Endogenous Iron Research Articles

Hypoxia-activated ROS burst liposomes boosted by local mild hyperthermia for photo/chemodynamic therapy

Single reactive oxygen species (ROS)-mediated therapy, photodynamic therapy (PDT) or chemodynamic therapy (CDT) is severely hindered in hypoxic solid tumor. Herein, to address the urgent challenge, a hypoxia-activated ROS burst liposome has been fabricated to achieve synergistic PDT/CDT that is initiated by the structural dissociation of poly(metronidazole) liposome in hypoxic tumor microenvironment (TME). The therapeutic enhancement of our ROS-blasting treatment is simultaneously regulated by external light-initiated PDT and endogenous iron oxide nanoclusters-triggered CDT, which is synergistically boosted and amplified by localized mild hyperthermia under 808/660 nm coirradiation. More importantly, in vitro and in vivo experiments demonstrate that electron-affinic poly(aminoimidazole) product from hypoxia-responsive transition of poly(metronidazole) polymers could efficiently enhance hypoxic cell apoptosis and induce solid tumor ablation. Thus, this work offers a potential hypoxia-activated ROS burst-PDT/CDT strategy with a superior antitumor efficacy, highlighting a promising clinical application.

Endogenous Labile Iron Pool-Mediated Free Radical Generation for Cancer Chemodynamic Therapy

Current chemodynamic therapy (CDT) primarily relies on the delivery of transition metal ions with Fenton activity to trigger hydroxyl radical production from hydrogen peroxide. However, administration of an excess amount of exogenous Fenton-type heavy metals may cause potential adverse effects to human health, including acute and chronic damages. Here, we present a new CDT strategy that uses intracellular labile iron pool (LIP) as the endogenous source of Fenton-reactive metals for eliciting free radical generation, and the discovery of hydroperoxides (R'OOH) as an optimal LIP-mediated chemodynamic agent against cancer. By simulating the metabolic fates of peroxo compounds within cells, R'OOH was found to have excellent free radical-producing ability in the presence of labile iron(II) and to suffer only moderate elimination by glutathione/glutathione peroxidase, which contributes to its superior chemodynamic efficacy. The LIP-initiated nontoxic-to-toxic transition of R'OOH, together with increased LIP levels in tumor cells, enabled efficient and specific CDT of cancer. Moreover, pH/labile iron(II) cascade-responsive nanomedicines comprising encapsulated methyl linoleate hydroperoxide and LIP-increasing agent in pH-sensitive polymer particles were fabricated to realize enhanced CDT. This work not only paves the way to using endogenous Fenton-type metals for cancer therapy but also offers a paradigm for the exploration of high-performance chemodynamic agents activated by intracellular LIP.

Application of a Novel Metallomics Tool to Probe the Fate of Metal-Based Anticancer Drugs in Blood Plasma: Potential, Challenges and Prospects.

Although metallodrugs are used to treat a variety of human disorders and exhibit a remarkable diversity of therapeutic properties, they constitute only a tiny minority of all medicinal drugs that are currently on the market. This undesirable situation must be partially attributed to our general lack of understanding the fate of metallodrugs in the extremely ligand-rich environment of the bloodstream. The challenge of gaining insight into these bioinorganic processes can be overcome by the application of 'metallomics tools', which involve the analysis of biological fluids (e.g., blood plasma) with a separation method in conjunction with multi-element specific detectors. To this end, we have developed a metallomics tool that is based on size-exclusion chromatography (SEC) hyphenated to an inductively coupled plasma atomic emission spectrometer (ICP-AES). After the successful application of SEC-ICPAES to analyze plasma for endogenous copper, iron and zinc-metalloproteins, it was subsequently applied to probe the metabolism of a variety of metal-based anticancer drugs in plasma. The versatility of this metallomics tool is exemplified by the fact that it has provided insight into the metabolism of individual Pt-based drugs, the modulation of the metabolism of cisplatin by sulfur-containing compounds, the metabolism of two metal-based drugs that contain different metals as well as a bimetallic anticancer drug, which contained two different metals. After adding pharmacologically relevant doses of metallodrugs to plasma, the temporal analysis of aliquots by SEC-ICP-AES allows to observe metal-protein adducts, metallodrug-derived degradation products and the parent metallodrug(s). This unique capability allows to obtain comprehensive insight into the fate of metal-based drugs in plasma and can be extended to in vivo studies. Thus, the application of this metallomics tool to probe the fate of novel metalcomplexes that exert the desired biological activity in plasma has the potential to advance more of these to animal/preclinical studies to fully explore the potential that metallodrugs inherently offer.

Sonication increases the porosity of uncooked rice kernels affording softer textural properties, loss of intrinsic nutrients and increased uptake capacity during fortification

This work investigates the effect of sonication on brown and milled rice grains of both waxy and non-waxy varieties. We report herein the microstructural analysis of uncooked rice kernels under sonication and its effect on the textural properties. X-ray computed tomography results showed the formation of microporous surfaces and the creation of cracks and fissures. Sonication increased the % porosity of the rice samples allowing for easy penetration of water during the cooking process and promotes softer texture. Moreover, the effect of sonication in brown rice resulted to the decrease in endogenous iron and phosphorus contents but increased its capacity for iron uptake through fortification when sonicated rice is soaked in the mineral solution.

Determination of Prussian Blue Nanoparticles in Rat Tissue in the Presence of Endogenous Iron Interferences by Inductively Coupled Plasma – Optical Emission Spectrometry (ICP-OES)

A modified calibration curve method based on the combination of standard addition and traditional calibration curve methods was employed for the quantification of Prussian blue nanoparticles in rats in the presence of endogenous iron interferences. The assay was performed using inductively coupled plasma – optical emission spectrometry (ICP-OES) with yttrium as the internal standard, and validated in biomatrices including liver, heart, kidneys, lungs, spleen and whole blood. For the liver tissue, the intra-day and inter-day precision were 7.84% or less, and the accuracy was between 99.88% and 102.37%. For kidneys, lungs, heart, spleen, and blood, at each exo-additive level from 0.4 to 3.2 µg/mL, the intra-day accuracy was between 98.74% and 102.09%, and the intra-day precision was 6.17% or less. For the addition of no analyte, the intra-day accuracy was between 96.42% and 107.52%, and the intra-day precision was 15.67% or less. The stability was investigated at 25 °C for 24 h and 4 °C for 15 days in liver standard addition samples, and no significant degradation occurred under these conditions. This method was successfully applied to the preliminary pharmacokinetics and tissue distribution study of Prussian blue nanoparticles in rats. This approach may also be applied to the quantification of other ferruginous materials in the biological matrices with endogenous iron.

Electron paramagnetic resonance spectroscopy reveals alterations in the redox state of endogenous copper and iron complexes in photodynamic stress-induced ischemic mouse liver

Divalent copper and iron cations have been acknowledged for their catalytic roles in physiological processes critical for homeostasis maintenance. Being redox-active, these metals act as cofactors in the enzymatic reactions of electron transfer. However, under pathophysiological conditions, owing to their high redox potentials, they may exacerbate stress-induced injury. This could be particularly hazardous to the liver - the main body reservoir of these two metals. Surprisingly, the involvement of Cu and Fe in liver pathology still remains poorly understood. Hypoxic stress in the tissue may act as a stimulus that mobilizes these ions from their hepatic stores, aggravating the systemic injury. Since ischemia poses a serious complication in liver surgery (e.g. transplantation) we aimed to reveal the status of Cu and Fe via spectroscopic analysis of mouse ischemic liver tissue. Herein, we establish a novel non-surgical model of focal liver ischemia, achieved by applying light locally when a photosensitizer is administered systemically. Photodynamic treatment results in clear-cut areas of the ischemic hepatic tissue, as confirmed by ultrasound scans, mean velocity measurements, 3D modelling of vasculature and (immuno)histological analysis. For reference, we assessed the samples collected from the animals which developed transient systemic endotoxemic stress induced by a non-lethal dose of lipopolysaccharide. The electron paramagnetic resonance (EPR) spectra recorded in situ in the liver samples reveal a dramatic increase in the level of Cu adducts solely in the ischemic tissues. In contrast, other typical free radical components of the liver EPR spectra, such as reduced Riske clusters are not detected; these differences are not followed by changes in the blood EPR spectra. Taken together, our results suggest that local ischemic stress affects paramagnetic species containing redox-active metals. Moreover, because in our model hepatic vascular flow is impaired, these effects are only local (confined to the liver) and are not propagated systemically.

High uptake and inward diffusion of iron fortificant in ultrasonicated milled rice

Nutritional iron content in milled rice is generally lost as a result of milling due to removal of aleurone layer. Iron fortification in milled rice is recommended to regain the lost nutrients and address the malnutrition issues. This work investigates the uptake of iron and its diffusion into the kernel on ultrasonic-treated milled rice. Rice samples were subjected to ultrasonic waves resulting in the formation of microporous surfaces and the creation of fissures in the milled rice. Sonication followed by soaking in aqueous iron solution resulted in the uptake of 321 ± 13.43 mg of iron per kg of rice, a 28-fold increase compared to the endogenous iron content of milled rice with retention of 82.9% upon washing and cooking. Cross-section mapping (μ-XRF) of the concentration of the fortificant into the uncooked grains showed inward diffusion at different rates reaching into the kernel core. Results also show that sonication decreased the amount of water-soluble phosphorus in rice suggesting the removal of potentially anti-nutrient phytic acid. Textural analysis of ultrasonic-treated iron-fortified rice premix revealed favorable properties that can be advantageous for its consumer acceptability.

Hepcidin-mediated Iron Regulation in P19 Cells is Detectable by Magnetic Resonance Imaging

Magnetic resonance imaging can be used to track cellular activities in the body using iron-based contrast agents. However, multiple intrinsic cellular iron handling mechanisms may also influence the detection of magnetic resonance (MR) contrast: a need to differentiate among those mechanisms exists. In hepcidin-mediated inflammation, for example, downregulation of iron export in monocytes and macrophages involves post-translational degradation of ferroportin. We examined the influence of hepcidin endocrine activity on iron regulation and MR transverse relaxation rates in multi-potent P19 cells, which display high iron import and export activities, similar to alternatively-activated macrophages. Iron import and export were examined in cultured P19 cells in the presence and absence of iron-supplemented medium, respectively. Western blots indicated the levels of transferrin receptor, ferroportin and ubiquitin in the presence and absence of extracellular hepcidin. Total cellular iron was measured by inductively-coupled plasma mass spectrometry and correlated to transverse relaxation rates at 3 Tesla using a gelatin phantom. Under varying conditions of iron supplementation, the level of ferroportin in P19 cells responds to hepcidin regulation, consistent with degradation through a ubiquitin-mediated pathway. This response of P19 cells to hepcidin is similar to that of classically-activated macrophages. The correlation between total cellular iron content and MR transverse relaxation rates was different in hepcidin-treated and untreated P19 cells: slope, Pearson correlation coefficient and relaxation rate were all affected. These findings may provide a tool to non-invasively distinguish changes in endogenous iron contrast arising from hepcidin-ferroportin interactions, with potential utility in monitoring of different macrophage phenotypes involved in pro- and anti-inflammatory signaling. In addition, this work demonstrates that transverse relaxivity is not only influenced by the amount of cellular iron but also by its metabolism.

Unpredicted photocatalytic activity of clinoptilolite-mordenite natural zeolite.

Zeolites are not often used directly as photocatalysts. Their framework and nanocavities have served as support or hosts for photoactive materials or traces of transition metals functioning as photoactive sites for catalysing decomposition and oxidation reactions in the gas phase. Research in this area has been limited to a few synthetic zeolites and in this context, efforts are directed to the preparation of new zeolite-based photocatalysts, when in nature there is an abundance of materials with properties yet to be discovered. We report the application of a natural clinoptilolite–mordenite zeolite as an efficient self-photocatalytic material for the decomposition of caffeine in aqueous solution. Adsorption experiments, combined with textural, crystallographic, and spectroscopic characterization were performed comparatively for the natural zeolite, a synthetic homologue, and the iron-exchanged zeolite. The neat zeolite containing 1.2 wt% of endogenous iron exhibited 99% decomposition of caffeine after 4 h irradiation and a faster reaction rate, followed by the synthetic sample. In contrast, the iron-loaded sample was the less effective zeolite because of pore blocking. Caffeine adsorption occurred on the outer zeolite surface and the photoproducts were hydroxylated pyrimidine rings and linear amide derivatives.

AB038. Pathological neovascularization in retinopathy of prematurity is regulated by heme-derived iron trafficking

Background: Retinopathy of prematurity (ROP) is an eye disease of the immature newborn characterized by pathological neovascularization (NV). ROP classically arises due to changes in oxygen availability in the retina. However, other factors, such as red blood cell (RBC) transfusion, independently contribute to disease severity. Heme molecules, rich in RBC, are the primary source of endogenous iron. Heme is metabolized by heme oxygenase (HO) into biliverdin, carbon monoxide, and ferrous ions. Low iron levels stabilize hypoxia-inducible factor 1α (HIF1 α), the main transcription factor of vascular endothelial growth factor (VEGF) that drives angiogenesis. Here we investigate the role of heme metabolism in pathological NV.

Introducing Specificity to Iron Oxide Nanoparticle Imaging by Combining 57Fe-Based MRI and Mass Spectrometry.

Iron oxide nanoparticles (ION) are highly sensitive probes for magnetic resonance imaging (MRI) that have previously been used for in vivo cell tracking and have enabled implementation of several diagnostic tools to detect and monitor disease. However, the in vivo MRI signal of ION can overlap with the signal from endogenous iron, resulting in a lack of detection specificity. Therefore, the long-term fate of administered ION remains largely unknown, and possible tissue deposition of iron cannot be assessed with established methods. Herein, we combine nonradioactive 57Fe-ION MRI with ex vivo laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging, enabling unambiguous differentiation between endogenous iron (56Fe) and iron originating from applied ION in mice. We establish 57Fe-ION as an in vivo MRI sensor for cell tracking in a mouse model of subcutaneous inflammation and for assessing the long-term fate of 57Fe-ION. Our approach resolves the lack of detection specificity in ION imaging by unambiguously recording a 57Fe signature.

Experimental study on the effect of iron accumulation on bonemass, intraosseous vessels and vascular endothelial cells in mice

Objective To investigate the effect of endogenous iron accumulation onbone mass, intraosseous vessels and the effect of exogenous iron on endothelial cell activity. Methods The mice were divided into control group (C57/BL6 mice without hepcidin knockout) and hepcidin-knockout group (10 mice in each group, 8 weeks old and weighing about 22 g). The mice in both groups were killed at the age of 16 weeks. Serum ferritin levels were measured by Enzyme-linked immunosorbent assay (ELISA), and iron accumulation in liver tissue was measured by Prussian blue staining, while femoral micro-structure was measured by micro-CT, and H-type vessel immunofluorescence staining was used to detect the number of H-vessels in bone. Cell experiments were divided into normal culture group (normal cell group) and intervention group (Fe group) with 200 μmol/L ammonium ferric citrate. Scratch test was used to detect the migration ability of vascular endothelial cells, and tube formation test was used to detect the function of vascular endothelial cells. The endothelial activity of vascular endothelial cells was detected by immunofluorescence. Results The level of serum ferritin (318.30±12.53 ng/ml) in the hepcidin-knockout group was significantly higher than that in control group (109.60±4.66 ng/ml). The percentage of blue area of Prussian liver iron staining in the hepcidin-knockout group (80.80%±3.156%) was significantly higher than that in control group (20.94%±2.813%). Bone mineral density in the hepcidin-knockout group (0.044±0.002 mg/m3) was significantly higher than that in control group (0.131±0.008 mg/m3). The number of intraosseous blood vessels in the hepcidin-depleted mice (17.06%±1.060%) was significantly lower than that in control group (38.76%±4.576%). There were significant differences between the two groups in each index (t=-49.367,-13.788, 35.293, 6.165; all P < 0.05). The scratches of vascular endothelial cells in Fe group were reduced by 24.300%±1.849% after 24 hours of culture, which was significantly lower than that in normal group (39.060%±3.211%). The area of vascular endothelial cells in Fe group (0.035±0.003 mm2) was significantly lower than that in normal group (0.330±0.018 mm2). The EMCN positive cells of vascular endothelial cells in Fe group were significantly lower than those in normal group. The percentage of cell number (12.000%±3.462%) was significantly lower than that of normal cell group (0.035%±0.003%). There were significant differences in cell indices between the two groups (t=9.790, 18.929, 13.922; all P< 0.05). Conclusion Endogenous iron accumulation aggravated bone loss in mice, and the number of intraosseous blood vessels decreased significantly. Vascular endothelial cells were inhibited by iron intervention in migration, tube-formation and endothelial ability. Key words: Mice; Osteoporosis; Endothelial cells; Ferritins

Diets containing naturally occurring iron or naturally occurring iron plus supplemental ferrous sulfate both maintain normal hematological status in adult dogs

Iron is an essential mineral for dogs due to its roles in physiological processes. The NRC recommends the adequate intake for iron in adult dogs is 0.5 mg/kg of body weight. While iron should be present in high enough concentrations in the diet to maintain normal hematological status and prevent iron deficiency anemia, too much dietary iron can increase lipid oxidation in the food during preparation and storage, subsequently reducing shelf life, palatability, and nutritional content of foods. In general, iron is supplemented to diets to ensure that no dogs are deficient. The primary objective of this study was to investigate the ability of a diet containing either 0 mg/kg or 80 mg/kg supplemental iron to support normal hematological parameters in adult dogs. Twenty-two adult dogs were randomly assigned to one of two treatment diets: Test Diet 1, Experimental maintenance formula with 115 mg/kg endogenous iron + 0 mg/kg supplemental iron; and Test Diet 2, Experimental maintenance formula with 115 mg/kg endogenous iron + 80 mg/kg supplemental iron (ferrous sulfate). Dogs consumed treatment diets for 26 weeks, with clinical assessments (e.g., hemoglobin concentration/total iron binding capacity) assessed throughout the trial (0, 2, 4, and 6 months). Baseline iron related endpoints were not different between diet treatments (P &gt; 0.50), except for mean corpuscular hemoglobin concentrations (P = 0.046). No differences were found for iron related end points between the two diet treatments (P&gt;0.05) at any time point. In some diets no supplemental iron will be needed, based on the diet matrix, whereas others may require some supplemental iron. By reducing iron inclusion in the formulations of canine diets, food stability and shelf life may be improved. This reduction in supplemental iron can also reduce cost of formulation, benefiting food manufacturers, consumers, and adult dogs.

Bone morphogenetic protein 2 is a depot-specific regulator of human adipogenesis

BackgroundBone morphogenetic proteins (BMPs) regulate adipogenesis but it is not clear whether they influence regional adipose tissue (AT) development in humans.ObjectiveTo characterise BMP2 expression, BMP2-SMAD1/5/8 signalling, and BMP2′s potential effect on proliferation and adipogenesis in human subcutaneous abdominal and gluteal AT and its constituent preadipocytes.MethodsBMP2 expression was measured in whole AT and immortalised preadipocytes via qPCR and Western blot; secreted/circulating BMP2 was measured by ELISA. The effect of BMP2 on preadipocyte proliferation was evaluated using a fluorescent assay. BMP2′s effect on adipogenesis in immortalised preadipocytes was determined via qPCR of adipogenic markers and cellular triacylglycerol (TAG) accumulation. BMP2-SMAD1/5/8 signalling was assessed in immortalised preadipocytes via Western blot and qPCR of ID1 expression.ResultsBMP2 was expressed and released by abdominal and gluteal AT and preadipocytes. Exogenous BMP2 dose dependently promoted adipogenesis in abdominal preadipocytes only; 50 ng/ml BMP2 increased PPARG2 expression (10-fold compared to vehicle, p < 0.001) and TAG accumulation (3-fold compared to vehicle; p < 0.001). BMP2 stimulated SMAD1/5/8 phosphorylation and ID1 expression in abdominal and gluteal preadipocytes but this was blocked by 500 nM K02288, a type 1 BMP receptor inhibitor (p < 0.001). Co-administration of 500 nM K02288 also inhibited the pro-adipogenic effect of 50 ng/ml BMP2 in abdominal cells; >90% inhibition of TAG accumulation (p < 0.001) and ~50% inhibition of PPARG2 expression (p < 0.001). The endogenous iron regulator erythroferrone reduced BMP2-SMAD1/5/8 signalling by ~30% specifically in subcutaneous abdominal preadipocytes (p < 0.01), suggesting it plays a role in restricting the expansion of the body’s largest AT depot during energy deficiency. Additionally, a waist-hip ratio-increasing common polymorphism near BMP2 is an eQTL associated with ~15% lower BMP2 expression in abdominal and gluteal AT (p < 0.05) as well as altered adipocyte size in male abdominal AT (p < 0.05).ConclusionsThese data implicate BMP2-SMAD1/5/8 signalling in depot-specific preadipocyte development and abdominal AT expansion in humans.

Treatment of petroleum hydrocarbons contaminated soil by Fenton like oxidation

Experimental tests were carried out in solid phase reactors on a microcosm scale, to removal old petroleum pollution by Fenton like oxidation process. In order to optimize the process, parametric study and statistically designed experiment have been undertaken by considering the amount influence of hydrogen peroxide (H2O2), endogenous and zero-valent iron (Fe) and ethylene diamine tetraacetic acid (EDTA) as chelating agent.The measurement of residual total petroleum hydrocarbons for different H2O2/Fe molar ratios and pH in the vicinity of neutrality highlighted oxidation rates ranging between 29.0 and 39.3%. The Fenton like (FL) oxidation was optimal for H2O2/Fe molar ratio of 15/4. The use EDTA led to result up 72.2% for H2O2/total Fe/EDTA molar ratio of 15/4/4 after 48 h of treatment.The statistical analysis of data by factorial design, has allowed the modeling of Fenton like process performances in the operating domain. It showed that hydrogen peroxide amount, interaction effects of oxidant-catalyst, catalyst-chelating agent, and oxidant-catalyst-chelating agent, were the influential parameters. Moreover, these results suggest that endogenous iron could be used as a source of iron in the presence of the chelating agent to activate FL oxidation. A better accuracy (80.0%) was obtained by statistical analysis for H2O2/endogenous Fe/EDTA molar ratio of 20/1/1.

Patents on Quantitative Susceptibility Mapping (QSM) of Tissue Magnetism.

Quantitative susceptibility mapping (QSM) depicts biodistributions of tissue magnetic susceptibility sources, including endogenous iron and calcifications, as well as exogenous paramagnetic contrast agents and probes. When comparing QSM with simple susceptibility weighted MRI, QSM eliminates blooming artifacts and shows reproducible tissue susceptibility maps independent of field strength and scanner manufacturer over a broad range of image acquisition parameters. For patient care, QSM promises to inform diagnosis, guide surgery, gauge medication, and monitor drug delivery. The Bayesian framework using MRI phase data and structural prior knowledge has made QSM sufficiently robust and accurate for routine clinical practice. To address the lack of a summary of US patents that is valuable for QSM product development and dissemination into the MRI community. We searched the USPTO Full-Text and Image Database for patents relevant to QSM technology innovation. We analyzed the claims of each patent to characterize the main invented method and we investigated data on clinical utility. We identified 17 QSM patents; 13 were implemented clinically, covering various aspects of QSM technology, including the Bayesian framework, background field removal, numerical optimization solver, zero filling, and zero-TE phase. Our patent search identified patents that enable QSM technology for imaging the brain and other tissues. QSM can be applied to study a wide range of diseases including neurological diseases, liver iron disorders, tissue ischemia, and osteoporosis. MRI manufacturers can develop QSM products for more seamless integration into existing MRI scanners to improve medical care.

Imaging endogenous macrophage iron deposits reveals a metabolic biomarker of polarized tumor macrophage infiltration and response to CSF1R breast cancer immunotherapy

Iron deposits are a phenotypic trait of tumor-associated macrophages (TAMs). Histological iron imaging and contrast-agent free magnetic resonance imaging (MRI) can detect these deposits, but their presence in human cancer, and correlation with immunotherapeutic response is largely untested. Here, primarily using these iron imaging approaches, we evaluated the spatial distribution of polarized macrophage populations containing high endogenous levels of iron in preclinical murine models and human breast cancer, and used them as metabolic biomarkers to correlate TAM infiltration with response to immunotherapy in preclinical trials. Macrophage-targeted inhibition of the colony stimulating factor 1 receptor (CSF1R) by immunotherapy was confirmed to inhibit macrophage accumulation and slow mammary tumor growth in mouse models while also reducing hemosiderin iron-laden TAM accumulation as measured by both iron histology and in vivo iron MRI (FeMRI). Spatial profiling of TAM iron deposit infiltration defined regions of maximal accumulation and response to the CSF1R inhibitor, and revealed differences between microenvironments of human cancer according to levels of polarized macrophage iron accumulation in stromal margins. We therefore demonstrate that iron deposition serves as an endogenous metabolic imaging biomarker of TAM infiltration in breast cancer that has high translational potential for evaluation of immunotherapeutic response.

Rutin abrogates manganese—Induced striatal and hippocampal toxicity via inhibition of iron depletion, oxidative stress, inflammation and suppressing the NF-κB signaling pathway

Excess exposure to Manganese (Mn) promotes oxidative stress and neuro-inflammation. Rutin (RUT) has been found to exhibit both anti-oxidative stress and anti-inflammatory properties. This study aimed to investigate the effects of RUT on Mn accumulation, endogenous iron (Fe) depletion, oxidative stress, inflammation and nuclear factor kappa B (NF-κB) signaling pathways in the hippocampus and striatum of Mn – induced rats. Rats were treated with 30 mg/kg Mn body weight alone or orally co-treated by gavage with RUT at 50 and at 100 mg/kg body weight for 35 consecutive days. Thereafter, we investigated Mn and endogenous Fe levels, acetylcholinesterase activity, oxidative stress markers, pro-inflammatory cytokines and nuclear factor kappa B (NF-κB) in the hippocampus and striatum of rats. The results indicate that Mn induced Mn – accumulation, Fe depletion, oxidative stress, inflammation and the activation of acetylcholinesterase activity and NF-κB signaling pathways in the hippocampus and striatum of the rats. However, RUT attenuated Fe depletion, oxidative stress and inflammation and suppressed acetylcholinesterase activity and NF-κB pathway via downstream regulations of tumor necrosis factor alpha, interleukin I beta and interleukin 6. Taken together, our present study demonstrates that RUT abrogates Mn – induced striatal and hippocampal toxicity via inhibition of Fe depletion, oxidative stress, inflammation and suppressing the NF-κB signaling pathways. Our results indicate that RUT may be of use as a neuroprotective agent against Mn – induced neuronal toxicity.

Iron regulatory protein 2 deficiency may correlate with insulin resistance

Iron is known to be a crucial regulator of glucose, and several studies have demonstrated that iron overload is one of the risk factors for insulin resistance and diabetes; however, the mechanism has not yet been clarified. To investigate the effect of iron overload on glucose metabolism and the underlying mechanism, Irp2 knockout (Irp2−/−) mice (endogenous iron overload model) were used. We found that Irp2−/− mice exhibited hyperglycemia and iron overload in the liver and skeletal muscle. Increased MDA, decreased SOD levels, and increased cell apoptosis were also found in the liver and muscle of Irp2−/− mice. Glucose concentrations were significantly higher in Irp2−/− mice in insulin tolerance tests. However, early-phase insulin secretion was not altered in Irp2−/− mice. The expression of hepatic IRS2 and muscle GLUT4 was declined in Irp2−/− mice at both mRNA and protein levels when compared with those of wild-type control. In conclusions, Irp2−/− mice showed hyperglycemia, which might due to insulin resistance rather than due to impaired insulin secretion.

Effects of Chelating Agents and Salts on Interfacial Properties and Lipid Oxidation in Oil-in-Water Emulsions.

The effects of chelating agents and salts on the interfacial characteristics and oxidative stability of oil-in-water emulsions containing an endogenous concentration of metal ions were investigated. Emulsions were fabricated by high-pressure homogenization of 10% oil phase (sacha inchi oil) and 90% aqueous phase (1% Tween 60 in phosphate buffer solution, pH 7, 50 mM). The oxidative stability of the emulsions was characterized by measuring peroxide values and thiobarbituric acid reactive substances throughout storage. Endogenous iron and copper ion levels in the emulsions were detected by atom absorption spectroscopy as 1.99 and 0.86 ppm, respectively. Incorporation of chelating agents, either ethylenediaminetetraacetic acid or sodium citrate, into the emulsions effectively inhibited lipid oxidation, showing that even these low levels of endogenous metal ions ( parts per million) were sufficient to promote oxidation. Conversely, the addition of monovalent salts, NaCl or KCl, slightly increased the rate of lipid oxidation in the emulsions, which was attributed to their impact on the physical properties of the surfactant layer at the oil droplet surfaces. The impact of chelating agents and salts on the electrical characteristics (ξ potential) and relaxation time (TR) of the surfactant-coated lipid droplets were characterized by particle electrophoresis and nuclear magnetic resonance spectroscopy, respectively. The chelating agents and salts altered the surface potential of the droplets, indicative of a change in the adsorption of metal ions to the droplet surfaces. Moreover, they altered the arrangement of surface-active molecules at the droplet surfaces, thereby impacting the contact of pro-/antioxidants with the oil phase. These results have important implications for the formulation of emulsion-based materials that are more stable to lipid oxidation.