The generation of HepG2 transmitochondrial cybrids to reveal the role of mitochondrial genotype in idiosyncratic drug-induced liver injury.

Background: Evidence supports an important link between mitochondrial DNA (mtDNA) variation and adverse drug reactions such as idiosyncratic drug-induced liver injury (iDILI). Here, we describe the generation of HepG2-derived transmitochondrial cybrids, to investigate the impact of mtDNA variation on mitochondrial (dys)function and susceptibility to iDILI. This study created 10 cybrid cell lines, each containing distinct mitochondrial genotypes of haplogroup H or haplogroup J backgrounds.

Time to Change: A Systems Pharmacology Approach to Disentangle Mechanisms of Drug-Induced Mitochondrial Toxicity.

An increasing number of commonly prescribed drugs are known to interfere with mitochondrial function, which is associated with almost half of all Food and Drug Administration black box warnings, a variety of drug withdrawals, and attrition of drug candidates. This can mainly be attributed to a historic lack of sensitive and specific assays to identify the mechanisms underlying mitochondrial toxicity during drug development. In the last decade, a better understanding of drug-induced mitochondrial dysfunction has been achieved by network-based and structure-based systems pharmacological approaches.

Enhanced hepatic respiratory capacity and altered lipid metabolism support metabolic homeostasis during short-term hypoxic stress.

Background: Tissue hypoxia is a key feature of several endemic hepatic diseases, including alcoholic and non-alcoholic fatty liver disease, and organ failure. Hypoxia imposes a severe metabolic challenge on the liver, potentially disrupting its capacity to carry out essential functions including fuel storage and the integration of lipid metabolism at the whole-body level. Mitochondrial respiratory function is understood to be critical in mediating the hepatic hypoxic response, yet the time-dependent nature of this response and the role of the respiratory chain in this remain unclear.

Assessment of the impact of mitochondrial genotype upon drug-induced mitochondrial dysfunction in platelets derived from healthy volunteers.

Mitochondrial DNA (mtDNA) is highly polymorphic and encodes 13 proteins which are critical to the production of ATP via oxidative phosphorylation. As mtDNA is maternally inherited and undergoes negligible recombination, acquired mutations have subdivided the human population into several discrete haplogroups. Mitochondrial haplogroup has been found to significantly alter mitochondrial function and impact susceptibility to adverse drug reactions.

Identification of the Additional Mitochondrial Liabilities of 2-Hydroxyflutamide When Compared With its Parent Compound, Flutamide in HepG2 Cells.

The androgen receptor antagonist, flutamide, is strongly associated with idiosyncratic drug-induced liver injury (DILI). Following administration, flutamide undergoes extensive first-pass metabolism to its primary metabolite, 2-hydroxyflutamide. Flutamide is a known mitochondrial toxicant; however there has been limited investigation into the potential mitochondrial toxicity of 2-hydroxyflutamide and its contribution to flutamide-induced liver injury.

Matrix Infrared Spectroscopic and Quantum Chemical Investigations of the Group 5 Transition Metal Atom and CX4 Molecule (X = H, F, and Cl) Reaction Products.

Laser-ablated vanadium, niobium, and tantalum atoms were reacted with CH2X2, CHX3, and CX4 (X = F and Cl) molecules in condensing argon, and the products were investigated by matrix isolation infrared spectroscopy. The major reaction products are new CH2-MX2, CHX-MX2, HC-MX3, and XC-MX3 complexes. These reactive species were identified by comparing their matrix infrared spectra with frequencies, intensities, and isotopic shifts from density functional theory calculations.

Effects of mid-respiratory chain inhibition on mitochondrial function and .

Relating the mitochondrial effects of drug candidates to likely outcomes remains challenging. Better understanding of this relationship, alongside improved methods to assess mitochondrial dysfunction , would both guide safer drug candidate selection and better support discovery programmes targeting mitochondria for pharmacological intervention. The aim of this study was to profile the effects of a compound with suspected complex III electron transport chain (ETC) inhibitory activity (GSK932121A) at doses associated with clinical signs, and relate findings back to data with the same compound.

Structure assignment, electronic properties, and magnetism quenching of endohedrally doped neutral silicon clusters, Si(n)Co (n = 10-12).

The structures of neutral cobalt-doped silicon clusters have been assigned by a combined experimental and theoretical study. Size-selective infrared spectra of neutral Si(n)Co (n = 10-12) clusters are measured using a tunable IR-UV two-color ionization scheme. The experimental infrared spectra are compared with calculated spectra of low-energy structures predicted at the B3P86 level of theory.

The geometric structure of silver-doped silicon clusters.

Cationic silver-doped silicon clusters, Si(n)Ag(+) (n=6-15), are studied using infrared multiple photon dissociation in combination with density functional theory computations. Candidate structures are identified using a basin-hopping global optimizations method. Based on the comparison of experimental and calculated IR spectra for the identified low-energy isomers, structures are assigned.

The structures of neutral transition metal doped silicon clusters, Si(n)X (n = 6-9; X = V, Mn).

We present a combined experimental and theoretical investigation of small neutral vanadium and manganese doped silicon clusters Si(n)X (n = 6-9, X = V, Mn). These species are studied by infrared multiple photon dissociation and mass spectrometry. Structural identification is achieved by comparison of the experimental data with computed infrared spectra of low-lying isomers using density functional theory at the B3P86∕6-311+G(d) level.

Infrared spectra of M-η2-C2H2 and HM-C≡CH produced in reactions of laser-ablated group 6 metal atoms with acetylene.

The π and C-H insertion complexes (M-η(2)-C(2)H(2) and HM-C≡CH) are identified in the matrix infrared spectra from reactions of laser-ablated Group 6 metal atoms with acetylene. In annealing, the π complex is produced, and it converts to the insertion product during photolysis with no trace of the vinylidene product. This observation is consistent with the considerably higher activation energy to H(2)CCM than that to HM-CCH in the previously proposed reaction path, whereas the three plausible products are in fact energetically comparable.

High magnetic moments in manganese-doped silicon clusters.

We report on the structural, electronic, and magnetic properties of manganese-doped silicon clusters cations, Si(n)Mn(+) with n=6-10, 12-14, and 16, using mass spectrometry and infrared spectroscopy in combination with density functional theory computations. This combined experimental and theoretical study allows several structures to be identified. All the exohedral Si(n)Mn(+) (n=6-10) clusters are found to be substitutive derivatives of the bare Si(n+1)(+) cations, while the endohedral Si(n)Mn(+) (n=12-14 and 16) clusters adopt fullerene-like structures.

Perturbation of microRNAs in rat heart during chronic doxorubicin treatment.

Anti-cancer therapy based on anthracyclines (DNA intercalating Topoisomerase II inhibitors) is limited by adverse effects of these compounds on the cardiovascular system, ultimately causing heart failure. Despite extensive investigations into the effects of doxorubicin on the cardiovascular system, the molecular mechanisms of toxicity remain largely unknown. MicroRNAs are endogenously transcribed non-coding 22 nucleotide long RNAs that regulate gene expression by decreasing mRNA stability and translation and play key roles in cardiac physiology and pathologies.

Gas-phase structures of neutral silicon clusters.

Vibrational spectra of neutral silicon clusters Si(n), in the size range of n = 6-10 and for n = 15, have been measured in the gas phase by two fundamentally different IR spectroscopic methods. Silicon clusters composed of 8, 9, and 15 atoms have been studied by IR multiple photon dissociation spectroscopy of a cluster-xenon complex, while clusters containing 6, 7, 9, and 10 atoms have been studied by a tunable IR-UV two-color ionization scheme. Comparison of both methods is possible for the Si(9) cluster.

Doxorubicin in vivo rapidly alters expression and translation of myocardial electron transport chain genes, leads to ATP loss and caspase 3 activation.

Background: Doxorubicin is one of the most effective anti-cancer drugs but its use is limited by cumulative cardiotoxicity that restricts lifetime dose. Redox damage is one of the most accepted mechanisms of toxicity, but not fully substantiated. Moreover doxorubicin is not an efficient redox cycling compound due to its low redox potential.

Probing C-O bond activation on gas-phase transition metal clusters: infrared multiple photon dissociation spectroscopy of Fe, Ru, Re, and W cluster CO complexes.

The binding of carbon monoxide to iron, ruthenium, rhenium, and tungsten clusters is studied by means of infrared multiple photon dissociation spectroscopy. The CO stretching mode is used to probe the interaction of the CO molecule with the metal clusters and thereby the activation of the C-O bond. CO is found to adsorb molecularly to atop positions on iron clusters.

Vibrational spectroscopy of neutral silicon clusters via far-IR-VUV two color ionization.

Tunable far-infrared-vacuum-ultraviolet two color ionization is used to obtain vibrational spectra of neutral silicon clusters in the gas phase. Upon excitation with tunable infrared light prior to irradiation with UV photons we observe strong enhancements in the mass spectrometric signal of specific cluster sizes. This allowed the recording of the infrared absorption spectra of Si(6), Si(7), and Si(10).

Formation and calculations of the simple terminal triplet pnictinidene molecules N/MF(3), P/MF(3), and As/MF(3) (M = Ti, Zr, Hf).

Laser-ablated Ti, Zr, and Hf atoms react with NF(3), PF(3), or AsF(3) to produce triplet state terminal pnictinidene N/MF(3), P/MF(3), or As/MF(3) molecules, which are trapped in an argon matrix. Products are identified from infrared spectra and comparison to theoretically predicted vibrations. Density functional theory calculations converge to C(3v) symmetry structures for these lowest energy products.

Pivotal role for two electron reduction in 2,3-dimethoxy-1,4-naphthoquinone and 2-methyl-1,4-naphthoquinone metabolism and kinetics in vivo that prevents liver redox stress.

2,3-dimethoxy-1,4-naphthoquinone (CAS-RN 6959-96-3) (DMNQ) and 2-methyl-1,4-naphthoquinone (CAS-RN 58-27-5) (MNQ:menadione) are effective one electron redox cycling chemicals in vitro. In addition, in vitro MNQ forms a thioether conjugate with glutathione by nucleophilic attack at the third carbon. In contrast, here we demonstrate that in vivo the major metabolic route is directly to the dihydronaphthoquinone for both DMNQ and MNQ followed by conjugation to mono- and di-glucuronides and sulfate.

Structures of silicon cluster cations in the gas phase.

We present gas-phase infrared spectra for small silicon cluster cations possessing between 6 and 21 atoms. Infrared multiple photon dissociation (IR-MPD) of these clusters complexed with a xenon atom is employed to obtain their vibrational spectra. These vibrational spectra give for the first time experimental data capable of distinguishing the exact internal structures of the silicon cluster cations.

Structures of neutral Au7, Au19, and Au20 clusters in the gas phase.

The catalytic properties of gold nanoparticles are determined by their electronic and geometric structures. We revealed the geometries of several small neutral gold clusters in the gas phase by using vibrational spectroscopy between 47 and 220 wavenumbers. A two-dimensional structure for neutral Au7 and a pyramidal structure for neutral Au20 can be unambiguously assigned.

Reactions of actinide metal atoms with ethane: computation and observation of new Th and U ethylidene dihydride, metallacyclopropane dihydride, and vinyl metal trihydride complexes.

A combined computational and experimental investigation provides evidence that excited thorium and uranium atoms activate ethane to form the vinyl metal trihydride, metallacyclopropane dihydride, and ethylidene metal dihydride for thorium and the latter complex and the inserted ethyl metal hydride for uranium. These products are trapped in solid argon and identified through deuterium isotopic substitution and vibrational frequencies calculated by density functional theory. Comparisons are made with group 4 and methane reaction products.

Infrared spectra and electronic structures of agostic uranium methylidene molecules.

Through reactions of laser-ablated uranium atoms with methylene halides CH2XY (XY = F2, FCl, and Cl2), a series of new actinide methylidene molecules CH2UF2, CH2UFCl, and CH2UCl2 are formed as the major products. The identification of these complexes has been accomplished via matrix infrared spectra, isotopic substitution, and relativistic density functional calculations of the vibrational frequencies and infrared intensities. Density functional calculations using the generalized gradient approach (PW91) show that these CH2UXY methylidene complexes prefer highly distorted agostic structures rather than the ethylene-like symmetric structures.

Formation of unprecedented actinide triple bond carbon in uranium methylidyne molecules.

Chemistry of the actinide elements represents a challenging yet vital scientific frontier. Development of actinide chemistry requires fundamental understanding of the relative roles of actinide valence-region orbitals and the nature of their chemical bonding. We report here an experimental and theoretical investigation of the uranium methylidyne molecules X(3)U CH (X = F, Cl, Br), F(2)ClU CH, and F(3)U CF formed through reactions of laser-ablated uranium atoms and trihalomethanes or carbon tetrafluoride in excess argon.