Tissue Iron Research Articles

Norcantharidin down-regulates iron contents in the liver and spleen of lipopolysaccharide-treated mice

ABSTRACT Objective The inhibiting effect of Norcantharidin (NCTD) on IL-6 (interleukin-6) and STAT3 and the involvement of the IL-6/STAT3 pathway in hepcidin expression prompted us to speculate that NCTD could affect iron metabolism. Methods We examined the effects of NCTD on serum iron (SI) and transferrin (Tf) saturation, iron and ferritin light chain (FTL), transferrin receptor 1 (TfR1), divalent metal transporter 1 (DMT1), ferroportin 1 (Fpn1), iron regulatory protein 1 (IRP1) and hepcidin, as well as IL-6 and STAT3 in the liver, spleen and duodenum of mice treated with lipopolysaccharide (LPS) in vivo, using RT-PCR, Western blotting and immunofluorescence analysis. Results NCTD could increase SI and Tf saturation and reduce tissue iron and FTL content by affecting expression of cell-iron transport proteins TfR1, DMT1 and Fpn1. The impact of NCTD on TfR1, DMT1 and Fpn1 expression is mediated by up-regulating IRP1 and down-regulating hepcidin expression, while NCTD-induced down-regulation of hepcidin is mediated by the IL-6/STAT3 signalling pathway in LPS-treated mice. Conclusions NCTD affects iron metabolism by modifying the expression of IL-6/JAK2/STAT3/hepcidin and IRP1 and suggest that the ability of NCTD to reduce tissue iron contents may be a novel mechanism associated with the anti-cancer effects of NCTD.

Hepatic Macrophage Abundance and Phenotype in Aging and Liver Iron Accumulation.

Liver macrophages serve important roles in iron homeostasis through phagocytosis of effete erythrocytes and the export of iron into the circulation. Conversely, intracellular iron can alter macrophage phenotype. Aging increases hepatic macrophage number and nonparenchymal iron, yet it is unknown whether age-related iron accumulation alters macrophage number or phenotype. To evaluate macrophages in a physiological model of iron loading that mimicked biological aging, young (6 mo) Fischer 344 rats were given one injection of iron dextran (15 mg/kg), and macrophage number and phenotype were evaluated via immunohistochemistry. A separate group of old (24 mo) rats was treated with 200 mg/kg deferoxamine every 12 h for 4 days. Iron administration to young rats resulted in iron concentrations that matched the values and pattern of tissue iron deposition observed in aged animals; however, iron did not alter macrophage number or phenotype. Aging resulted in significantly greater numbers of M1 (CD68+) and M2 (CD163+) macrophages in the liver, but neither macrophage number nor phenotype were affected by deferoxamine. Double-staining experiments demonstrated that both M1 (iNOS+) and M2 (CD163+) macrophages contained hemosiderin, suggesting that macrophages of both phenotypes stored iron. These results also suggest that age-related conditions other than iron excess are responsible for the accumulation of hepatic macrophages with aging.

Myocardial Iron Deficiency and Mitochondrial Dysfunction in Advanced Heart Failure in Humans.

BackgroundMyocardial iron deficiency (MID) in heart failure (HF) remains largely unexplored. We aim to establish defining criterion for MID, evaluate its pathophysiological role, and evaluate the applicability of monitoring it non‐invasively in human explanted hearts.Methods and ResultsBiventricular tissue iron levels were measured in both failing (n=138) and non‐failing control (NFC, n=46) explanted human hearts. Clinical phenotyping was complemented with comprehensive assessment of myocardial remodeling and mitochondrial functional profiles, including metabolic and oxidative stress. Myocardial iron status was further investigated by cardiac magnetic resonance imaging. Myocardial iron content in the left ventricle was lower in HF versus NFC (121.4 [88.1–150.3] versus 137.4 [109.2–165.9] μg/g dry weight), which was absent in the right ventricle. With a priori cutoff of 86.1 μg/g d.w. in left ventricle, we identified 23% of HF patients with MID (HF‐MID) associated with higher NYHA class and worsened left ventricle function. Respiratory chain and Krebs cycle enzymatic activities were suppressed and strongly correlated with depleted iron stores in HF‐MID hearts. Defenses against oxidative stress were severely impaired in association with worsened adverse remodeling in iron‐deficient hearts. Mechanistically, iron uptake pathways were impeded in HF‐MID including decreased translocation to the sarcolemma, while transmembrane fraction of ferroportin positively correlated with MID. Cardiac magnetic resonance with T2* effectively captured myocardial iron levels in failing hearts.ConclusionsMID is highly prevalent in advanced human HF and exacerbates pathological remodeling in HF driven primarily by dysfunctional mitochondria and increased oxidative stress in the left ventricle. Cardiac magnetic resonance demonstrates clinical potential to non‐invasively monitor MID.

116-LB: Interaction between Iron Stores and Metformin Action

The mechanism of action of MET (MET) remains controversial. MET induces an iron starvation response in yeast, so we hypothesized that tissue iron might influence MET responsiveness in higher organisms. We reviewed electronic health records to correlate MET responsiveness in diabetic humans with serum ferritin, a measure of iron stores. Both higher and subnormal serum ferritin were associated with decreased HbA1c response to MET (N=80, p<0.001) , and MET responsiveness was lost entirely at higher than normal ferritin. Mice were placed on diabetogenic diets with different iron contents, and treated or not with MET. MET responses of fasting glucose values were superior in mice on low-normal and normal iron diets compared to those on high iron: Fasting glucose decreased 60.4 mg/dL on low-normal iron (N=9, p<0.001) , 40.5 mg/dL on normal iron (N=23, p<0.01) and 2.6 mg/dL on high-normal iron (N=27, p=NS) , with significant interaction between iron and MET (p=0.0015, ANOVA) . Other effects of iron (e.g. leptin expression) are known to be mediated by protein modification by O-linked N-acetylglucosamine (O-GlcNAc) . MET increased O-GlcNAc levels 200% in mice on normal iron (p=0.04) but not high-normal iron diets (-8%, p=NS) . In mice with elevated O-GlcNAc resulting from heterozygous deletion of the O-GlcNAcase gene, MET’s ability to decrease fasting glucose levels in mice on high iron was restored, with differences between MET and placebo being 30.3, 61.3, and 56.5 mg/dL on low-normal, normal, and high-normal iron diets (p<0.0001 by ANOVA) ; in contrast to wild type mice, the significant effects of iron and its interaction with MET were lost (p=0.13 and 0.47) . We conclude that tissue iron affects glycemic responses to MET, supporting the hypothesis that MET induces an iron starvation response but that high iron overwhelms that signal. The results on protein O-GlcNAc modification suggest that it mediates the interaction of iron and MET. MET responsiveness in patients with diabetes could be optimized by modulating iron stores. Disclosure D. A. Mcclain: None. C. O. Usoh: None. F. Lorenzo: None. A. V. Harrison: None. Funding VA Research Service 2I01 BX001140; NIH 1P30DK12472

Comparing the two concentrations of Co0.6 Zn0.4 Fe2O4 nanoparticles coated with dimercaptosuccinic acid based on T2-and T2*- weighted MRI: An animal study

PurposeThis study aimed to compare two different concentrations of Cobalt-zinc (Co–Zn) ferrite (Co0.6 Zn0.4 Fe2O4 or CZFO) nanoparticles (NPs) included 1.5 and 2.5 mg Fe/kg coated with dimercaptosuccinic acid (DMSA) based on T2-and T2*- weighted magnetic resonance imaging (MRI) of rats liver. Materials and methodsThe structural and crystal phase of CZFO magnetic NPs were determined using X-ray diffraction (XRD) and FTIR analysis. Two groups of rats (six for each group) were studied, in which the first and second groups received 1.5 and 2.5 mg/ml of Fe/kg body weight of the mentioned NPs, respectively. After the injection of the NPs, the signal intensity of the liver at different times (30, 38, 75, and 120 min) as well as the pathological characteristics of the liver and kidney tissues (24 h after injection) were investigated for the two groups. ResultsFor group 1, the maximum contrast enhancement in the rat liver was 58.46% and 77.13% occurred at 30 and 120 min, respectively, for T2 and for T2* weighted images. For group 2, these values were obtained at 57.96% and 75.77% occurred at 30 and 75 min, respectively. There was not found a remarkable iron in the kidney tissue, however, a small amount of iron was observed in the two rats livers for each investigated group, which was negligible after 24 h. ConclusionOur results demonstrated that for both investigated groups, it seems that the synthesized CZFO NPs coated with DMSA are appropriate agents for increasing the contrast intensity based on T2-and T2*- weighted MR imaging in rat liver.

Phenotypic and genetic associations of quantitative magnetic susceptibility in UK Biobank brain imaging

A key aim in epidemiological neuroscience is identification of markers to assess brain health and monitor therapeutic interventions. Quantitative susceptibility mapping (QSM) is an emerging magnetic resonance imaging technique that measures tissue magnetic susceptibility and has been shown to detect pathological changes in tissue iron, myelin and calcification. We present an open resource of QSM-based imaging measures of multiple brain structures in 35,273 individuals from the UK Biobank prospective epidemiological study. We identify statistically significant associations of 251 phenotypes with magnetic susceptibility that include body iron, disease, diet and alcohol consumption. Genome-wide associations relate magnetic susceptibility to 76 replicating clusters of genetic variants with biological functions involving iron, calcium, myelin and extracellular matrix. These patterns of associations include relationships that are unique to QSM, in particular being complementary to T2* signal decay time measures. These new imaging phenotypes are being integrated into the core UK Biobank measures provided to researchers worldwide, creating the potential to discover new, non-invasive markers of brain health.

The Role of Iron in Atherosclerosis in Apolipoprotein E Deficient Mice.

The role of iron in atherosclerosis is still a controversial and unsolved issue. Here, we investigated serum iron, expression of iron regulatory, transport and storage proteins, pro-inflammatory chemokines and cytokines in ApoE–/– mice. We demonstrated that ApoE–/– induced atherosclerosis and an increase in iron contents, expression of transferrin receptor 1 (TfR1), iron regulatory proteins (IRPs), heme oxygenase 1 (HO1), cellular adhesion molecules and pro-inflammatory cytokines, production of reactive oxygen species (ROS), and a reduction in expression of superoxide dismutase and glutathione peroxidase enzyme in aortic tissues. All of these changes induced by ApoE deficiency could be significantly abolished by deferoxamine. The data showed that the increased iron in aortic tissues was mainly due to the increased iron uptake via IRP/TfR1 upregulation. These findings plus a brief analysis of the controversial results reported previously showed that ApoE deficiency-induced atherosclerosis is partly mediated by the increased iron in aortic tissues.

Sipeimine ameliorates PM2.5-induced lung injury by inhibiting ferroptosis via the PI3K/Akt/Nrf2 pathway: A network pharmacology approach

Fine particulate matter (PM2.5) exposure can cause lung injury and a large number of respiratory diseases. Sipeimine is a steroidal alkaloid isolated from Fritillaria roylei which has been associated with anti-inflammatory, antitussive and antiasthmatic properties. In this study, we explored the potential effects of sipeimine against PM2.5-induced lung injury in Sprague Dawley rats. Sipeimine alleviated lung injury caused by PM2.5 and decreased pulmonary edema, inflammation and the levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the bronchoalveolar lavage fluid. In addition, sipeimine upregulated the glutathione (GSH) expression and downregulated the expression of 4-hydroxynonenal (4-HNE), tissue iron and malondialdehyde (MDA). The downregulation of proteins involved in ferroptosis, including nuclear factor E2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), heme oxygenase-1 (HO-1) and solute carrier family 7 member 11 (SLC7A11) was reversed by sipeimine. The administration of RSL3, a potent ferroptosis-triggering agent, blocked the effects of sipeimine. Using network pharmacology, we found that the effects of sipeimine were presumably mediated through the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. A PI3K inhibitor (LY294002) blocked the PI3K/Akt signaling pathway and reversed the effects of sipeimine. Overall, this study suggested that the protective effect of sipeimine against PM2.5-induced lung injury was mainly mediated through the PI3K/Akt pathway, ultimately leading to a reduction in ferroptosis.

Effects of Exogenous Transferrin on the Regulation of Iron Metabolism and Erythropoiesis in Iron Deficiency With or Without Anemia.

Erythropoietic response is controlled not only by erythropoietin but also by iron. In addition to its role in iron delivery, transferrin also functions as a signaling molecule, with effects on both iron homeostasis and erythropoiesis. We investigated hematologic parameters, iron status and expression of key proteins, including the hepatic iron regulatory protein hepcidin and the suppressive erythroid factor Erfe, in mice subject to dietary iron deficiency with and without anemia. The acute effect of iron on these parameters was investigated by administration of exogenous iron-loaded transferrin (holoTf) in each of the mouse models. Serum iron in mice with iron deficiency (ID) is modestly lower with hematologic parameters maintained by utilization of iron stores in mice with ID. As expected, erythropoietin expression and concentration, along with marrow Erfe are unaffected in ID mice. Administration of holoTf restores serum iron and Tf saturation levels to those observed in control mice and results in an increase in hepcidin compared to ID mice not treated with holoTf. The expression of the Bmp signaling molecule Bmp6 is not significantly increased following Tf treatment in ID mice. Thus, the expression level of the gene encoding hepcidin, Hamp1, is increased relative to Bmp6 expression in ID mice following treatment with holoTf, leading us to speculate that Tf saturation may influence Bmp sensitivity. In mice with iron deficiency anemia (IDA), decreased hematologic parameters were accompanied by pronounced decreases in serum and tissue iron concentrations, and an increase in serum erythropoietin. In the absence of exogenous holoTf, the greater serum erythropoietin was not reflected by an increase in marrow Erfe expression. HoloTf administration did not acutely change serum Epo in IDA mice. Marrow Erfe expression was, however, markedly increased in IDA mice following holoTf, plausibly accounting for the lack of an increase in Hamp1 following holoTf treatment in the IDA mice. The increase in Erfe despite no change in erythropoietin suggests that Tf acts to increase erythropoietin sensitivity. These observations underscore the importance of Tf in modulating the erythropoietic response in recovery from iron deficiency anemia, with implications for other stress erythropoiesis conditions.

Ablation of Na+/H+ exchanger‐3 prevents tissue iron loading in the Hfe mouse model of hereditary hemochromatosis

Several common hereditary disorders are associated with toxic iron overload which leads to liver cirrhosis, cardiomyopathy, and endocrine disorders. Hereditary hemochromatosis arises from mutations in the genes coding for any of several proteins involved in iron sensing (e.g. Hfe), hepcidin production (e.g. hemojuvelin), or hepcidin action, resulting in elevated iron absorption relative to the iron need. Divalent metal‐ion transporter‐1 (DMT1) is a H+‐coupled Fe2+ transporter and the principal or only mechanism by which nonheme iron is taken up at the intestinal brush border [Shawki A et al (2015) Am J Physiol Gastrointest Liver Physiol 309, G635–G647]. DMT1 is a validated therapeutic target in treating iron overload. We have shown that Na+/H+ exchanger‐3 (NHE3) is required for adequate iron absorption, via its physiological role in generating at the intestinal brush border an acidic microclimate that energizes DMT1‐mediated H+‐coupled Fe2+ transport [Shawki A et al (2016) Am J Physiol Gastrointest Liver Physiol 311, G423–G430], so we have explored here the contribution of NHE3 to pathological iron loading. We tested the hypothesis that NHE3 activity is necessary for pathological iron loading. We examined the effect of ablating the SLC9A3 gene coding for NHE3 in the Hfe mouse model of hereditary hemochromatosis. We measured tissue iron levels, hematological and blood‐iron variables, and the hepatic expression of Hamp1 (coding for hepcidin) by using qPCR in male and female FVB/N mice, age ≍ 120 d, fed a normal diet (NIH‐07). We examined four genotypes in both sexes: wildtype mice, NHE3 knockout (NHE3−/−), Hfe knockout (hemochromatosis disease model, Hfe−/−), and double knockout (NHE3−/− | Hfe−/−) (n = 12–26 mice per group). We chose α = 0.05, and analyzed our data (mean, SD) by using multifactorial ANOVA. We found that ablation of NHE3 prevented the liver iron loading characteristic of the Hfe−/− mouse model, an effect that was independent of sex. We observed a similar effect on iron loading in the spleen. Ablation of NHE3 produced no sign of overt anemia. Hepatic expression of hepcidin was depressed in NHE3−/− and in Hfe−/− mice relative to wildtype mice, and remained low in the NHE3−/− | Hfe−/− mice, providing a plausible explanation for the observation that, despite correction of the tissue iron levels in NHE3−/− | Hfe−/− mice, iron levels remained high in the readily accessible serum iron pool (typically 0.1% of total body iron). We conclude that ablation of NHE3 prevents pathological tissue iron loading in the Hfe mouse model of hemochromatosis. Pharmacological blockade of NHE3 may offer a means of inhibiting iron absorption in hereditary hemochromatosis.

BMP Signaling and Iron Homeostasis

Iron is an essential nutrient that is critical for fundamental cellular and organismal processes including oxygen transport and energy generation. However, excess iron can catalyze the formation of toxic free oxygen radicals. Cellular and systemic iron homeostasis are therefore tightly regulated to titrate the iron supply to match iron needs. The master regulator of systemic iron homeostasis is the liver hormone hepcidin, which binds and degrades the iron exporter ferroportin to limit iron release from dietary sources and body stores. To maintain normal systemic iron homeostasis, liver hepcidin production is coordinated by a number of signals that communicate body iron needs. Iron deficiency and anemia suppress hepcidin production to increase iron availability for red blood cell production and other essential functions. Conversely, increases in serum or tissue iron stimulate hepcidin production to prevent iron overload. Inflammation also stimulates hepcidin production to restrict iron availability to infectious microorganisms. Abnormal regulation of the hepcidin‐ferroportin axis has a pathogenic role in most disorders of systemic iron homeostasis including the anemia of inflammation, the iron overload disorder hereditary hemochromatosis, and iron‐loading anemias such as beta‐thalassemia. We have discovered a key role for the bone morphogenetic protein (BMP)‐SMAD signaling pathway in controlling liver hepcidin transcription. This talk will present recent insights into how BMP‐SMAD signaling coordinates liver hepcidin transcription in response to body iron levels and the iron demand of red blood cell production to maintain systemic iron homeostasis.

MP38-08 HUMAN UMBILICAL CORD MESENCHYMAL STEM CELLS AMELIORATE ERECTILE DYSFUNCTION IN TYPE I AND TYPE II DIABETES MELLITUS RATS THROUGH THE ATTENUATION OF FERROPTOSIS BY SLC7A11/GPX4/ACSL4 PATHWAY

You have accessJournal of UrologyCME1 May 2022MP38-08 HUMAN UMBILICAL CORD MESENCHYMAL STEM CELLS AMELIORATE ERECTILE DYSFUNCTION IN TYPE I AND TYPE II DIABETES MELLITUS RATS THROUGH THE ATTENUATION OF FERROPTOSIS BY SLC7A11/GPX4/ACSL4 PATHWAY Huan Feng, Tao Wang, and Jihong Liu Huan FengHuan Feng More articles by this author , Tao WangTao Wang More articles by this author , and Jihong LiuJihong Liu More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002592.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Diabetic Erectile Dysfunction (DMED) is a common complication of diabetes, which seriously impairs the life of male patients of all ages. Diabetes could destroy various cells in the corpus cavernosum, such as nerve cells, endothelial cells, smooth muscle cells. Human Umbilical Cord Mesenchymal Stem Cells (hUCMSCs) are cells with multipotential differentiation potential.The present study aims to investigate the therapeutic role and mechanism of hUCMSCs on type I and type II diabetes mellitus rats. METHODS: Fifty male Sprague-Dawley rats received intraperitoneal injection with streptozotocin for 3 days to induce type 1 diabetes. Another 50 male ZDF rats were fed with Purina 5008 to induce type 2 DMED. After 8 weeks, type 1 and type 2 DMED rats were separately selected by the apomorphine (APO) test. Both of types DMED rats were divided into normal control group (NC), diabetic group (DM), cavernous injection (1×106) group (CI), tail vein injection (1×106) group (VI). Stem cells were labeled with Edu prior to injection for subsequent observation. Primary corpus cavernous smooth muscle cells (CCSMCs) from healthy rats were cultured and treated with berberine. Mitochondria in ccSMCs were observed by transmission electron microscopy (TEM). RESULTS: None of rats received stem cell injection had obvious adverse reactions. Injection of hUCMSCs improved erectile function, reduced levels of NADPH oxidases, ROS production and tissue iron content. Among the type 1 DMED rats, the results showed that mICP/MAP of DM (0.232±0.082 mmHg) was significantly lower than NC (0.793±0.153 mmHg), CI (0.333±0.104 mmHg) and VI (0.384±0.095 mmHg) were improved compared with DM, and similar phenomenon also showed among the type 2 DMED rats. Besides, co-cultured CCSMCs with hUCMSCs exhibited a lower level of ferroptosis by SLC7A11/GPX4/ACSL4 pathway with high glucose (HG) treatment. TEM showed that the mitochondria shrunk, the cristae of mitochondria were destroyed, and exhibited high electron density in CCSMCs treated with HG, and these effects could be obviously reversed by hUCMSCs. CONCLUSIONS: Human umbilical cord mesenchymal stem cells can safely and effectively ameliorate erectile dysfunction in both type I and type II diabetes mellitus rats, and attenuate ferroptosis of CCSMCs through SLC7A11/GPX4/ACSL4 pathway. It provides preclinical evidence for application of hUCMSCs to DMED treatment and potential molecular mechanism of it. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e621 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Huan Feng More articles by this author Tao Wang More articles by this author Jihong Liu More articles by this author Expand All Advertisement PDF DownloadLoading ...

Assessment of Liver, Thyroid Gland and Growth Hormone Functions in Beta Thalassemia Major

Labile plasma iron and tissue iron overload are major complications of thalassemia disease that increase mortality rate. The iron that is exceeding the capacity of transferrin and ferritin is the leading cause of cell oxidation of many organs such as liver, heart, endocrine systems, etc. This study is designed to investigate the status of liver, thyroid gland and the growth hormone in beta thalassemia patients. In a cross-sectional study, 65 samples of beta thalassemia major were taken who were on a regular chelation therapy and blood transfusion and were to be compared with reference values. The results of the study estimated that 98.46% of the cases had high serum ferritin level, 12.3% high ALT, 27.7% high AST, 86.15% high ALP, 69.23% high total serum bilirubin, and 36.92% high TSH level. The results revealed that more than half of the patients had Growth Hormone Deficiency (GHD). The serum ferritin was found to be correlated with ALT and AST enzymes (p< 0.01. Furthermore, alkaline phosphatase and serum bilirubin can be good markers for monitoring bile duct obstruction resulted from hemolysis and blood transfusion.

Subcortical brain iron deposition in individuals with schizophrenia

Subcortical structures play a critical role the pathophysiology and treatment of schizophrenia (SZ), yet underlying neurophysiological processes, in vivo, remain largely unexplored. Brain tissue iron, which can be measured with magnetic resonance-based methods, is a crucial component of a variety of neuronal functions including neurotransmitter synthesis. Here we used a proxy measure of tissue iron to examine basal ganglia and thalamic structures in an adult cohort of individuals with chronic SZ. A publicly available dataset of 72 individuals with SZ between ages 18 and 65, and a matched sample of 74 healthy control (HC) participants were included. A novel method that calculated the inverse-normalized T2*-weighted contrast (1/nT2*) was used to estimate brain iron within the basal ganglia and thalamus. Between group, age- and sex-related differences in 1/nT2* were examined, in addition to correlations with measures of psychopathology and cognition. Individuals with SZ showed greater 1/nT2* (iron index) compared to HCs in the thalamus (p < 0.01, FWE corrected). Age-related 1/nT2* accumulation was noted in regions of the basal ganglia, coinciding with prior work, and prominent sex-differences were noted in the caudate and thalamus (p < 0.01, FWE corrected). No significant relationship was observed between 1/nT2* and measures of neurocognition or psychopathology. Overall, our findings characterize a non-invasive proxy measure of tissue iron in SZ and highlight thalamic iron accumulation as a potential marker of illness.

P581. Inverse Relationships Between Basal Ganglia Iron and Positive Psychotic Symptoms in Early Psychotic Spectrum Disorders

Iron is critical for healthy brain biochemistry and function. While deficient peripheral iron was found to increase psychiatric morbidity risk, in vivo brain iron examinations in psychotic spectrum disorders (PSD) are lacking. Here, we examined tissue iron changes in PSD and their associations with psychotic symptoms in iron-rich basal ganglia structures and thalamus using MRI.

Association between Hepatic Oxidative Stress Related Factors and Activation of Wnt/β-Catenin Signaling in NAFLD-Induced Hepatocellular Carcinoma

Simple SummaryActivation of the Wnt/β-catenin signaling pathway may reduce the efficacy of immune checkpoint inhibitors, which are first-line therapeutic agents for the treatment of hepatocellular carcinoma (HCC). Following gadoxetate-enhanced MRI, HCC lesions may exhibit equal or higher signal intensities in the hepatobiliary phase than normal tissue. Thus, MRI could be used to monitor the therapeutic effect of antitumor agents. In this study, we investigated the relationship between intrahepatic iron overload markers and oxidative stress and activation of the Wnt/β-catenin signaling pathway. We found that for nonalcoholic fatty liver disease-induced HCC, MRI yielded a sensitivity of 57.2% and a specificity of 100%. Serum ferritin > 77.5 ng/mL had a sensitivity of 85.7% and a specificity of 85.7%. We conclude that serum ferritin levels may further improve the accuracy with which activation of Wnt/β-catenin signaling can be predicted.We investigated the association between iron overload, oxidative stress (8-oxo-7,8-dihydroguanine: 8-oxo-dG scores), Wnt/β-catenin pathway activation (expression of glutamine synthetase: GS), and tumor hyperintensity in the Gd-EOB-DTPA-enhanced MRI hepatobiliary phase (relative enhancement ratio: RER). This was a retrospective analysis of 94 hepatocellular carcinoma (HCC) patients who underwent surgical resection. In HBV-, HCV-, and alcohol-associated HCC, serum ferritin levels in the high and low RER groups were equivalent. In contrast, ferritin levels were elevated in the ‘high RER’ group of patients with nonalcoholic fatty liver disease (NAFLD)-HCC. As predictors of GS positivity, high RER had a sensitivity of 57.2% and a specificity of 100%. High serum ferritin had a sensitivity of 85.7% and a specificity of 85.7%. All cases with serum ferritin ≥275.5 ng/mL and high RER were 8-oxo-dG- and iron staining-positive. Additionally, GS positivity was seen in all cases with “serum ferritin levels above the upper limits or iron staining-positive” and ‘8-oxo-dG high’ cases. Therefore, combining serum ferritin levels with RER may increase the accuracy with which activated Wnt/β-catenin signaling is predicted in NAFLD-HCC. We suggest that 8-oxo-dG accumulates following increased oxidative stress due to hepatic tissue iron deposition; this may activate Wnt/β-catenin signaling and trigger carcinogenesis.

Changes in corticostriatal connectivity and striatal tissue iron associated with efficacy of clozapine for treatment‑resistantschizophrenia.

RationaleThough numerous studies demonstrate the superiority of clozapine (CLZ) for treatment of persistent psychotic symptoms that are characteristic of treatment-refractory schizophrenia (TRS), what remains unknown are the neural and molecular mechanisms underlying CLZ’s efficacy. Recent work implicates increased corticostriatal functional connectivity as a marker of response to non-CLZ, dopamine (DA) D2-receptor blocking antipsychotic drugs. However, it is undetermined whether this connectivity finding also relates to CLZ’s unique efficacy, or if response to CLZ is associated with changes in striatal DA functioning.ObjectiveIn a cohort of 22 individuals with TRS, we examined response to CLZ in relation to the following: (1) change in corticostriatal functional connectivity; and (2) change in a magnetic resonance-based measure of striatal tissue iron (R2’), which demonstrates utility as a proxy measure for elements of DA functioning.MethodsParticipants underwent scanning while starting CLZ and after 12 weeks of CLZ treatment. We used both cortical and striatal regions of interest to examine changes in corticostriatal interactions and striatal R2’ in relation to CLZ response (% reduction of psychotic symptoms).ResultsWe first found that response to CLZ was associated with an increase in corticostriatal connectivity between the dorsal caudate and regions of the frontoparietal network (P < 0.05, corrected). Secondly, we observed no significant changes in striatal R2’ across CLZ treatment.ConclusionOverall, these results indicate that changes in corticostriatal networks without gross shifts in striatal DA functioning underlies CLZ response. Our results provide novel mechanistic insight into response to CLZ treatment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00213-022-06138-0.

Gestational Iron Supplementation Improves Fetal Outcomes in a Rat Model of Prenatal Alcohol Exposure.

Prenatal alcohol exposure causes neurodevelopmental disability and is associated with a functional iron deficiency in the fetus and neonate, even when the mother consumes an apparently iron-adequate diet. Here, we test whether gestational administration of the clinically relevant iron supplement Fer-In-Sol mitigates alcohol’s adverse impacts upon the fetus. Pregnant Long-Evans rats consumed an iron-adequate diet and received 5 g/kg alcohol by gavage for 7 days in late pregnancy. Concurrently, some mothers received 6 mg/kg oral iron. We measured maternal and fetal weights, hematology, tissue iron content, and oxidative damage on gestational day 20.5. Alcohol caused fetal anemia, decreased fetal body and brain weight, increased hepatic iron content, and modestly elevated hepatic malondialdehyde (p’s < 0.05). Supplemental iron normalized this brain weight reduction in alcohol-exposed males (p = 0.154) but not female littermates (p = 0.031). Iron also reversed the alcohol-induced fetal anemia and normalized both red blood cell numbers and hematocrit (p’s < 0.05). Iron had minimal adverse effects on the mother or fetus. These data show that gestational iron supplementation improves select fetal outcomes in prenatal alcohol exposure (PAE) including brain weight and hematology, suggesting that this may be a clinically feasible approach to improve prenatal iron status and fetal outcomes in alcohol-exposed pregnancies.

Gestational and Lactational Iron Deficiency Anemia Impairs Myelination and the Neurovascular Unit in Infant Rats.

Iron deficiency anemia is a prevalent health problem among pregnant women and infants, particularly in the developing countries that causes brain development deficits and poor cognitive outcomes. Since tissue iron depletion may impair myelination and trigger cellular hypoxic signaling affecting blood vessels, we studied myelination and the neurovascular unit (NVU) in infant rats born to mothers fed with an iron deficient (ID) or control diet from embryonic day 5 till weaning. Blood samples and brains of rat pups at postnatal day (PND) 14 and 30 were analyzed. PND 14 ID rats had severe microcytic hypochromic anemia that was almost reversed at PND 30 although hypomyelination and astrocyte immature phenotype in the corpus callosum were significant at that age. In CA1 hippocampal region, PND 14 and PND 30 ID rats showed significant reduced expression of the receptor β of the platelet-derived growth factor localized in pericytes and associated to aquaporin 4 (AQP4) immunopositive capillaries. Shorter AQP4 + capillaries and reduced AQP4 expression were also evidenced in PND 14 and PND 30 ID rats. In addition, pericyte membrane permeability through large-pore channels was transiently increased in ID rats at PND 14 but not at PND 30, while the blood-brain barrier permeability was not affected. Remarkably, transient increased pericyte permeability found in PND 14 ID rats was not directlyrelated to iron depletion, suggesting the involvement of other iron deficiency anemia-induced mechanisms. In summary, severe ID during gestation and lactation produces persistent hypomyelination and significantly affects hippocampal pericytes and astrocytes in the NVU which may trigger impaired neurovascular function.

Maresin1 Protect Against Ferroptosis-Induced Liver Injury Through ROS Inhibition and Nrf2/HO-1/GPX4 Activation.

Drugs, viruses, and chemical poisons stimulating live in a short period of time can cause acute liver injury (ALI). ALI can further develop into serious liver diseases such as cirrhosis and liver cancer. Therefore, how to effectively prevent and treat ALI has become the focus of research. Numerous studies have reported Maresin1 (MaR1) has anti-inflammatory effect and protective functions on organs. In the present study, we used d-galactosamine/lipopolysaccharide (D-GalN/LPS) to establish an ALI model, explored the mechanism of liver cells death caused by D-GalN/LPS, and determined the effect of MaR1 on D-GalN/LPS-induced ALI. In vivo experiments, we found that MaR1 and ferrostatin-1 significantly alleviated D-GalN/LPS-induced ALI, reduced serum alanine transaminase and aspartate transaminase levels, and improved the survival rate of mice. Meanwhile, MaR1 inhibited hepatocyte death, inhibited tissue reactive oxygen species (ROS) expression, reduced malondialdehyde (MDA), reduced glutathione (GSH), GSH/oxidized glutathione (GSSG), and iron content induced by D-GalN/LPS in mice. In addition, MaR1 inhibited ferroptosis-induced liver injury through inhibiting the release of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6. Subsequently, western blot showed that MaR1 improved the expression of nuclear factor E2-related factor 2(Nrf2)/heme oxygenase-1 (HO-1)/glutathione peroxidase 4 (GPX4). In vitro experiments, we found that MaR1 inhibited LPS-induced and erastin-induced cell viability reduction. Meanwhile, we found that MaR1 increased the MDA and GSH levels in cells. Western blot showed that MaR1 increased the expression level of Nrf2/HO-1/GPX4. Next, the Nrf2 was knocked down in HepG2 cells, and the results showed that the protective effect of MaR1 significantly decreased. Finally, flow cytometry revealed that MaR1 inhibited ROS production and apoptosis. Overall, our study showed MaR1 inhibited ferroptosis-induced liver injury by inhibiting ROS production and Nrf2/HO-1/GPX4 activation.