induced liver fibrosis, accompanied by collagen downregulation. In vitro, G-Rg3 contributed to HSC inactivation, leading to decreased collagen production. G-Rg3 induced HSC ferroptosis, characterized by increased iron accumulation, depletion of glutathione, malondialdehyde levels, and generation of lipid reactive oxygen species. Moreover, G-Rg3 promoted ACSL4 demethylation and restored its expression. Notably, DNMT3B counteracted the effect of G-Rg3-mediated inhibition of ACSL4 methylation and was targeted by miR-6945–3p. Further investigations revealed that G-Rg3 suppressed ACSL4 methylation through miR-6945–3p-mediated DNMT3B inhibition. Consistent with this, miR-6945–3p inhibition reversed G-Rg3-induced ACSL4 expression and HSC ferroptosis. ConclusionG-Rg3 inhibits ACSL4 methylation by miR-6945–3p-mediated DNMT3B inhibition, thereby promoting HSC ferroptosis and mitigating liver fibrosis.

MsYSL6, A Metal Transporter Gene of Alfalfa, Increases Iron Accumulation and Benefits Cadmium Resistance.

Iron (Fe) is necessary for plant growth and development. The mechanism of uptake and translocation in Cadmium (Cd) is similar to iron, which shares iron transporters. Yellow stripe-like transporter (YSL) plays a pivotal role in transporting iron and other metal ions in plants. In this study, MsYSL6 and its promoter were cloned from leguminous forage alfalfa. The transient expression of MsYSL6-GFP indicated that MsYSL6 was localized to the plasma membrane and cytoplasm. The expression of MsYSL6 was induced in alfalfa by iron deficiency and Cd stress, which was further proved by GUS activity driven by the MsYSL6 promoter. To further identify the function of MsYSL6, it was heterologously overexpressed in tobacco. MsYSL6-overexpressed tobacco showed better growth and less oxidative damage than WT under Cd stress. MsYSL6 overexpression elevated Fe and Cd contents and induced a relatively high Fe translocation rate in tobacco under Cd stress. The results suggest that MsYSL6 might have a dual function in the absorption of Fe and Cd, playing a role in the competitive absorption between Fe and Cd. MsYSL6 might be a regulatory factor in plants to counter Cd stress. This study provides a novel gene for application in heavy metal enrichment or phytoremediation and new insights into plant tolerance to toxic metals.

Ferritin was involved in interleukin-17A enhanced osteogenesis through autophagy activation

Periodontitis is a prevalent inflammatory immune disease that involves tissue inflammation and excessive bone loss. In murine periodontitis models and periodontitis patients, upregulated interleukin-17A (IL-17A) expression was observed, and its level seemed to correlate with the disease severity. In this study, we intended to investigate the specific role of ferritin, a critical iron storage protein, in IL-17A enhanced osteogenic differentiation as well as the underlying mechanism. Under osteogenic induction, IL-17A stimulation promoted differentiation and mineralization of murine calvarial osteoblasts. In addition, increased iron accumulation and ferritin expression were detected in osteoblasts treated with IL-17A, indicating an alteration in iron metabolism during osteogenesis. Administration of iron chelator deferoxamine (DFO) and transfection with small interfering RNA (siRNA) targeting ferritin heavy chain (FTH) further revealed that ferritin suppression consequently inhibited osteoblast differentiation. Autophagy activation was also found upon IL-17A stimulation, which played a positive role in osteogenic differentiation and was subsequently suppressed by DFO or siRNA targeting FTH. In conclusion, IL-17A induced ferritin expression in osteoblasts, which further enhanced osteogenic differentiation via autophagy activation. These findings may provide further insight into the role of IL-17A in osteoblast differentiation and demonstrate ferritin as a potential target in modulating alveolar bone homeostasis.

Iron chelators as a therapeutic option for Alzheimer's disease-A mini-review.

Neurodegenerative disorders, particularly Alzheimer's disease (AD), remain a great challenge regarding the finding of effective treatment, one main reason being the incomplete understanding of their etiology. With many intensely debated hypotheses, a newer approach based on the impact of iron imbalance in sustaining neurodegeneration in the central nervous system becomes increasingly popular. Altered iron homeostasis leads to increased iron accumulation in specific brain areas, explaining the clinical picture of AD patients. Moreover, growing evidence sustains the significant impact of iron metabolism in relationship to other pathological processes encountered in the AD-affected brain, such as the amyloidogenic pathway, chronic inflammation, or oxidative stress. In this context, this mini-review aims to summarize the novel data from the continuously expanding literature on this topic in a didactic manner. Thus, in the first part, the authors briefly highlight the most relevant aspects related to iron absorption, transport, regulation, and elimination at the cerebral level, focusing on the role of the blood-brain barrier and the newer concept of ferroptosis. Subsequently, currently available iron chelation therapies are discussed, including an overview of the most relevant clinical trials on this topic. In the final part, based on the latest results from in vitro and in vivo studies, new research directions are suggested to enhance the development of effective antidementia therapies.

Erythroferrone exacerbates iron overload and ineffective extramedullary erythropoiesis in a mouse model of β-thalassemia.

β-thalassemia is characterized by chronic hepcidin suppression and iron overload, even in patients who have not undergone transfusion. The HbbTh3/+ (Th3/+) mouse model of nontransfusion-dependent β-thalassemia (NTDBT) partially recapitulates the human phenotype but lacks chronic hepcidin suppression, progressive iron accumulation into adulthood, or the interindividual variation of the rate of iron loading observed in patients. Erythroferrone (ERFE) is an erythroid regulator that suppresses hepcidin during increased erythropoiesis. ERFE concentrations in the sera of patients with NTDBT correlate negatively with hepcidin levels but vary over a broad range, possibly explaining the variability of iron overload in patients. To analyze the effect of high ERFE concentrations on hepcidin and iron overload in NTDBT, we crossed Th3/+ mice with erythroid ERFE-overexpressing transgenic mice. Th3/ERFE-transgenic mice suffered high perinatal mortality, but embryos at E18.5 showed similar viability, appearance, and anemia effects as Th3/+ mice. Compared with Th3/+ littermates, adult Th3/ERFE mice had similarly severe anemia but manifested greater suppression of serum hepcidin and increased iron accumulation in the liver, kidney, and spleen. The Th3/ERFE mice had much higher concentrations of serum ERFE than either parental strain, a finding attributable to both a higher number of erythroblasts and higher production of ERFE by each erythroblast.Th3/+ and Th3/ERFE mice had similar red blood cell count and shortened erythrocyte lifespan, but Th3/ERFE mice had an increased number of erythroid precursors in their larger spleens, indicative of aggravated ineffective extramedullary erythropoiesis. Thus, high ERFE concentrations increase the severity of nontransfusional iron overload and ineffective erythropoiesis in thalassemic mice but do not substantially affect anemia or hemolysis.

The potential impact of hereditary hemochromatosis on the heart considering the disease stage and patient age-the role of echocardiography.

Hereditary hemochromatosis (HH) is a genetic disease that leads to increased iron accumulation in several organs. Cardiomyocytes are highly susceptible to this damage owing to their high iron uptake, and cardiovascular complications account for 1/3 of the deaths in the natural course of HH. Additionally, excess iron intake and associated oxidative stress may accelerate the aging of the cardiovascular system, regardless of the age of patients with HH. We aimed to investigate the role of standard and speckle-tracking echocardiography (STE) in revealing heart differences in patients with HH considering the disease stage and the patient age. Consecutive patients with HH (n = 58) without heart pathologies (except hypertension) and 29 age- and sex-matched healthy individuals underwent echocardiography. Patients were compared according to the time since HH diagnosis (the recently diagnosed HH group [31 patients] with diagnosed HH for less than 6 months and had no more than one venesection; the medium group [11 patients] with diagnosed HH between 6 and 24 months; and the long-lasting group [16 patients] with diagnosed HH for more than 2 years) and the quartile contribution of their age. Standard echocardiography revealed differences in diastolic parameters between patients with HH and controls, which were the most prominent between healthy and long-lasting HH patients. Regarding systolic function, left ventricular ejection fraction was lower in HH patients, with the most evident differences between the healthy and recently diagnosed HH patients. STE revealed additional differences in systolic parameters, with LV rotation the worst in recently diagnosed patients and its increase in patients with medium and long-lasting HH. Significantly worse peak systolic longitudinal strain values were observed in all patients with HH. Analyses of the results according to the age quartiles of patients with HH revealed that some changes ocurred earlier than expected according to age. Echocardiography can reveal possible heart damage in HH patients at different stages of the disease and highlight potential features of accelerated myocardial aging in these patients.

Exposure to ZnO nanoparticles induced blood-milk barrier dysfunction by disrupting tight junctions and cell injury

Zinc oxide nanoparticles (ZnO-NPs) are one of the most widely used nanomaterials with excellent chemical and biological properties. However, their widespread application has led to increased risk to the natural environment and public health. A growing number of studies have shown that ZnO-NPs deposited in target organs interact with internal barriers to trigger injurious responses. The underlying mechanism of ZnO-NPs on the blood-milk barrier dysfunction remains to be understood. Our results revealed that excessive accumulation of ZnO-NPs induced histopathological injuries in the mammary gland, leading to the distribution of ZnO-NPs in the milk of lactating mice. A prominent diffusion of blood-milk barrier permeability marker, albumin-fluorescein isothiocyanate conjugate (FITC-albumin) was observed at cell-cell junction after ZnO-NPs exposure. Meanwhile, ZnO-NPs weakened the blood-milk barrier function by altering the expression of tight junction proteins. The excessive accumulation of ZnO-NPs also induced inflammatory response by activating the NF-κB and MAPK signaling pathways, leading to the dysfunctional blood-milk barrier. Furthermore, we found that ZnO-NPs led to increased iron accumulation and lipid oxidation, thus increasing oxidative injury and ferroptosis in mammary glands. These results indicated that ZnO-NPs weaken the integrity of the blood-milk barrier by directly affecting tight junctions and cellular injury in different ways.

Iron accumulation in the ventral tegmental area in Parkinson's disease.

The ventral tegmental area (VTA) is less affected compared to substantia nigra pars compacta (SNc) in Parkinson's disease (PD). This study aimed to quantitatively evaluate iron content in the VTA across different stages of PD in order to help explain the selective loss of dopamine neurons in PD. Quantitative susceptibility mapping (QSM) data were obtained from 101 PD patients, 35 idiopathic rapid eye movement sleep behavior disorder (RBD) patients, and 62 healthy controls (HCs). The mean QSM values in the VTA and SNc were calculated and compared among the groups. Both RBD and PD patients had increased iron values in the bilateral SNc compared with HCs. RBD and PD patients in the Hoehn-Yahr (H & Y) stage 1 did not show elevated iron values in the VTA, while PD patients with more than 1.5 H & Y staging had increased iron values in bilateral VTA compared to HCs. This study shows that there is no increased iron accumulation in the VTA during the prodromal and early clinical stages of PD, but iron deposition increases significantly as the disease becomes more severe.

Activation of Nrf2 signaling pathway by Tectoridin protects against ferroptosis in particulate matter-induced lung injury.

Our previous research showed that ferroptosis plays a crucial role in the pathophysiology of PM2.5-induced lung injury. The present study aimed to investigate the protective role of the Nrf2 signaling pathway and its bioactive molecule tectoridin (Tec) in PM2.5-induced lung injury by regulating ferroptosis. We examined the regulatory effect of Nrf2 on ferroptosis in PM2.5-induced lung injury and Beas-2b cells using Nrf2-knockout (KO) mice and Nrf2 siRNA transfection. Moreover, the effect and underlying mechanism of Tec on PM2.5-induced lung injury were evaluated in vitro and in vivo. As anticipated, Nrf2 deletion increased iron accumulation and ferroptosis-related protein expression in vivo and vitro, further exacerbating lung injury and cell death in response to PM2.5 exposure. Tec significantly activated Nrf2 target genes and ameliorated cell death caused by PM2.5. In addition, Tec prevented lipid peroxidation, iron accumulation, and ferroptosis in vitro, but in siNrf2-treated cells, these effects almost disappeared. In addition, Tec effectively mitigated PM2.5-induced respiratory system damage, as evaluated by HE, PAS, and inflammatory factors. Tec also augmented the antioxidative Nrf2 signaling pathway and prevented changes in ferroptosis-related morphological and biochemical indicators, including MDA levels, GSH depletion and GPX4 and xCT downregulation, in PM2.5-induced lung injury. However, the effects of Tec on ferroptosis and respiratory injury nearly vanished in Nrf2-KO mice. Our data proposed the protective effect of Nrf2 activation on PM2.5-induced lung injury by inhibiting ferroptosis-mediated lipid peroxidation and highlight the potential of Tec as a PM2.5-induced lung injury treatment.