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Parthanatos is a PARP1-dependent, caspase-independent, cell-death pathway that is distinct from apoptosis, necrosis, or other known forms of cell death. Parthanatos is a multistep pathway that plays a pivotal role in tumorigenesis. There are many molecules in the parthanatos cascade that can be exploited to create therapeutic interventions for cancer management, including PARP1, PARG, ARH3, AIF, and MIF. These critical molecules are involved in tumor cell proliferation, progression, invasion, and metastasis. Therefore, these molecular signals in the parthanatos cascade represent promising therapeutic targets for cancer therapy. In addition, intimate interactions occur between parthanatos and other forms of cancer cell death, such as apoptosis and autophagy. Thus, co-targeting a combination of parthanatos and other death pathways may further provide a new avenue for cancer precision treatment. In this review, we elaborate on the signaling pathways of canonical parthanatos and briefly introduce the non-canonical parthanatos. We also shed light on the role parthanatos and its associated components play in tumorigenesis, particularly with respect to the aforementioned five molecules, and discuss the promise targeted therapy of parthanatos and its associated components holds for cancer therapy. Show less

Numerous colon cancer cases are resistant to chemotherapy based on oxaliplatin and suffer from relapse. A number of survival- and prognosis-related biomarkers have been identified based on database mining for patients who develop drug resistance, but the single individual gene biomarker can not attain high specificity and sensitiv-ity in prognosis predictionh. This work was conducted aiming to establish a new gene signature using oxaliplatin resistance-related genes to predict the prognosis for colon cancer. To this end, we downloaded gene expression profile data of cell lines resistant and not resistant to oxaliplatin from the Gene Expression Omnibus (GEO) database. Altogether 495 oxaliplatin resistance-related genes were searched by weighted gene co-expression network analysis (WGCNA) and differential expression analysis. As suggested by functional analysis, the above genes were mostly enriched into cell adhesion and immune processes. Besides, a signature was built based on 4 oxaliplatin resistance-related genes selected from training set to predict the overall survival (OS) by stepwise regression and least absolute shrinkage and selection op-erator (LASSO) Cox analysis. Relative to low risk score group, the high risk score group had dismal OS (P 0.7). Additionally, multivariate Cox regression suggested that, the signature constructed based on 4 oxaliplatin re-sistance-related genes predicted the prognosis for colon cancer cases (HR, 2.77; 95% CI, 2.03–3.78; P<0.001). Finally, external test sets were utilized to further validate the stability and accuracy of oxaliplatin resistance-related gene signature for prog-nosis of colon cancer patients. To sum up, this study establishes a signature based on 4 oxaliplatin resistance-related genes for predicting the survival of colon cancer pa-tients, which sheds more lights on the mechanisms of oxaliplatin resistance and helps to identify colon cancer cases with dismal prognostic outcome. Show less

Cellular oxidative stress is considered an inducer of carcinogenesis but the association of reactive oxygen species (ROS) with cancer is sometimes contradictory. The antihypertensive drugs candesartan and valsartan were reported to behave as antioxidant agents. In the present study, we prepared their Zn(II) coordination complexes, [ZnCand(H2O)2]·2H2O (ZnCand) and [ZnVals(H2O)2] (ZnVals), and determined that they also depleted ROS by the induction of a reductive state in response to glutathione (GSH) generation and decreased lung cancer cell viability (IC50 = 175 and 220 µM, respectively), while being non-cytotoxic for normal lung fibroblasts (MRC5). The Zn complexes affected the mitochondria membrane, increased the pro- and anti-apoptotic protein ratio, Bax/Bcl-XL, and caspase-9 activation, by late apoptosis. Their co-incubation with N-acetylcysteine (NAC) exacerbated ROS reduction and increased cell death, whereas the H2O2 co-treatment restored the ROS values and normal cell growth. These data suggest that the excess reducing equivalents and low levels of ROS are also critical for the functioning of A549 cells. Show less

A rise in atmospheric carbon dioxide levels, following years of burning fossil fuels, has brought about increase in global temperatures and climate change due to the green-house effect. As such, recent efforts aimed at addressing this problem have been directed to the use of carbon dioxide as an inexpensive and non-toxic single carbon source for making chemical products. Herein, we report the use of tetrazolyl complexes as catalysts precursors for hydrogenation of carbon dioxide. Specifically, tetrazolyl compounds bearing phosphorus-sulfur bonds have been synthesized with the view of using these as phosphorus-nitrogen bidentate tetrazolyl ligands that can coordinate to iridium(III) thereby forming heteroatomic five-member complexes. Interestingly, reacting the phosphorus-nitrogen bidentate tetrazolyl ligands with iridium dimer led to serendipitous isolation of chiral-at-metal iridium(III) half-sandwich complexes instead. The complexes were obtained via prior formation non-chiral iridium half-sandwich complexes. The complexes undergo initial phosphorus-sulfur bond heterolysis of the precursor ligands, which then ultimately results in new half-sandwich iridium complexes featuring monodentate phosphine co-ligands with proton responsive functionalities. Conditions necessary to significantly affect the rate of phosphorus-sulfur bond heterolysis in the precursor ligand and the subsequent coordination to iridium have been reported. The complexes served as catalyst precursors and exhibited activity in carbon dioxide and bicarbonate hydrogenation in excellent catalytic activity, at low catalyst loadings, producing concentrated formate solutions exclusively. Catalyst precursors with proton responsive phosphines were found to influence catalytic activity when present as racemates, while ease of dissociation of the ligand from the iridium centre was observed to influence activity in spite of the presence of electron-donating ligands. A test for homogeneity indicated that hydrogenation of carbon dioxide proceeded by homogenous means. Subsequently, the mechanism of the reaction by the iridium catalyst precursors was studied using proton NMR techniques. This revealed that a chiral-at-metal iridium hydride species generated in situ, served as the active catalyst. Show less

Ten manganese(I) tricarbonyl diimine complexes bound to variably functionalised 5‐aryl‐tetrazolato ligands were prepared, and their photochemical properties were investigated. Upon exposure to light at 365 nm, each complex decomposed to its free diimine and tetrazolato ligands, simultaneously dissociating three CO ligands, as evidenced by changes in the IR spectra of the irradiated complexes over time. The anti‐bacterial properties of one of these complexes were tested against Escherichia coli. While the complex displayed no effect on the bacterial growth in the dark, pre‐irradiated solutions inhibited bacterial growth. Comparative studies revealed that the antibacterial properties originate from the presence of free 1,10‐phenanthroline. Show less

Ferroptosis is an iron-dependent form of necrotic cell death marked by oxidative damage to phospholipids1,2. To date, ferroptosis has been thought to be controlled only by the phospholipid hydroperoxide-reducing enzyme glutathione peroxidase 4 (GPX4)3,4 and radical-trapping antioxidants5,6. However, elucidation of the factors that underlie the sensitivity of a given cell type to ferroptosis7 is crucial to understand the pathophysiological role of ferroptosis and how it may be exploited for the treatment of cancer. Although metabolic constraints8 and phospholipid composition9,10 contribute to ferroptosis sensitivity, no cell-autonomous mechanisms have been identified that account for the resistance of cells to ferroptosis. Here we used an expression cloning approach to identify genes in human cancer cells that are able to complement the loss of GPX4. We found that the flavoprotein apoptosis-inducing factor mitochondria-associated 2 (AIFM2) is a previously unrecognized anti-ferroptotic gene. AIFM2, which we renamed ferroptosis suppressor protein 1 (FSP1) and which was initially described as a pro-apoptotic gene11, confers protection against ferroptosis elicited by GPX4 deletion. We further demonstrate that the suppression of ferroptosis by FSP1 is mediated by ubiquinone (also known as coenzyme Q10, CoQ10): the reduced form, ubiquinol, traps lipid peroxyl radicals that mediate lipid peroxidation, whereas FSP1 catalyses the regeneration of CoQ10 using NAD(P)H. Pharmacological targeting of FSP1 strongly synergizes with GPX4 inhibitors to trigger ferroptosis in a number of cancer entities. In conclusion, the FSP1-CoQ10-NAD(P)H pathway exists as a stand-alone parallel system, which co-operates with GPX4 and glutathione to suppress phospholipid peroxidation and ferroptosis. Show less

AbstractThe covalent nature of the low‐barrier N−H−N hydrogen bonds in the negative thermal expansion material H3[Co(CN)6] has been established by using a combination of X‐ray and neutron diffraction electron density analysis and theoretical calculations. This finding explains why negative thermal expansion can occur in a material not commonly considered to be built from rigid linkers. The pertinent hydrogen atom is located symmetrically between two nitrogen atoms in a double‐well potential with hydrogen above the barrier for proton transfer, thus forming a low‐barrier hydrogen bond. Hydrogen is covalently bonded to the two nitrogen atoms, which is the first experimentally confirmed covalent hydrogen bond in a network structure. Source function calculations established that the present N−H−N hydrogen bond follows the trends observed for negatively charge‐assisted hydrogen bonds and low‐barrier hydrogen bonds previously established for O−H−O hydrogen bonds. The bonding between the cobalt and cyanide ligands was found to be a typical donor–acceptor bond involving a high‐field ligand and a transition metal in a low‐spin configuration. Show less

Korenaga and coworkers presented evidence to suggest that the Earth's mantle was dry and water filled the ocean to twice its present volume 4.3 billion years ago. Carbon dioxide was constantly exhaled during the mafic to ultramafic volcanic activity associated with magmatic plumes that produced the thick, dense, and relatively stable oceanic crust. In that setting, two distinct and major types of sub-marine hydrothermal vents were active: ~400 °C acidic springs, whose effluents bore vast quantities of iron into the ocean, and ~120 °C, highly alkaline, and reduced vents exhaling from the cooler, serpentinizing crust some distance from the heads of the plumes. When encountering the alkaline effluents, the iron from the plume head vents precipitated out, forming mounds likely surrounded by voluminous exhalative deposits similar to the banded iron formations known from the Archean. These mounds and the surrounding sediments, comprised micro or nano-crysts of the variable valence FeII/FeIII oxyhydroxide known as green rust. The precipitation of green rust, along with subsidiary iron sulfides and minor concentrations of nickel, cobalt, and molybdenum in the environment at the alkaline springs, may have established both the key bio-syntonic disequilibria and the means to properly make use of them-the elements needed to effect the essential inanimate-to-animate transitions that launched life. Specifically, in the submarine alkaline vent model for the emergence of life, it is first suggested that the redox-flexible green rust micro- and nano-crysts spontaneously precipitated to form barriers to the complete mixing of carbonic ocean and alkaline hydrothermal fluids. These barriers created and maintained steep ionic disequilibria. Second, the hydrous interlayers of green rust acted as engines that were powered by those ionic disequilibria and drove essential endergonic reactions. There, aided by sulfides and trace elements acting as catalytic promoters and electron transfer agents, nitrate could be reduced to ammonia and carbon dioxide to formate, while methane may have been oxidized to methyl and formyl groups. Acetate and higher carboxylic acids could then have been produced from these C1 molecules and aminated to amino acids, and thence oligomerized to offer peptide nests to phosphate and iron sulfides, and secreted to form primitive amyloid-bounded structures, leading conceivably to protocells. Show less

INTRODUCTION: The mode of action of dimethyl fumarate (DMF), an immunomodulatory treatment for relapsing-remitting multiple sclerosis (RRMS), has not yet been fully elucidated. While in-vitro experiments and animal studies suggest effects on immune cell survival, proliferation, migration and oxidative stress response, corresponding observations from human studies are lacking. This study aims to characterize ex-vivo and in-vivo effects in a cohort of DMF treated RRMS patients. METHODS: Blood samples were collected from twenty well-characterized RRMS patients at baseline and after 3, 6 and 12 months of DMF treatment and an age- and gender-matched cohort of 20 healthy individuals at 0 and 3 months. Leukocyte subpopulations, immunoglobulin levels and cytokine secretion were measured. T cells were assessed for their levels of reactive oxygen species (ROS), metabolic status and their proliferative capacity. Levels of antioxidants were determined in serum by mass spectrometry. Responses of monocyte activation markers as well as NFkB and MAPK pathways to DMF were analysed. RESULTS: Upon DMF treatment, all lymphocyte subpopulations dropped significantly over the course of 12 months with cytotoxic and effector T cells being affected most significantly. DMF induced cell death and inhibited proliferation of T cells in-vitro. Interestingly, this anti-proliferative effect decreased under treatment. In-vivo DMF treatment led to decreased T cell glycolysis and higher turn-over of antioxidants. In line with these results a significant increase of cytosolic ROS levels after 3 months treatment was detected in T cells. In-vitro DMF treatment reduced NFkB (p65) translocation to the nucleus and MAPK (p38) levels decreased upon stimulation with monomethyl fumarate (MMF) in-vitro and ex-vivo. Consequently, the expression of co-stimulatory molecules like CD40 and CD150 was decreased in antigen presenting cells both in-vitro and ex-vivo. CONCLUSION: This study translates knowledge from in-vitro and animal studies on DMF into the clinical setting. Our data suggest that DMF not only alters lymphocyte composition, but also has profound effects on proliferation and induces oxidative stress in T cells. It also acts on innate immunity by reducing the activation status of antigen presenting cells (APCs) via NFkB and MAPK inactivation. Show less

Although cisplatin and its analogues have been widely utilized as anticancer metallodrugs in clinics, their serious side effects and damage to normal tissues cannot be avoided because cisplatin kills cancer cells by attacking genomic DNA. Thus the design of metallodrugs possessing different actions of anti-cancer mechanism is promising. G-quadruplex nucleic acid, which is formed by self-assembly of guanine-rich nucleic acid sequences, has recently been considered as an attractive target for anticancer drug design. The basic unit of a G-quadruplex is a G-quartet, a planar motif generated from four guanine residues pairing together through Hoogsteen like hydrogen bonds. DNA G-quadruplex (G4) structures exist in the chromosomal telomeric sequences and the promoter regions of numerous genes, including oncogenetic promoters. Formation of G4 structures within the 3′-overhang of telomeric DNA can inhibit the telomerase activity, which is silent in normal cells but up-regulated in most cancer cells, thus significantly shortening telomeres and preventing cancer cell proliferation and immortalization. Intramolecular G4 structures formed within the oncogene promoter regions can effectively inhibit oncogenen transcription and expression. Thus rational design of small molecular ligands to selectively interact, stabilize or cleave G4 structures is a promising strategy for developing potent anti-cancer drugs with selective toxicity towards cancer cells over normal ones. This review will highlight the recent development of G4-interacting metal complexes, termed G4-ligands, discussing their binding modes with G-quadruplex DNA and their potential to serve as anticancer drugs in the medical field. Introduction to the international collaboration The collaboration between Prof. Zong-Wan Mao from Sun Yat-Sen University, P. R. China and Prof. Roland K. O. Sigel from the University of Zurich, Switzerland officially began in January, 2014. The international collaborative research project titled “Chemical Biology Research of New Metallodrugs for Cancer Therapy” is supported by the Science and Technology Program of Guangdong Provincial Government [20130501c]. With the rapid development of tumor molecular pharmacology, molecular targeted anti-tumor drugs have become a hot spot in the research of cancer therapy. This international collaborative research project combines the computer simulation and in vitro drug screening platform to design a series of metallodrugs that are systematic and have structural diversity, which can target specific nucleic acid structures (e.g. G-quadruplexes), key proteins (DNA topoisomerase, telomerase, CDK kinase) associated with the occurrence and development of tumor. With the advantages of both laboratories, the structural–functional relationship, interaction modes, co-crystallization, and mechanisms of action of these newly designed metallodrugs are intensively studied, and their in vitro and in vivo anti-tumor activities are comprehensively evaluated. Show less

UNLABELLED: Artesunate, an anti-malarial drug, has been repurposed as an anticancer drug due to its induction of cell death via reactive oxygen species (ROS) production. However, the molecular mechanisms regulating cancer cell death and the resistance of cells to artesunate remain unclear. We investigated the molecular mechanisms behind the antitumor effects of artesunate and an approach to overcome artesunate resistance in head and neck cancer (HNC). The effects of artesunate and trigonelline were tested in different HNC cell lines, including three cisplatin-resistant HNC cell lines. The effects of these drugs as well as the inhibition of Keap1, Nrf2, and HO-1 were assessed by cell viability, cell death, glutathione (GSH) and ROS production, protein expression, and mouse tumor xenograft models. Artesunate selectively killed HNC cells but not normal cells. The artesunate sensitivity was relatively low in cisplatin-resistant HNC cells. Artesunate induced ferroptosis in HNC cells by decreasing cellular GSH levels and increasing lipid ROS levels. This effect was blocked by co-incubation with ferrostatin-1 and a trolox pretreatment. Artesunate activated the Nrf2-antioxidant response element (ARE) pathway in HNC cells, which contributed to ferroptosis resistance. The silencing of Keap1, a negative regulator of Nrf2, decreased artesunate sensitivity in HNC cells. Nrf2 genetic silencing or trigonelline reversed the ferroptosis resistance of Keap1-silenced and cisplatin-resistant HNC cells to artesunate in vitro and in vivo. Nrf2-ARE pathway activation contributes to the artesunate resistance of HNC cells, and inhibition of this pathway abolishes ferroptosis-resistant HNC. CONDENSED ABSTRACT: Our results show the effectiveness and molecular mechanism of artesunate treatment on head and neck cancer (HNC). Artesunate selectively killed HNC cells but not normal cells by inducing an iron-dependent, ROS-accumulated ferroptosis. However, this effect may be suboptimal in some cisplatin-resistant HNCs because of Nrf2-antioxidant response element (ARE) pathway activation. Inhibition of the Nrf2-ARE pathway increased artesunate sensitivity and reversed the ferroptosis resistance in resistant HNC cells. Show less

Iron-sulphur proteins are ancient and drive fundamental processes in cells, notably electron transfer and CO2 fixation. Iron-sulphur minerals with equivalent structures could have played a key role in the origin of life. However, the 'iron-sulphur world' hypothesis has had a mixed reception, with questions raised especially about the feasibility of a pyrites-pulled reverse Krebs cycle. Phylogenetics suggests that the earliest cells drove carbon and energy metabolism via the acetyl CoA pathway, which is also replete in Fe(Ni)S proteins. Deep differences between bacteria and archaea in this pathway obscure the ancestral state. These differences make sense if early cells depended on natural proton gradients in alkaline hydrothermal vents. If so, the acetyl CoA pathway diverged with the origins of active ion pumping, and ancestral CO2 fixation might have been equivalent to methanogens, which depend on a membrane-bound NiFe hydrogenase, energy converting hydrogenase. This uses the proton-motive force to reduce ferredoxin, thence CO2 . The mechanism suggests that pH could modulate reduction potential at the active site of the enzyme, facilitating the difficult reduction of CO2 by H2 . This mechanism could be generalised under abiotic conditions so that steep pH differences across semi-conducting Fe(Ni)S barriers drives not just the first steps of CO2 fixation to C1 and C2 organics such as CO, CH3 SH and CH3 COSH, but a series of similar carbonylation and hydrogenation reactions to form longer chain carboxylic acids such as pyruvate, oxaloacetate and α-ketoglutarate, as in the incomplete reverse Krebs cycle found in methanogens. We suggest that the closure of a complete reverse Krebs cycle, by regenerating acetyl CoA directly, displaced the acetyl CoA pathway from many modern groups. A later reliance on acetyl CoA and ATP eliminated the need for the proton-motive force to drive most steps of the reverse Krebs cycle. © 2017 IUBMB Life, 69(6):373-381, 2017. Show less

Iron-sulfur (Fe-S) clusters are fundamental to numerous biological processes in most organisms, but these protein cofactors can be prone to damage by various oxidants (e.g., O2, reactive oxygen species, and reactive nitrogen species) and toxic levels of certain metals (e.g., cobalt and copper). Furthermore, their synthesis can also be directly influenced by the level of available iron in the environment. Consequently, the cellular need for Fe-S cluster biogenesis varies with fluctuating growth conditions. To accommodate changes in Fe-S demand, microorganisms employ diverse regulatory strategies to tailor Fe-S cluster biogenesis according to their surroundings. Here, we review the mechanisms that regulate Fe-S cluster formation in bacteria, primarily focusing on control of the Isc and Suf Fe-S cluster biogenesis systems in the model bacterium Escherichia coli. Show less

Two new mononuclear water soluble copper(II) complexes, [Cu{(5-pyrazinyl)tetrazolate}2(1,10-phenanthroline)] 1 and [Cu{(5-pyrazinyl)tetrazolate}(1,10-phenanthroline)2](NO3)0.5(N3)0.52, have been synthesized using the metal mediated [2 + 3] cycloaddition reaction between copper bound azide and pyrazinecarbonitrile. The interactions of these copper tetrazolate complexes 1 and 2 with biomolecules like DNA and bovine serum albumin (BSA) are studied and the catecholase like catalytic activity of compound 2 is also explored. Structural determination reveals that both compounds 1 and 2 are octahedral in nature. Screening tests were conducted to quantify the binding ability of complexes (1 and 2) towards DNA and it was revealed that complex 2 has a stronger affinity to bind to CT-DNA. DFT studies indicated that a lower HOMO–LUMO energy gap between the DNA fragment and metal complexes might be the reason for this type of stronger interaction. DNA cleavage activity was explored by gel-electrophoresis and moderate to strong DNA cleavage properties were observed in the presence and absence of co-reagents. Inhibition of cleavage in the presence of sodium azide indicates the propagation of the activity through the production of singlet molecular oxygen. Furthermore enzyme kinetic studies reflect that complex 2 is also effective in mimicking catecholase like activities. An ESI-MS spectral study indicates the probable involvement of dimeric species [(phen)2Cu-(OH)2-Cu(phen)2]2+ in the catalytic cycle. Show less

Many metalloenzymes that inject and extract reducing equivalents at the beginning and the end of electron transport chains involved in chemiosmosis are suggested, through phylogenetic analysis, to have been present in the Last Universal Common Ancestor (LUCA). Their active centres are affine with the structures of minerals presumed to contribute to precipitate membranes produced on the mixing of hydrothermal solutions with the Hadean Ocean ~4 billion years ago. These mineral precipitates consist of transition element sulphides and oxides such as nickelian mackinawite ([Fe>Ni]2S2), a nickel-bearing greigite (~FeSS[Fe3NiS4]SSFe), violarite (~NiSS[Fe2Ni2S4]SSNi), a molybdenum bearing complex (~Mo(IV/VI)2Fe3S(0/2-)9) and green rust or fougerite (~[Fe(II)Fe(III)(OH)4](+)[OH](-)). They may be respectively compared with the active centres of Ni-Fe hydrogenase, carbon monoxide dehydrogenase (CODH), acetyl coenzyme-A synthase (ACS), the complex iron-sulphur molybdoenzyme (CISM) superfamily and methane monooxygenase (MMO). With the look of good catalysts - a suggestion that gathers some support from prebiotic hydrothermal experimentation - and sequestered by short peptides, they could be thought of as the original building blocks of proto-enzyme active centres. This convergence of the makeup of the LUCA-metalloenzymes with mineral structure and composition of hydrothermal precipitates adds credence to the alkaline hydrothermal (chemiosmotic) theory for the emergence of life, specifically to the possibility that the first metabolic pathway - the acetyl CoA pathway - was initially driven from either end, reductively from CO2 to CO and oxidatively and reductively from CH4 through to a methane thiol group, the two entities assembled with the help of a further thiol on a violarite cluster sequestered by peptides. By contrast, the organic coenzymes were entirely a product of the first metabolic pathways. This article is part of a Special Issue entitled: Metals in Bioenergetics and Biomimetics Systems. Show less

BACKGROUND: Macrophages of the reticuloendothelial system play a key role in recycling iron from hemoglobin of senescent or damaged erythrocytes. Heme oxygenase 1 degrades the heme moiety and releases inorganic iron that is stored in ferritin or exported to the plasma via the iron export protein ferroportin. In the plasma, iron binds to transferrin and is made available for de novo red cell synthesis. The aim of this study was to gain insight into the regulatory mechanisms that control the transcriptional response of iron export protein ferroportin to hemoglobin in macrophages. DESIGN AND METHODS: Iron export protein ferroportin mRNA expression was analyzed in RAW264.7 mouse macrophages in response to hemoglobin, heme, ferric ammonium citrate or protoporphyrin treatment or to siRNA mediated knockdown or overexpression of Btb And Cnc Homology 1 or nuclear accumulation of Nuclear Factor Erythroid 2-like. Iron export protein ferroportin promoter activity was analyzed using reporter constructs that contain specific truncations of the iron export protein ferroportin promoter or mutations in a newly identified MARE/ARE element. RESULTS: We show that iron export protein ferroportin is transcriptionally co-regulated with heme oxygenase 1 by heme, a degradation product of hemoglobin. The protoporphyrin ring of heme is sufficient to increase iron export protein ferroportin transcriptional activity while the iron released from the heme moiety controls iron export protein ferroportin translation involving the IRE in the 5'untranslated region. Transcription of iron export protein ferroportin is inhibited by Btb and Cnc Homology 1 and activated by Nuclear Factor Erythroid 2-like involving a MARE/ARE element located at position -7007/-7016 of the iron export protein ferroportin promoter. CONCLUSIONS: This finding suggests that heme controls a macrophage iron recycling regulon involving Btb and Cnc Homology 1 and Nuclear Factor Erythroid 2-like to assure the coordinated degradation of heme by heme oxygenase 1, iron storage and detoxification by ferritin, and iron export by iron export protein ferroportin. Show less

Lithiation of 1-benzyl-1H-tetrazole followed by transmetallation with [AuCl(PPh3)], [Au(C6F5)(tht)] or [AuCl(tht)] (tht = tetrahydrothiophene) and subsequent alkylation afforded cationic 1-benzyl-4-methyl-4,5-dihydro-1H-1,2,3,4-tetrazol-5-ylidene(triphenylphosphine)gold(I), 1, neutral 1-benzyl-4-methyl-4,5-dihydro-1H-1,2,3,4-tetrazol-5-ylidene(pentafluorophenyl)gold(I), 2, and a cationic biscarbene complex, bis(1-benzyl-4-methyl-4,5-dihydro-1H-1,2,3,4-tetrazol-5-ylidene)gold(I), 3. The first complex underwent a homoleptic rearrangement in solution to form 3. Reaction of [Au(N3)PPh3] with the three isocyanides (CH3)2C6H3NC, tBuNC and CyNC, respectively, yielded the corresponding neutral tetrazolyl(phosphine) complexes of gold, [1-(2,6-dimethylphenyl)-1H-tetrazol-5-yl](triphenylphosphine)gold(I), 4, [1-(tert-butyl)-1H-tetrazol-5-yl](triphenylphosphine)gold(I), 6, and [1-(cyclohexyl)-1H-tetrazol-5-yl](triphenylphosphine)gold(I), 7. Alkylation of 4 with methyl triflate on N4 allowed isolation of the crystalline carbene complex 1-(2,6-dimethylphenyl)-4-methyl-4,5-dihydro-1H-1,2,3,4-tetrazol-5-ylidene)(triphenylphosphine)gold(I), 5. Complex 7 was not isolable in pure form but converts by isocyanide substitution of triphenylphosphine into [1-cyclohexylisocyanide][1-(cyclohexyl)-1H-tetrazol-5-yl]gold(I), 8. From a product mixture of 7 and 8 the transformed molecules [(cyclohexylamino)(ethoxy)carbene](1-cyclohexyl-1H-tetrazol-5-yl)gold(I), 9, and [bis(cyclohexylamino)carbene](1-cyclohexyltetrazol-5-yl)gold(I), 10, co-crystallised spontaneously after a long time at −20 °C. Show less

In the present review we summarize different strategies to induce DNA compaction and decompaction. DNA compaction is achieved using different cationic co-solutes, such as trivalent ions, surfactant, and polycations. In addition, single-chained DNA compaction can also be achieved in solvents with low dielectric constants and by confinement. The decompaction strategies depend, naturally, on the method used for the compaction and can be accomplished by, for example, heparins, cyclodextrins, non-ionic or anionic surfactants. Show less

AbstractA brief overview is given of platinum anticancer drugs in routine clinical use and under clinical development worldwide. Details of the binding of these drugs with nucleic acids, the preferred binding site, etc. are discussed as well. Using the mechanistic knowledge at the molecular level, in particular DNA binding, possibilities for new drugs are explored. A major part of the review deals with design, synthesis and biochemical/biophysical studies of such new compounds and their possible applications as cytostatic drugs. Special attention is given to the application of bifunctionality in such new compounds. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) Show less

The interaction of hexamminecobalt(III), Co(NH(3))(6)(3+), with 160 and 3000-8000 bp length calf thymus DNA has been investigated by circular dichroism, acoustic and densimetric techniques. The acoustic titration curves of 160 bp DNA revealed three stages of interaction: (i) Co(NH(3))(6)(3+) binding up to the molar ratio [Co(NH(3))(6)(3+)]/[P] = 0.25, prior to DNA condensation; (ii) a condensation process between [Co(NH(3))(6)(3+)]/[P] = 0.25 and 0.30; and (iii) precipitation after [Co(NH(3))(6)(3+)]/[P] = 0.3. In the case of 3000-8000 bp DNA only two processes were observed: (i) binding up to [Co(NH(3))(6)(3+)]/[P] = 0.3; and (ii) precipitation after this point. In agreement with earlier observations, long DNA aggregates without changes in its B-form circular dichroism spectrum, while short DNA demonstrates a positive B-->Psi transition after [Co(NH(3))(6)(3+)]/[P] = 0.25. From ultrasonic and densimetric measurements the effects of Co(NH(3))(6)(3+) binding on volume and compressibility have been obtained. The binding of Co(NH(3))(6)(3+) to both short and long DNA is characterized by similar changes in volume and compressibility calculated per mole Co(NH(3))(6)(3+): DeltaV = 9 cm(3) mol(-1) and Deltakappa = 33 x 10(-4) cm(3) mol(-1) bar(-1). The positive sign of the parameters indicates dehydration, i.e. water release from Co(NH(3))(6)(3+) and the atomic groups of DNA. This extent of water displacement would be consistent with the formation of two direct, hydrogen bonded contacts between the cation and the phosphates of DNA. Show less

We showed recently that the high-salt transition of poly[d(G-C)]. poly[d(G-C)] between B-DNA and Z-DNA (at [NaCl] = 2.25 M or [MgCl(2)] = 0.7 M) can be ascribed to the lesser electrostatic free energy of the B form, due to better immersion of the phosphates in the solution. This property was incorporated in cylindrical DNA models that were analyzed by Poisson-Boltzmann theory. The results are insensitive to details of the models, and in fair agreement with experiment. In contrast, the Z form of the poly[d(G-m5C)] duplex is stabilized by very small concentrations of magnesium. We now show that this striking difference is accommodated quantitatively by the same electrostatic theory, without any adjustable parameter. The different responses to magnesium of the methylated and nonmethylated polymers do not come from stereospecific cation-DNA interactions: they stem from an experimentally derived, modest difference in the nonelectrostatic component of the free energy difference (or NFED) between the Z and B forms. The NFED is derived from circular DNA measurements. The differences between alkaline earth and transition metal ions are explained by weak coordination of the latter. The theory also explains the induction of the transition by micromolar concentrations of cobalt hexammine, again without specific binding or adjustable parameters. Hence, in the case of the B-Z transition as in others (e.g., the folding of tRNA and of ribozymes), the effect of multivalent cations on nucleic acid structure is mediated primarily by nonspecific ion-polyelectrolyte interactions. We propose this as a general rule for which convincing counter-examples are lacking. Show less

Blocks of potential Z-DNA-forming (dA-dC)n.(dG-dT)n sequences are ubiquitous in eukaryotic genomes. We examined whether naturally occurring polyamines, putrescine, spermidine and spermine, could provoke the Z-DNA conformation in plasmids pDHf2 and pDHf14 with 23 and 60 bp inserts respectively of (dA-dC)n.(dG-dT)n sequences using an e.l.i.s.a. Spermidine and spermine could provoke Z-DNA conformation in these plasmids, but putrescine was ineffective. For pDHf2 and pDHf14, the concentration of spermidine at the midpoint of B-DNA to Z-DNA transition was 25 microM, whereas that of spermine was 16 microM. Polyamine structural specificity was evident in the ability of spermidine homologues to induce Z-DNA. Inorganic cations, Co(NH3)6(3+) and Ru(NH3)6(3+), were ineffective. Our experiments also showed increased binding of anti-DNA autoantibodies from lupus patients as well as autoimmune MRL-lpr/lpr mice to pDHf2 and pDHf14 in the presence of polyamines. These data demonstrate that small blocks of (dA-dC)n.(dG-dT)n sequences could assume the Z-DNA conformation in the presence of natural polyamines. Increased concentrations of polyamines in the sera of lupus patients might facilitate immune complex-formation involving circulating DNA and anti-Z-DNA antibodies. Show less

The interaction of calf-thymus DNA with cobalt-hexammine and cobalt-pentammine cations was investigated, in aqueous solution at pH 6-7 with cation/DNA(phosphate) molar ratios r = 1/80, 1/40, 1/20, 1/10, 1/4, 1/2 and 1, using Fourier Transform infrared (FTIR) difference spectroscopy. Correlations between spectral changes, DNA condensation and helical stabilization due to the cation interaction as well as conformational features are established. At a very low cation concentration (r = 1/80), the binding of cobalt-hexammine cation with DNA is through the H-bond formation between cation NH3 groups and the PO2 groups of the backbone, resulting in duplex stability. As the cation concentration increases, hydrogen bonding expands towards guanine N-7 and O-6 atoms. At r > 1/20, DNA condensation occurs with major reduction in the intensity of several DNA in-plane vibrations and that of the phosphate group. The cobalt-pentammine cation binding is via the PO2 groups (directly) at very low metal cation concentration (r = 1/80) and the guanine N-7 and the O-6 groups (indirectly) at higher ratios. At r > 1/10, DNA condensation begins with some degree of direct cation-base binding. No major conformational changes from the B-family structure were observed before and after DNA collapse, in the presence of cobalt-ammine cations. Show less

Hexammine cobalt(III) chloride (Co(NH3)6(3+) provokes a B-DNA----Z-DNA----psi-DNA conformational transition in poly(dG-dC).poly(dG-dC) and poly(dG-m5dC).poly(dG-m5dC). The circular dichroism spectrum of psi-DNA is characterized by a manyfold increase of positive ellipticity in the range of 300-225 nm and the complete absence of a negative peak. In order to ascertain the helical handedness of psi-DNA, we used a recently developed enzyme immunoassay technique. This method consisted of treating the polynucleotides with Co(NH3)6(3+) to convert them to the Z- or psi-DNA forms and immobilizing these conformations on a microtiter plate. The plates were subsequently treated with a monoclonal anti-Z-DNA antibody Z22, alkaline phosphatase conjugated, affinity purified immunoglobulins, and the phosphatase substrate. The enzyme-substrate reaction was monitored by reading the absorbance at 405 nm with a microplate autoreader. The monoclonal anti-Z-DNA antibody had no reactivity to the B-DNA form, but bound strongly to both the Z- and psi-DNA forms, showing that Co(NH3)6(3+)-induced psi-DNA form of the polynucleotides exists in the left-handed Z-DNA conformation. Show less