Recent developments in electrochemical investigations into iron carbonyl complexes relevant to the iron centres of hydrogenases.

In this brief review mainly based on our own work, we summarised the electrochemical investigations into those iron carbonyl complexes relevant to the iron centres of [FeFe]-and [Fe]-hydrogenases in the following aspects: (i) electron transfer (E) coupled with a chemical reaction (C), EC process, (ii) two-electron process with potential inversion (ECisoE), and (iii) proton-coupled electron transfer (PCET) and the role of an internal base group in the non-coordination sphere. Through individual examples, these processes involved in the electrochemistry of the iron carbonyl complexes are discussed. In probing the complexes involving a two-electron process with potential inversion, the co-existence of one- and two-electron for a complex is demonstrated by incorporating intramolecularly a ferrocenyl group(s) into the complex. Our studies on proton reduction catalysed by three diiron complexes involving the PCET mechanism are also summarised. Finally, perspectives of the electrochemical study in iron carbonyl complexes inspired by the iron-containing enzymes are mentioned in the sense of developing mimics of low overpotentials for hydrogen evolution through exploiting the PCET effect.

Magnetism-Actuated Superhydrophobic Flexible Microclaw: From Spatial Microdroplet Maneuvering to Cross-Species Control.

The flexible maneuvering of microliter liquid droplets is significant in both fundamental science and practical applications. However, most current strategies are limited to the rigid locomotion on confined geographies platforms, which greatly hinder their practical uses. Here, we propose a magnetism-actuated superhydrophobic flexible microclaw (MSFM) with hierarchical structures for water droplet manipulation. By virtue of precise femtosecond laser patterning on magnetism-responsive poly(dimethylsiloxane) (PDMS) films doped with carbonyl iron powder, this MSFM without chemical contamination exhibits powerful spatial droplet maneuvering advantages with fast response (<100 ms) and lossless water transport (∼50 cycles) in air. We further performed quantitative analysis of diverse experimental parameters including petal number, length, width, and iron element proportion in MSFM impacting the applicable maneuvering volumes. By coupling the advantages of spatial maneuverability and fast response into this versatile platform, typical unique applications are demonstrated such as programmable coalescence of droplets, collecting debris via droplets, tiny solid manipulation in aqueous severe environments, and harmless living creature control. We envision that this versatile MSFM should provide great potential for applications in microfluidics and cross-species robotics.

A comparative analysis of solvent cast 3D printed carbonyl iron powder reinforced polycaprolactone polymeric stents for intravascular applications.

In the present research, the effectiveness of developed methodology based on solvent cast 3D printing technique was investigated by printing the different geometries of the stents. The carbonyl iron powder (CIP) reinforced polycaprolactone (CIPC) was used to print three pre-existing stent designs such as ABBOTT BVS1.1, PALMAZ-SCHATZ, and ART18Z. The physicochemical behavior was analyzed by X-ray diffraction and scanning electron microscopy. The radial compression test, three-point bending test and stent deployment test were carried out to analyze the mechanical behavior. The degradation behavior of the stents was investigated in static as well as dynamic environment. To investigate the hemocompatible and cytocompatible behaviors of the stents, platelet adhesion test, hemolysis test, protein adsorption, in vitro cell viability test, and live/dead cell viability assay were performed. The results revealed that stents had the adequate mechanical properties to perform the necessary functions in the human coronary. The degradation studies showed slower degradation rate in the dynamic environment in comparison to static environment. in vitro biological analysis indicated that the stents represented excellent resistance to thrombosis, hemocompatible functions as well as cytocompatible nature. The results concluded that PALMAZ-SCHATZ stent represented better mechanical properties, cell viability, blood compatibility, and degradation behavior.

Programmed ROS/CO-releasing nanomedicine for synergetic chemodynamic-gas therapy of cancer.

BACKGROUND: To improve the outcome of cancer treatment, the combination of multiple therapy models has proved to be effective and promising. Gas therapy (GT) and chemodynamic therapy (CDT), mainly targeting the mitochondrion and nucleus, respectively, are two emerging strategy for anti-cancer. The development of novel nanomedicine for integrating these new therapy models is greatly significant and highly desired. METHODS: A new nanomedicine is programmed by successive encapsulation of MnO2 nanoparticles and iron carbonyl (FeCO) into mesoporous silica nanoparticle. By decoding the nanomedicine, acidity in the lysosome drives MnO2 to generate ROS, ·OH among which further triggers the decomposition of FeCO into CO, realizing the effective combination of chemodynamic therapy with gas therapy for the first time. RESULTS: Acidity in the TEM drives MnO2 to generate ROS, ∙OH among which further triggers the decomposition of FeCO into CO, realizing the effective combination of CDT and CDGT. The co-released ROS and CO do damage to DNA and mitochondria of various cancer cells, respectively. The mitochondrial damage can effectively cut off the ATP source required for DNA repair, causing a synergetic anti-cancer effect in vitro and in vivo. CONCLUSIONS: The combination of CDT and CDGT causing a synergetic anti-cancer effect in vitro and in vivo. The proposed therapy concept and nanomedicine designing strategy might open a new window for engineering high-performance anti-cancer nanomedicine.

Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis.

We have previously demonstrated that iron overload in hepatic reticuloendothelial system cells (RES) is associated with severe nonalcoholic steatohepatitis (NASH) and advanced fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). Recruited myeloid-derived macrophages have gained a pivotal position as drivers of NASH progression and fibrosis. In this study, we used bone marrow-derived macrophages (BMDM) from C57Bl6 mice as surrogates for recruited macrophages and examined the effect of iron on macrophage polarization. Treatment with iron (ferric ammonium citrate, FAC) led to increased expression levels of M1 markers: CCL2, CD14, iNOS, IL-1ß, IL-6, and TNF-α; it also increased protein levels of CD68, TNF-α, IL-1ß, and IL-6 by flow cytometry. This effect could be reversed by desferrioxamine, an iron chelator. Furthermore, iron loading of macrophages in the presence of IL-4 led to the down-regulation of M2 markers: arginase-1, Mgl-1, and M2-specific transcriptional regulator, KLF4. Iron loading of macrophages with IL-4 also resulted in reduced phosphorylation of STAT6, another transcriptional regulator of M2 activation. Dietary iron overload of C57Bl6 mice led to hepatic macrophage M1 activation. Iron overload also stimulated hepatic fibrogenesis. Histologic analysis revealed that iron overload resulted in steatohepatitis. Furthermore, NAFLD patients with hepatic RES iron deposition had increased hepatic gene expression levels of M1 markers, IL-6, IL-1ß, and CD40 and reduced gene expression of an M2 marker, TGM2, relative to patients with hepatocellular iron deposition pattern. We conclude that iron disrupts the balance between M1/M2 macrophage polarization and leads to macrophage-driven inflammation and fibrogenesis in NAFLD.

Solvent Quality Controls Macromolecular Structural Dynamics of a Dendrimeric Hydrogenase Model.

We report a spectroscopic investigation of the ultrafast dynamics of the second-generation poly(aryl ether) dendritic hydrogenase model using two-dimensional infrared (2D-IR) spectroscopy to probe the metal carbonyl vibrations of the dendrimer and a reference small molecule, [Fe(µ-S)(CO)3]2. We find that the structural dynamics of the dendrimer are reflected in a slow phase of the spectral diffusion, which is absent from [Fe(µ-S)(CO)3]2, and we relate the slow phase to the quality of the solvent for poly(aryl ether) dendrimers. We observe a solvent-dependent modulation of the initial phase of vibrational relaxation of the carbonyl groups, which we attribute to an inhibition of solvent assistance in the intramolecular vibrational redistribution process for the dendrimer. There is also a clear solvent dependence of the vibrational frequencies of both the dendrimer and [Fe(µ-S)(CO)3]2. Our data represent the first 2D-IR study of a dendritic complex and provide insight into the solvent dependence of molecular conformation in solution and the ultrafast dynamics of moderately sized, conformationally mobile compounds.

Novel insights into mitochondrial molecular targets of iron-induced neurodegeneration: Reversal by cannabidiol.

Evidence has demonstrated iron accumulation in specific brain regions of patients suffering from neurodegenerative disorders, and this metal has been recognized as a contributing factor for neurodegeneration. Using an experimental model of brain iron accumulation, we have shown that iron induces severe memory deficits that are accompanied by oxidative stress, increased apoptotic markers, and decreased synaptophysin in the hippocampus of rats. The present study aims to characterize iron loading effects as well as to determine the molecular targets of cannabidiol (CBD), the main non-psychomimetic compound of Cannabis sativa, on mitochondria. Rats received iron in the neonatal period and CBD for 14 days in adulthood. Iron induced mitochondrial DNA (mtDNA) deletions, decreased epigenetic modulation of mtDNA, mitochondrial ferritin levels, and succinate dehydrogenase activity. CBD rescued mitochondrial ferritin and epigenetic modulation of mtDNA, and restored succinate dehydrogenase activity in iron-treated rats. These findings provide new insights into molecular targets of iron neurotoxicity and give support for the use of CBD as a disease modifying agent in the treatment of neurodegenerative diseases.

Effects of two aerobic exercise training protocols on parameters of oxidative stress in the blood and liver of obese rats.

We evaluated the effects of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) protocols on the alterations in oxidative stress parameters caused by a high-fat diet (HFD), in the blood and liver of rats. The HFD enhanced thiobarbituric acid reactive substances (TBA-RS) and protein carbonyl content, while reducing total sulfhydryl content and catalase (CAT) and glutathione peroxidase (GSH-Px) activities in the blood. Both training protocols prevented an increase in TBA-RS and protein carbonyl content, and prevented a reduction in CAT. HIIT protocol enhanced SOD activity. In the liver, HFD didn't alter TBA-RS, total sulfhydryl content or SOD, but increased protein carbonyl content and CAT and decreased GSH-Px. The exercise protocols prevented the increase in protein carbonyl content and the MICT protocol prevented an alteration in CAT. In conclusion, HFD elicits oxidative stress in the blood and liver and both protocols prevented most of the alterations in the oxidative stress parameters.

Methyl Fumarate-Derived Iron Carbonyl Complexes (FumET-CORMs) as Powerful Anti-inflammatory Agents.

Autoimmune diseases are characterized by dendritic cell (DC)-driven activation of pro-inflammatory T cell responses. Therapeutic options for these severe diseases comprise small molecules such as dimethyl fumarate, or "gasotransmitters" such as CO. Herein we describe the synthesis of bifunctional enzyme-triggered CO-releasing molecules (ET-CORMs) that allow the simultaneous intracellular release of both CO and methyl fumarate. Using bone-marrow-derived DCs the impressive therapeutic potential of these methyl fumarate-derived compounds (FumET-CORMs) is demonstrated by strong inhibition of lipopolysaccharide-induced pro-inflammatory signaling pathways and blockade of downstream interleukin-12 or -23 production. The data also show that FumET-CORMs are able to transform DCs into an anti-inflammatory phenotype. Thus, these novel compounds have great clinical potential, for example, for the treatment of psoriasis or other inflammatory conditions of the skin.

A mononuclear iron carbonyl complex [Fe(µ-bdt)(CO)2(PTA)2] with bulky phosphine ligands: a model for the [FeFe] hydrogenase enzyme active site with an inverted redox potential.

A mononuclear hexa-coordinated iron carbonyl complex [Fe(µ-bdt)(CO)2(PTA)2] 1 (bdt = 1,2-benzenedithiolate; PTA = 1,3,5-triaza-7-phosphaadamantane) with two bulky phosphine ligands in the trans position was synthesized and characterized by X-ray structural analysis coulometry data, FTIR, electrochemistry and electronic structure calculations. The complex undergoes a facilitated two-electron reduction 1/12- and shows an inverted one-electron reduction for 1/1- at higher potentials. Electrochemical investigations of 1 are compared to the closely related [Fe(bdt)(CO)2(PMe3)2] compound. A mechanistic suggestion for the hydrogen evolution reaction upon proton reduction from acid media is derived. The stability of 1 in both weak and strong acids is monitored by cyclic voltammetry.

Influence of ripeness and maceration of the grapes on levels of furan and carbonyl compounds in wine - Simultaneous quantitative determination and assessment of the exposure risk to these compounds.

The validated method based on the use of headspace solid phase microextraction (HS-SPME) coupled with the comprehensive two-dimensional gas chromatography with time-of-flight mass spectrometric detection (GC×GC/TOFMS) proved to be appropriate for this first simultaneous quantitative determination of six toxic compounds (formaldehyde, acetaldehyde, ethyl carbamate, furan, furfural and acrolein) found in wines. Acetaldehyde and acrolein coeluted with other wine compounds, which indicated that difficulties could arise if only one-dimensional gas chromatography was used for the determination of these compounds. The advancement of the ripeness degree and increasing the grape maceration time seems to result in higher concentrations of toxic compounds. The exposure to furan, acrolein and ethyl carbamate through wine consumption may pose risks to consumer health, since calculated MOE values were lower than 10,000.

Effects of carbonyl iron powder on iron deficiency anemia and its subchronic toxicity.

Carbonyl iron powder (CIP) has been used as a food additive or mineral supplement. However, the effects of CIP on iron deficiency anemia (IDA) and its subchronic toxicity have not been investigated. We found that oral administration of CIP at a dose of 2.96 mg/kg recovered the hemoglobin concentration of erythrocytes of IDA rats to the normal level after 8 days. The no observed adverse effect level of CIP in rats was considered to be > 200 mg/kg. The hematological and serum biochemical parameters of the rats did not differ significantly between the control and treated groups. There were no morphological changes observed in the organs including liver, kidneys, spleen, testes, stomach and intestine. Therefore, CIP might be a safe iron supplement.

Breath carbonyl compounds as biomarkers of lung cancer.

OBJECTIVE: Lung cancer dysregulations impart oxidative stress which results in important metabolic products in the form of volatile organic compounds (VOCs) in exhaled breath. The objective of this work is to use statistical classification models to determine specific carbonyl VOCs in exhaled breath as biomarkers for detection of lung cancer. MATERIALS AND METHODS: Exhaled breath samples from 85 patients with untreated lung cancer, 34 patients with benign pulmonary nodules and 85 healthy controls were collected. Carbonyl compounds in exhaled breath were captured by silicon microreactors and analyzed by Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS). The concentrations of carbonyl compounds were analyzed using a variety of statistical classification models to determine which compounds best differentiated between the patient sub-populations. Predictive accuracy of each of the models was assessed on a separate test data set. RESULTS: Six carbonyl compounds (C(4)H(8)O, C(5)H(10)O, C(2)H(4)O(2), C(4)H(8)O(2), C(6)H(10)O(2), C(9)H(16)O(2)) had significantly elevated concentrations in lung cancer patients vs. CONTROLS: A model based on counting the number of elevated compounds out of these six achieved an overall classification accuracy on the test data of 97% (95% CI 92%-100%), 95% (95% CI 88%-100%), and 89% (95% CI 79%-99%) for classifying lung cancer patients vs. non-smokers, current smokers, and patients with benign nodules, respectively. These results were comparable to benchmarking based on established statistical and machine-learning methods. The sensitivity in each case was 96% or higher, with specificity ranging from 64% for benign nodule patients to 86% for smokers and 100% for non-smokers. CONCLUSION: A model based on elevated levels of the six carbonyl VOCs effectively discriminates lung cancer patients from healthy controls as well as patients with benign pulmonary nodules.

Quercetin prevents ethanol-induced iron overload by regulating hepcidin through the BMP6/SMAD4 signaling pathway.

Emerging evidence has demonstrated that chronic ethanol exposure induces iron overload, enhancing ethanol-mediated liver damage. The purpose of this study was to explore the effects of the naturally occurring compound quercetin on ethanol-induced iron overload and liver damage, focusing on the signaling pathway of the iron regulatory hormone hepcidin. Adult male C57BL/6J mice were pair-fed with isocaloric-Lieber De Carli diets containing ethanol (accounting for 30% of total calories) and/or carbonyl iron (0.2%) and treated with quecertin (100 mg/kg body weight) for 15 weeks. Mouse primary hepatocytes were incubated with ethanol (100 mM) and quercetin (100 µM) for 24 h. Mice exposed to either ethanol or iron presented significant fatty infiltration and iron deposition in the liver; these symptoms were exacerbated in mice cotreated with ethanol and iron. Quercetin attenuated the abnormity induced by ethanol and/or iron. Ethanol suppressed BMP6 and intranuclear SMAD4 as well as decreased hepcidin expression. These effects were partially alleviated by quercetin supplementation in mice and hepatocytes. Importantly, ethanol caused suppression of SMAD4 binding to the HAMP promoter and of hepcidin messenger RNA expression. These effects were exacerbated by anti-BMP6 antibody and partially alleviated by quercetin or human recombinant BMP6 in cultured hepatocytes. In contrast, co-treatment with iron and ethanol, especially exposure of iron alone, activated BMP6/SMAD4 pathway and up-regulated hepcidin expression, which was also normalized by quercetin in vivo. Quercetin prevented ethanol-induced hepatic iron overload different from what carbonyl iron diet elicited in the mechanism, by regulating hepcidin expression via the BMP6/SMAD4 signaling pathway.

The HydG enzyme generates an Fe(CO)2(CN) synthon in assembly of the FeFe hydrogenase H-cluster.

Three iron-sulfur proteins--HydE, HydF, and HydG--play a key role in the synthesis of the [2Fe](H) component of the catalytic H-cluster of FeFe hydrogenase. The radical S-adenosyl-L-methionine enzyme HydG lyses free tyrosine to produce p-cresol and the CO and CN(-) ligands of the [2Fe](H) cluster. Here, we applied stopped-flow Fourier transform infrared and electron-nuclear double resonance spectroscopies to probe the formation of HydG-bound Fe-containing species bearing CO and CN(-) ligands with spectroscopic signatures that evolve on the 1- to 1000-second time scale. Through study of the (13)C, (15)N, and (57)Fe isotopologs of these intermediates and products, we identify the final HydG-bound species as an organometallic Fe(CO)2(CN) synthon that is ultimately transferred to apohydrogenase to form the [2Fe](H) component of the H-cluster.

Photoactive metal carbonyl complexes as potential agents for targeted CO delivery.

The surprising discovery of carbon monoxide (CO) as a signaling molecule in mammalian physiology has recently raised interest in this toxic gas among researchers in biochemical and pharmaceutical community. CO is endogenously produced mainly from catabolism of heme by the enzyme heme oxygenase (HO) and participates in a myriad of anti-inflammatory, anti-proliferative, and vasoregulatory pathways. In animal models, low doses of CO have exhibited beneficial effects in suppression of organ graft rejection and safeguarding the heart during reperfusion after cardiopulmonary bypass surgery. The salutary effects of CO have naturally drawn attention of the pharmaceutical industry for its use as a cytoprotective agent. Safety-related concerns of the use of this noxious gas have prompted research in the area of syntheses of CO-releasing molecules (CORMs) and to date, several metal carbonyls (metal complexes of CO) have been employed as CORMs in promoting prolonged (and safe) delivery of low doses of CO to cellular targets. Because many carbonyl complexes release CO upon illumination, investigators have recently began to explore the possibility of "controlled CO delivery" through the use of light. During the past few years, a number of photoactive CORMs or "photoCORMs" have been synthesized that release CO upon illumination with UV or visible light. The utility of these photoCORMs in CO delivery has also been confirmed. Novel design principles for isolation of photoCORMs have started to appear in recent reports. Scrutiny of the literature reveals the emergence of a new exciting area of drug development in such efforts. The potential of photoCORMs as CO-donating pharmaceuticals along with a brief overview of the physiological roles of CO is presented in this review.

Stability and viscoelasticity of magneto-Pickering foams.

We have developed a new class of bistable Pickering foams, which can remain intact for weeks at room temperature but can be destroyed rapidly and on-demand with the use of a magnetic field. Such responsive foam systems can find application in various industrial and environmental processes that require controlled defoaming. These foams are stabilized by particles of hypromellose phthalate (HP-55) and contain oleic acid-coated carbonyl iron particles embedded in the HP-55 matrix. The complex behavior of these foams arises from several factors: a robust anisotropic particle matrix, the capacity to retain a high amount of water, as well as an age-dependent response to an external field. We report how the structure and viscoelastic properties of the foams change with time and affect their collapse characteristics. The evolution of foam properties is quantified by measuring the rate of liquid drainage from the foam as well as the rate of bubble growth in the foam with respect to time elapsed (in the absence of a magnetic field). We also evaluate the time necessary for foam collapse in magnetic fields as a function of magnetic particle content. A decreasing liquid volume fraction in the foam during aging leads to an increase in the elasticity and rigidity of the foam structure. These data allow us to identify a transition time separating two distinct stages of foam development in the absence of field. We propose different mechanisms which control foam collapse for each stage in a magnetic field. The stiffening of foam films between air bubbles with age plays a key role in distinguishing between the two destabilization regimes.

Reversible intramolecular coupling of the terminal borylene and a carbonyl ligand of [Cp(CO)2Mn=B-tBu].

Cyclic complex 2 with bridging carbonyl ligands was synthesized from a facile and reversible intermolecular carbonyl-borylene ligand coupling reaction at room temperature. Complex 2 exhibits an unprecedented coordination mode for boron-metal complexes, which is also reflected in its remarkable (11)B NMR chemical shift of -57.2 ppm. Findings from spectroscopic, X-ray, and computational studies are presented, along with a proposed mechanism.

Synthesis of ethers from esters via Fe-catalyzed hydrosilylation.

Triiron dodecacarbonyl allows for the selective reduction of esters into the corresponding ethers. This protocol has a wide substrate scope. In addition, cholesteryl pelarogonate has been reduced under the reaction conditions with an excellent yield.