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Mitochondrial Atm1 proteins play important roles in the maturation of certain cytosolic proteins. Here, the authors exploit cryo-EM to capture several structures of an Atm1. The findings shed new light on the molecular function of Atm1 transporters.In eukaryotes, iron-sulfur clusters are essential cofactors for numerous physiological processes, but these clusters are primarily biosynthesized in mitochondria. Previous studies suggest mitochondrial ABCB7-type exporters are involved in maturation of cytosolic iron-sulfur proteins. However, the molecular mechanism for how the ABCB7-type exporters participate in this process remains elusive. Here, we report a series of cryo-electron microscopy structures of a eukaryotic homolog of human ABCB7, CtAtm1, determined at average resolutions ranging from 2.8 to 3.2 angstrom, complemented by functional characterization and molecular docking in silico. We propose that CtAtm1 accepts delivery from glutathione-complexed iron-sulfur clusters. A partially occluded state links cargo-binding to residues at the mitochondrial matrix interface that line a positively charged cavity, while the binding region becomes internalized and is partially divided in an early occluded state. Collectively, our findings substantially increase the understanding of the transport mechanism of eukaryotic ABCB7-type proteins.

Background. Oral iron supplement is commonly prescribed to heart failure patients with iron deficiency. However, the effects of oral iron for heart failure remain controversial. This study included randomized controlled trials (RCTs) for meta-analysis to evaluate the effects of oral iron for heart failure patients. Methods. Nine databases (The Cochrane Library, Embase, PubMed, CINAHL, Web of science, CNKI, SinoMed, VIP, and Wanfang) were searched for RCTs of oral iron for heart failure from inception to October 2021. The effects were assessed with a meta-analysis using Revman 5.3 software. The trial sequential analysis was performed by TSA 0.9.5.10 beta software. The risk of bias of trials was evaluated via Risk of Bias tool. The evidence quality was assessed through GRADE tool. Results. Four studies including 582 patients with heart failure and iron deficiency were enrolled. The results indicated that oral iron treatment could improve left ventricular ejection fraction (LVEF, MD = 1.52 % , 95% CI: 0.69 to 2.36, P = 0.0003 ) and serum ferritin ( MD = 1.64 , 95% CI: 0.26 to 3.02, P = 0.02 ). However, there was no between-group difference in the 6-minute walk distances (6MWT), N terminal pro B type natriuretic peptide (NT-proBNP) or hemoglobin level when compared with control group. Subgroup analyses revealed that the effects of oral iron on 6 MWT and serum ferritin could not be affected by duration and frequency of oral iron uptakes. In trial sequential analysis of LVEF and serum ferritin, the Z-curves crossed the traditional boundary and trail sequential monitoring boundary but did not reach the required information size. Conclusion. This analysis showed that oral iron could improve cardiac function measured by LVEF, and iron stores measured serum ferritin, but lack of effect on exercise capacity measured by 6 MWT, and iron stores measured by hemoglobin. Given the overall poor methodological quality and evidence quality, these findings should be treated cautiously.

Gaudichaudione H (GH), a caged polyprenylated xanthone from Garcinia plants, showed anti-cancer and anti-inflammatory effects in vitro. However, the in vivo toxicity of this compound has never been reported. The present study was aimed to address the toxic effects of Gaudichaudione H using zebrafish embryos and larvae as an in vivo test model. The zebrafish embryos were treated with GH having different concentrations (0, 0.28, 0.38 and 0.57 μg/mL). The results revealed that GH induces significant embryonic mortality, decreased heartbeat, cardiotoxicity, cardiovascular defects, increased apoptosis and decreased hemoglobinization in zebrafish embryos and larvae. According to transcriptome analysis, 1841 genes were significantly differentially expressed (1185 down-regulated and 656 up-regulated) after GH treatment. The main functions of these genes were related to iron metabolism pathways. The toxicity of GH on zebrafish embryonic development and cardiovascular may due to large amounts of downregulated genes involved in metabolic pathways and DEGs related to 'Iron ion binding' and 'Heme binding' functions.

Nanocomposites, based on iron salts and soluble flaxseed gum (FG), were prepared as potential treatments of iron deficiency anemia (IDA). FG was extracted, characterized, and formulated into iron-loading nanocomposites via ion-exchange against FeCl_3, Fe_2(SO_4)_3, FeCl_2, and FeSO_4·7H_2O. FG-iron nanocomposites preparation condition was optimized, and physicochemical properties of the nanocomposites were investigated. In vitro release kinetics of iron in simulated gastric fluid (SGF) was also evaluated. FG heteropolysaccharide, consisting of rhamnose (33.73%), arabinose (24.35%), xylose (14.23%), glucose (4.54%), and galactose (23.15%) monosaccharides, linked together via varieties of glycosidic bonds, was a good recipient for both ferric and ferrous irons under screened conditions (i.e., 80 °C, 2 h, I/G = 1:2). Iron loaded contents in the nanocomposites prepared from FG-FeCl_3, FG-Fe_2(SO_4)_3, FG-FeCl_2, and FG-FeSO_4·7H_2O were 25.51%, 10.36%, 5.83%, and 22.83%, respectively. Iron in these nanocomposites was mostly in a bound state, especially in FG-FeCl_3, due to chelation forming bonds between iron and polysaccharide hydroxyl or carboxyl groups and formed stable polysaccharide-iron crystal network structures. Free iron ions were effectively removed by ethanol treatments. Because of chelation, the nanocomposites delayed iron release in SGF and the release kinetics were consistent with Korsmeyer-Peppas model. This indicates that such complexes might reduce side effects of free iron in human stomach. Altogether, this study indicates that these synthetic FG-iron nanocomposites might be developed as novel iron supplements for iron deficiency, in which FG-FeCl_3 is considered as the best option.

Xiaohui Duan,1,* Liejing Lu,1,* Yong Wang,2 Fang Zhang,1 Jiaji Mao,1 Minghui Cao,1 Bingling Lin,1 Xiang Zhang,1 Xintao Shuai,2,3 Jun Shen1 1Department of Radiology, Sun Yat-Sen Memorial Hospital, 2PCFM Lab of Ministry of Education, School of Materials Science and Engineering, 3BME Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People’s Republic of China *These authors contributed equally to this work Abstract: Understanding the long-term fate and potential mechanisms of mesenchymal stem cells (MSCs) after transplantation is essential for improving functional benefits of stem cell-based stroke treatment. Magnetic resonance imaging (MRI) is considered an attractive and clinically translatable tool for longitudinal tracking of stem cells, but certain controversies have arisen in this regard. In this study, we used SPION-loaded cationic polymersomes to label green fluorescent protein (GFP)-expressing MSCs to determine whether MRI can accurately reflect survival, long-term fate, and potential mechanisms of MSCs in ischemic stroke therapy. Our results showed that MSCs could improve the functional outcome and reduce the infarct volume of stroke in the brain. In vivo MRI can verify the biodistribution and migration of grafted cells when pre-labeled with SPION-loaded polymersome. The dynamic change of low signal volume on MRI can reflect the tendency of cell survival and apoptosis, but may overestimate long-term survival owing to the presence of iron-laden macrophages around cell graft. Only a small fraction of grafted cells survived up to 8 weeks after transplantation. A minority of these surviving cells were differentiated into astrocytes, but not into neurons. MSCs might exert their therapeutic effect via secreting paracrine factors rather than directing cell replacement through differentiation into neuronal and/or glial phenotypes. Keywords: mesenchymal stem cells, magnetic resonance imaging, superparamagnetic iron oxide nanoparticles, polymersome, ischemic stroke, green fluorescence protein

In the present study, we demonstrated that the luminescent molybdenum disulfide (MoS 2 ) nanosheets, which were prepared hydrothermally by using sodium molybdate and thiourea as precursors, possessed peroxidase-like activity, and could catalyze the oxidation of peroxidase substrate o-phenylenediamine (OPD) in the presence of hydrogen peroxide (H 2 O 2 ) to produce a yellow color reaction. Further addition of Fe 2+ into the nanosheets led to peroxidase mimetics with greatly enhanced catalytic activity. The observation was exploited to develop a label-free colorimetric nanozyme sensor for detection of Fe 2+ . The fabricated MoS 2 /OPD/H 2 O 2 sensor showed a wide linear range of 0.01–0.8 µM with a detection limit of 7 nM. Moreover, it was found that the MoS 2 /OPD/H 2 O 2 sensor displayed enhanced sensitivity and selectivity toward Fe 2+ compared with the OPD/H 2 O 2 sensor, suggesting that the MoS 2 nanosheets could improve the performance of the Fe 2+ sensor. An advanced chemometrics algorithm, multivariate curve resolution by alternating least squares (MCR-ALS), was further applied to interpret the origin of enhancing sensitivity and selectivity in the Fe 2+ sensor with the MoS 2 nanosheets. The time-dependent UV–vis spectral data of the studied systems were collected, and submitted to the MCR-ALS. The results showed that the increased sensitivity and selectivity of the MoS 2 /OPD/H 2 O 2 sensor for Fe 2+ detection likely arose from its large reaction rate constant. Finally, the proposed MoS 2 /OPD/H 2 O 2 sensor was successfully applied for detection of Fe 2+ in water samples.

pH-responsive biocompatible Fe(III)-gallic acid nanoparticles with strong near-infrared absorbance are very stable in mild acidic conditions, but easily decomposed in neutral conditions, which enables the nanoparticles to be stable in a tumor and easily metabolized in other organs, thus providing a safe nanoplatform for in vivo photoacoustic imaging/photothermal therapy theranostic applications.

Great progresses have been made to carry out Fenton oxidation under neutral or alkaline pH in which, nevertheless, organic acids and other acidic intermediates usually result in acidic Fenton effluent. To eliminate the classical neutralization step prior to biological treatment, acid-tolerant microbes were here screened and used for purification of acidic Fenton effluent to achieve pH increase and further COD (chemical oxygen demand) removal. The bacterial and fungal community diversity was analyzed before and after screening for acid-tolerant microbes. After screening the bacterial diversity sharply decreased while the fungal diversity at the genus level became richer, mainly including Phialemoniopsis (relative abundance 38.69%), Vanrija (20.08%), Hypocreaceae (18.44%) and Candida (14.74%). Acidic pH and residual H2O2 are the features of Fenton effluent; hence, effects of pH and H2O2 on the screened acid-tolerant microbes were investigated in the aspects of growth rate and oxygen uptake rate. The kinetic parameters, including YH–biomass yield coefficient; Kd–biomass decay coefficient; μm–specific maximum COD removal rate; Ks–half saturation constant for COD removal, of the acid-tolerant microbes using 1/5 YM (yeast extract and malt extract culture medium) as substrate at 25 °C were measured by respirometric methodology. In BAC (biological activated carbon) inoculated with acid-tolerant microbes to treat actual Fenton effluent, the average COD removal efficiency was 72% at HRT (hydraulic retention time) of 3 h and the effluent pH was above 6 after removing the dissolved CO2 by air stripping. This study will provide a basis for developing a new combined process including Fenton and biological oxidation without pH adjustment.

The cytochromes P450 are drug metabolizing enzymes in the body that typically react with substrates through a monoxygenation reaction. During the catalytic cycle two reduction and protonation steps generate a high-valent iron (IV)-oxo heme cation radical species called Compound I. However, with sufficient reduction equivalents present, the catalytic cycle should be able to continue to the reduced species of Compound I, called Compound II, rather than a reaction of Compound I with substrate. In particular, since electron transfer is usually on faster timescales than atom transfer, we considered this process feasible and decided to investigate the reaction computationally. In this work we present a computational study using density functional theory methods on active site model complexes alongside quantum mechanics/molecular mechanics calculations on full enzyme structures of cytochrome P450 enzymes. Specifically, we focus on the relative reactivity of Compound I and II with a model substrate for O&ndash, H bond activation. We show that generally the barrier heights for hydrogen atom abstraction are higher in energy for Compound II than Compound I for O&ndash, H bond activation. Nevertheless, for the activation of such bonds, Compound II should still be an active oxidant under enzymatic conditions. As such, our computational modelling predicts that under high-reduction environments the cytochromes P450 can react with substrates via Compound II but the rates will be much slower.

Brain iron levels in patients of Parkinson’s disease (PD) are usually measured in postmortem samples or by MRI imaging including R2* and SWI. In this study we performed a meta-analysis to understand PD-associated iron changes in various brain regions, and to evaluate the accuracy of MRI detections comparing with postmortem results. Databases including Medline, Web of Science, CENTRAL and Embase were searched up to 19th November 2015. Ten brain regions were identified for analysis based on data extracted from thirty-three-articles. An increase in iron levels in substantia nigra of PD patients by postmortem, R2* or SWI measurements was observed. The postmortem and SWI measurements also suggested significant iron accumulation in putamen. Increased iron deposition was found in red nucleus as determined by both R2* and SWI, whereas no data were available in postmortem samples. Based on SWI, iron levels were increased significantly in the nucleus caudatus and globus pallidus. Of note, the analysis might be biased towards advanced disease and that the precise stage at which regions become involved could not be ascertained. Our analysis provides an overview of iron deposition in multiple brain regions of PD patients, and a comparison of outcomes from different methods detecting levels of iron.

Aims Iron deficiency (ID) is associated with adverse outcomes in heart failure (HF) but the underlying mechanisms are incompletely understood. Intracellular iron availability is secured by two mRNA-binding iron-regulatory proteins (IRPs), IRP1 and IRP2. We generated mice with a cardiomyocyte-targeted deletion of Irp1 and Irp2 to explore the functional implications of ID in the heart independent of systemic ID and anaemia. Methods and results Iron content in cardiomyocytes was reduced in Irp-targeted mice. The animals were not anaemic and did not show a phenotype under baseline conditions. Irp-targeted mice, however, were unable to increase left ventricular (LV) systolic function in response to an acute dobutamine challenge. After myocardial infarction, Irp-targeted mice developed more severe LV dysfunction with increased HF mortality. Mechanistically, the activity of the iron-sulphur cluster-containing complex I of the mitochondrial electron transport chain was reduced in left ventricles from Irp-targeted mice. As demonstrated by extracellular flux analysis in vitro, mitochondrial respiration was preserved at baseline but failed to increase in response to dobutamine in Irp-targeted cardiomyocytes. As shown by 31P-magnetic resonance spectroscopy in vivo, LV phosphocreatine/ATP ratio declined during dobutamine stress in Irp-targeted mice but remained stable in control mice. Intravenous injection of ferric carboxymaltose replenished cardiac iron stores, restored mitochondrial respiratory capacity and inotropic reserve, and attenuated adverse remodelling after myocardial infarction in Irp-targeted mice but not in control mice. As shown by electrophoretic mobility shift assays, IRP activity was significantly reduced in LV tissue samples from patients with advanced HF and reduced LV tissue iron content. Conclusions ID in cardiomyocytes impairs mitochondrial respiration and adaptation to acute and chronic increases in workload. Iron supplementation restores cardiac energy reserve and function in iron-deficient hearts.

The reaction pathways for 5′-hydroxylation and N-demethylation of nicotine catalyzed by cytochrome P450 were investigated by performing a series of first-principle electronic structure calculations on a catalytic reaction model system. The computational results indicate that 5′-hydroxylation of nicotine occurs through a two-state stepwise process, i.e. an initial hydrogen atom transfer from nicotine to Cpd I (i.e. the HAT step) followed by a recombination of the nicotine moiety with the iron-bound hydroxyl group (i.e. the rebound step) on both the high-spin (HS) quartet and low-spin (LS) doublet states. The HAT step is the rate-determining one. This finding represents the first case that exhibits genuine rebound transition state species on both the HS and the LS states for Cα-H hydroxylation of amines. N-demethylation of nicotine involves a N-methylhydroxylation to form N-(hydroxymethyl)nornicotine, followed by N-(hydroxymethyl)nornicotine decomposition to nornicotine and formaldehyde. The N-methylhydroxylation step is similar to 5′-hydroxylation, namely that a rate-determining HAT step followed by a rebound step. The decomposition process occurs on the deprotonated state of N-(hydroxymethyl)nornicotine assisted by a water molecule and the energy barrier is significantly lower than that of the N-methylhydroxylation process. Comparison of the rate-determining free energy barriers for the two reaction pathways predicts a preponderance of 5′-hydroxylation over the N-demethylation by roughly a factor of 18:1, which is in excellent agreement with the factor of 19:1 derived from available experimental data.

It is shown that H-abstraction reactivity by oxoiron(IV) complexes with a quintet ground state is highly enhanced due to exchange-stabilization endowed by the increased number of the exchange d-d interactions near the transition state. It is postulated that nonheme enzymes evolved to make use of this fundamental mechanism in activation of strong C-H bonds.

Objective Previous work has showed that excess iron accumulation is harmful to reproduction and even promotes death; however, whether the multiple biological toxicity of iron (Fe) exposure could be transferred to progeny remains unknown. The present study used Caenorhabditis elegans to analyze the multiple toxicities of iron exposure and their possible transferable properties. Methods Three concentrations of iron sulfate solution (2.5 μmol/L, 75 μmol/L, and 200 μmol/L) were used. The endpoints of lifespan, body size, generation time, brood size, head thrash and body bend frequencies, and chemotaxis plasticity were selected to investigate Fe toxicity and its effect on progeny in Caenorhabditis elegans . Results The Fe toxicity could cause multiple biological defects in a dose-dependent manner by affecting different endpoints in nematodes. Most of the multiple biological defects and behavior toxicities could be transferred from Fe-exposed Caenorhabditis elegans to their progeny. Compared to the parents, no recovery phenotypes were observed for some of the defects in the progeny, such as body bend frequency and life span. We further summarized the defects caused by Fe exposure into 2 groups according to their transferable properties. Conclusion Our results suggest that Fe exposure could cause multiple biological defects, and most of these severe defects could be transferred from Fe exposed nematodes to their progeny.

Hydrogen peroxide interference on chemical oxygen demand (COD) measurement has been a big problem in the application of the Fenton process. However, there is no simple and effective method available to address this problem, although several methods have been reported in the literature. In this study, a new method has been developed based on Na 2 SO 3 reduction and O 2 oxidation, which has easy operation and short time requirement. Na 2 SO 3 reduction was used to remove H 2 O 2 in water samples, which was independent of pH in the investigated range of 2.50–11.95. Residual Na 2 SO 3 was removed by subsequent O 2 oxidation, and effects of initial solution pH, ferric ion dosage, and stirring speed were explored. Solution pH below 3.0 and stirring speed of 700 rev min −1 could ensure a sufficiently high oxidation rate for Na 2 SO 3 with ferric ion higher than 0.469 mM. This new method was proven to be effective in the matrix of Fenton treating real landfill leachate. Meanwhile, the procedure for this method in other applications was proposed in detail. To the best of our knowledge, this newly developed method is the most simple and effective way to avoid H 2 O 2 interference on COD analysis.

Trace elements have been recognized to play an important role in the development of Parkinson's disease (PD). However, it is difficult to precisely identify the relationship between these elements and the progression of PD because of an insufficient number of patients. In this study, quantifications of selenium (Se), copper (Cu), iron (Fe) and zinc (Zn) by atomic absorption spectrophotometry were performed in plasma from 238 PD patients and 302 controls recruited from eastern China, which is so far the largest cohort of PD patients and controls for measuring plasma levels of these elements. We found that plasma Se and Fe concentrations were significantly increased whereas Cu and Zn concentrations decreased in PD patients as compared with controls. Meanwhile, these four elements displayed differential changes with regard to age. Linear and logistic regression analyses revealed that both Fe and Zn were negatively correlated with age in PD patients. Association analysis suggests that lower plasma Se and Fe levels may reduce the risk for PD, whereas lower plasma Zn is probably a PD risk factor. Finally, a model was generated to predict PD patients based on the plasma concentrations of these four trace elements as well as other features such as sex and age, which achieved an accuracy of 80.97±1.34% using 10-fold cross-validation. In summary, our data provide new insights into the roles of Se, Cu, Fe and Zn in PD progression.