Cationic chitosan@Ruthenium dioxide hybrid nanozymes for photothermal therapy enhancing ROS-mediated eradicating multidrug resistant bacterial infection.

Antibiotic resistanceand biofilm formation are the main challenges of bacterial infectious diseases, and enhancing the permeability of drugs to biofilms may be a promising strategy. Herein, we constructed a cationic chitosan coated ruthenium dioxide nanozyme (QCS-RuO2@RBT, SRT NSs)。RuO2 nanosheets (RuO2 NSs) are modified with positively charged Quaternary ammonium-chitosan (QCS) to improve biocompatibility, and enhance the interaction between RuO2 nanozymes and bacterial membranes. An antibacterial drug, [Ru(bpy)2(tip)]2+ (RBT) can be loaded onto QCS-RuO2 by π-π stacking and hydrophobic interaction. SRT NSs exhibit NIR light enhanced peroxidase-like catalytic activity, thereby effectively fighting against planktonic bacteria and damaging biofilms. In the biofilm, extracellular DNA (eDNA) was cleaved by high levels of hydroxyl radicals (•OH) catalyzed by SRT NSs, thereby disrupting the rigid biofilm. In addition, in vivo studies demonstrate that SRT NSs can significantly rescue skin wound infections and the chronic lung infection in mice caused by P. aeruginosa, and hold the same therapeutic efficacy as first-line clinically anchored anti P. aeruginosa drug ciprofloxacin. Accordingly, the research work has realized the efficient production of ·OH, and the permeability of drugs to biofilms.it provides a promising response strategy for the management of biofilm-associated infections, including chronic lung infection.

Calcium supplementation relieves high-fat diet-induced liver steatosis by reducing energy metabolism and promoting lipolysis.

Nonalcoholic fatty liver disease (NAFLD) is a chronic disease affecting the health of many people worldwide. Previous studies have shown that dietary calcium supplementation may alleviate NAFLD, but the underlying mechanism is not clear. In this study investigating the effect of calcium on hepatic lipid metabolism, 8-week-old male C57BL/6J mice were divided into four groups (n = 6): (1) mice given a normal chow containing 0.5% calcium (CN0.5), (2) mice given a normal chow containing 1.2% calcium (CN1.2), (3) mice given a high-fat diet (HFD) containing 0.5% calcium (HFD0.5), and (4) mice fed a HFD containing 1.2% calcium (HFD1.2). To understand the underlying mechanism, cells were treated with oleic acid and palmitic acid to mimic the HFD conditions in vitro. The results showed that calcium alleviated the increase in triglyceride accumulation induced by oleic acid and/or palmitic acid in HepG2, AML12, and primary hepatocyte cells. Our data demonstrated that calcium supplementation alleviated HFD-induced hepatic steatosis through increased liver lipase activity, proving calcium is involved in the regulation of hepatic lipid metabolism. Moreover, calcium also increased the level of glycogen in the liver, and at the same time had the effect of reducing glycolysis and promoting glucose absorption. Calcium addition increased calcium levels in the mitochondria and cytoplasm. Taken together, we concluded that calcium supplementation could relieve HFD-induced hepatic steatosis by changing energy metabolism and lipase activity.

Modulation of Diverse Procoagulant Venom Activities by Combinations of Platinoid Compounds.

Procoagulant snake venoms have been inhibited by the ruthenium containing compounds CORM-2 and RuCl3 separately, presumably by interacting with critical histidine or other sulfur-containing amino acids on key venom enzymes. However, combinations of these and other platinoid containing compounds could potentially increase, decrease or not affect the procoagulant enzyme function of venom. Thus, the purpose of this investigation was to determine if formulations of platinoid compounds could inhibit venom procoagulant activity and if the formulated compounds interacted to enhance inhibition. Using a human plasma coagulation kinetic model to assess venom activity, six diverse venoms were exposed to various combinations and concentrations of CORM-2, CORM-3, RuCl3 and carboplatin (a platinum containing compound), with changes in venom activity determined with thrombelastography. The combinations of CORM-2 or CORM-3 with RuCl3 were found to enhance inhibition significantly, but not in all venoms nor to the same extent. In sharp contrast, carboplatin-antagonized CORM-2 mediated the inhibition of venom activity. These preliminary results support the concept that platinoid compounds may inhibit venom enzymatic activity at the same or different molecular sites and may antagonize inhibition at the same or different sites. Further investigation is warranted to determine if platinoid formulations may serve as potential antivenoms.

Effects of mitochondria-associated Ca2+ transporters suppression on oocyte activation.

Oocyte activation deficiency leads to female infertility. [Ca2+ ]i oscillations are required for mitochondrial energy supplement transition from the resting to the excited state, but the underlying mechanisms are still very little known. Three mitochondrial Ca2+ channels, Mitochondria Calcium Uniporter (MCU), Na+ /Ca2+ Exchanger (NCLX) and Voltage-dependent Ca2+ Channel (VDAC), were deactivated by inhibitors RU360, CGP37157 and Erastin, respectively. Both Erastin and CGP37157 inhibited mitochondrial activity significantly while attenuating [Ca2+ ]i and [Ca2+ ]m oscillations, which caused developmental block of pronuclear formation. Thus, NCLX and VDAC are two mitochondria-associated Ca2+ transporter proteins regulating oocyte activation, which may be used as potential targets to treat female infertility. SIGNIFICANCE OF THE STUDY: NCLX and VDAC are two mitochondria-associated Ca2+ transporter proteins regulating oocyte activation.

Boosting type I process of Ru(II) compounds by changing tetrazole ligand for enhanced photodynamic therapy against lung cancer.

Boosting the photosensitization type I process will enhance the phototherapy efficacy because the superoxide radicals (O2-) generated during type I process are more toxic than the singlet oxygen (1O2) in type II process. Herein, [Ru(Hdtza)(phen)2][PF6] (1) and [Ru(pytz)(phen)2][PF6] (2) (phen = 1,10-phenanthroline) based on two nitrogen-rich tetrazole ligands, di(2H-tetrazol-5-yl) amine (H2dtza) and 5-(2-pyridyl)tetrazole (Hpytz) have been developed for photodynamic therapy (PDT) against lung cancer, respectively. Nanoprecipitation was used to prepare the nanoparticles (NPs) of both compounds. [Ru(Hdtza)(phen)2][PF6] NPs mainly undergo an electron transfer process to generate O2- while [Ru(pytz)(phen)2][PF6] the direct energy transfer to produce 1O2, which is responsible for the higher phototoxicity of [Ru(Hdtza)(phen)2][PF6] NPs (IC50 ~ 4.8 µg/mL) than that of [Ru(pytz)(phen)2][PF6] NPs (IC50 ~ 13.6 µg/mL) on human lung cancer cells (A549). Furthermore, in vivo study indicates that the tumor proliferation of nude mice can be effectively inhibited with the help of laser when the mice were injected with [Ru(pytz)(phen)2][PF6] NPs. This work may provide a simple strategy to design type I photosensitizers for enhanced photodynamic therapy.

A self-assembled Ru-Pt metallacage as a lysosome-targeting photosensitizer for 2-photon photodynamic therapy.

Photodynamic therapy (PDT) is a treatment procedure that relies on cytotoxic reactive oxygen species (ROS) generated by the light activation of a photosensitizer. The photophysical and biological properties of photosensitizers are vital for the therapeutic outcome of PDT. In this work a 2D rhomboidal metallacycle and a 3D octahedral metallacage were designed and synthesized via the coordination-driven self-assembly of a Ru(II)-based photosensitizer and complementary Pt(II)-based building blocks. The metallacage showed deep-red luminescence, a large 2-photon absorption cross-section, and highly efficient ROS generation. The metallacage was encapsulated into an amphiphilic block copolymer to form nanoparticles to encourage cell uptake and localization. Upon internalization into cells, the nanoparticles selectively accumulate in the lysosomes, a favorable location for PDT. The nanoparticles are almost nontoxic in the dark, and can efficiently destroy tumor cells via the generation of ROS in the lysosomes under 2-photon near-infrared light irradiation. The superb PDT efficacy of the metallacage-containing nanoparticles was further validated by studies on 3D multicellular spheroids (MCS) and in vivo studies on A549 tumor-bearing mice.

Studies of KP46 and KP1019 and the Hydrolysis Product of KP1019 in Lipiodol Emulsions: Preparation and Initial Characterizations as Potential Theragnostic Agents.

BACKGROUND: Lipiodol (iodized poppy seed oil) accumulates predominately in the tumor rather than in the liver tissue [1, 2]. Therefore, mixing anticancer drugs with Lipiodol may enhance the antitumor effect by increasing the local drug concentration. OBJECTIVE: In this pilot study, we made use of Lipiodol as a potential carrier of three promising antitumor metal complexes (tris(8-quinolato)gallium(III) (KP46), tetrachlorobis(indazole)ruthenate(III) (KP1019) and the hydrolysis product of KP1019, mer,trans-[RuCl3(H2O)(Hind)2]. METHODS: The stability of the drugs in Lipiodol and the release profile into the aqueous phase were examined independently by three different analytical techniques (high pressure liquid chromatography, HPLC; atom absorption spectroscopy, AAS; and electron spray ionization mass spectrometry, ESI-MS). RESULTS: The complexes were stable and remained in the Lipiodol emulsion over 3 days. In contrast to KP1019 and KP46, evaluation of Lipiodol emulsions of mer,trans-[RuCl3 (H2O) (Hind) 2] was not possible due to the insolubility of the compound in Lipiodol. KP1019 released rapidly into the aqueous phase in the first week and after 1 month it was not possible to detect the complex in the emulsion. KP46 showed a gradual release with the time resulting in the release of about 6.4 % of KP46 into the aqueous phase after 1 month of incubation. CONCLUSION: The initial results show that Lipiodol can be successfully employed as a carrier of anticancer Ru- or Ga-complexes. Furthermore, advantages can overcome the poor water solubility of the metal complexes, opening new perspectives for the use of Lipiodol emulsions in molecular imaging and cancer therapy as theragnostic agents.

Hydrogen Evolution Activity of Ruthenium Phosphides Encapsulated in Nitrogen- and Phosphorous-Codoped Hollow Carbon Nanospheres.

RuPx nanoparticles (NPs) encapsulated in uniform N,P-codoped hollow carbon nanospheres (RuPx @NPC) have been synthesized through a facile route in which aniline-pyrrole copolymer nanospheres are used to disperse Ru ions followed by a gas phosphorization process. The as-prepared RuPx @NPC exhibits a uniform core-shell hollow nanospherical structure with RuPx NPs as the core and N,P-codoped carbon (NPC) as the shell. This strategy integrates many advantages of hollow nanostructures, which provide a conductive substrate and the doping of a nonmetal element. At high temperatures, the obtained thin NPC shell can not only protect the highly active phase of RuPx NPs from aggregation and corrosion in the electrolyte but also allows variation in the electronic structures to improve the charge-transfer rate greatly by N,P codoping. The optimized RuPx @NPC sample at 900 °C exhibits a Pt-like performance for the hydrogen evolution reaction (HER) and long-term durability in acidic, alkaline, and neutral solutions. The reaction requires a small overpotential of only 51, 74, and 110 mV at 10 mA cm-2 in 0.5 m H2 SO4 , 1.0 m KOH, and 1.0 m phosphate-buffered saline, respectively. This work provides a new way to design unique phosphide-doped carbon heterostructures through an inorganic-organic hybrid method as excellent electrocatalysts for HER.

Density functionalized [RuII(NO)(Salen)(Cl)] complex: Computational photodynamics and in vitro anticancer facets.

Photodynamic therapy (PDT) is a treatment that uses photosensitizing agents to kill cancer cells. Scientific community has been eager for decades to design an efficient PDT drug. Under such purview, the current report deals with the computational photodynamic behavior of ruthenium(II) nitrosyl complex containing N, N'-salicyldehyde-ethylenediimine (SalenH2), the synthesis and X-ray crystallography of which is already known [Ref. 38,39]. Gaussian 09W software package was employed to carry out the density functional (DFT) studies. DFT calculations with Becke-3-Lee-Yang-Parr (B3LYP)/Los Alamos National Laboratory 2 Double Z (LanL2DZ) specified for Ru atom and B3LYP/6-31G(d,p) combination for all other atoms were used using effective core potential method. Both, the ground and excited states of the complex were evolved. Some known photosensitizers were compared with the target complex. Pthalocyanine and porphyrin derivatives were the compounds selected for the respective comparative study. It is suggested that effective photoactivity was found due to the presence of ruthenium core in the model complex. In addition to the evaluation of theoretical aspects in vitro anticancer aspects against COLO-205 human cancer cells have also been carried out with regard to the complex. More emphasis was laid to extrapolate DFT to depict the chemical power of the target compound to release nitric oxide. A promising visible light triggered nitric oxide releasing power of the compound has been inferred. In vitro antiproliferative studies of [RuCl3(PPh3)3] and [Ru(NO)(Salen)(Cl)] have revealed the model complex as an excellent anticancer agent. From IC50 values of 40.031mg/mL in former and of 9.74mg/mL in latter, it is established that latter bears more anticancer potentiality. From overall study the DFT based structural elucidation and the efficiency of NO, Ru and Salen co-ligands has shown promising drug delivery property and a good candidacy for both chemotherapy as well as light therapy.

Hypoxia-selective inhibition of angiogenesis development by NAMI-A analogues.

The antimetastatic ruthenium(III) complex (H2Im)[trans-RuCl4(HIm)(DMSO)] (NAMI-A) as well as its two analogues (H2Ind)[trans-RuCl4(HInd)(DMSO)] (Ru-Ind) and (HIsq)[trans-RuCl4(Isq)(DMSO)] (Ru-Isq) (HIm-imidazole, HInd-indazole, Isq-isoquinoline, DMSO-dimethyl sulfoxide) were tested for their effect on endothelial cell functions in vitro on human skin microvascular endothelial cells (HSkMEC) and human endothelial progenitor cells (HPEC-CB.2) under normoxic (21 % O2) and hypoxic (1 % O2) conditions. All studied complexes showed very low cytotoxicity profiles towards both mature microvascular and precursor endothelial cells (ECs), independently of oxygen concentration. Among tested compounds Ru-Ind exhibited the highest cytotoxicity. The antiangiogenic activity of ruthenium complexes was evaluated for their influence on pseudo-vessels formation by microvascular endothelial cells (HSkMEC) because of their involvement in melanoma progression. Our studies indicated that Ru-Ind and Ru-Isq exhibited hypoxia- and dose-dependent-inhibition of angiogenesis on Matrigel™. Significant hypoxia-selective downregulation of pseudo-vessels formation by Ru-Isq correlates with efficient inhibition of cell motility. Interestingly, in the applied concentration doses migration of endothelial cells was also inhibited by NAMI-A, but the pseudo-vessels formation on Matrigel™ was unaffected. Angiogenesis-related genes expression profile for both mature and precursor ECs indicated that inhibition of angiogenesis, mainly due to Ru-Isq, as compared to NAMI-A and Ru-Ind correlated with downregulation of CD31 and CD144 expression and upregulation of NOTCH4 expression in mature ECs, which is essential for endothelial cell motility and stalk cells organization control. The hypoxia-selective antiangiogenic activity of Ru-Ind and Ru-Isq, NAMI-A analogues makes them potent antimetastatic therapeutics for their selective action in hypoxia which controls tumor pathologic angiogenesis.

Translocation of iron from lysosomes to mitochondria during acetaminophen-induced hepatocellular injury: Protection by starch-desferal and minocycline.

Acetaminophen (APAP) overdose causes hepatotoxicity involving mitochondrial dysfunction and the mitochondrial permeability transition (MPT). Iron is a critical catalyst for ROS formation, and reactive oxygen species (ROS) play an important role in APAP-induced hepatotoxicity. Previous studies show that APAP disrupts lysosomes, which release ferrous iron (Fe(2+)) into the cytosol to trigger the MPT and cell killing. Here, our aim was to investigate whether iron released from lysosomes after APAP is then taken up into mitochondria via the mitochondrial electrogenic Ca(2+), Fe(2+) uniporter (MCFU) to cause mitochondrial dysfunction and cell death. Hepatocytes were isolated from fasted male C57BL/6 mice. Necrotic cell killing was assessed by propidium iodide fluorimetry. Mitochondrial membrane potential (ΔΨ) was visualized by confocal microscopy of rhodamine 123 (Rh123) and tetramethylrhodamine methylester (TMRM). Chelatable Fe(2+) was monitored by quenching of calcein (cytosol) and mitoferrofluor (MFF, mitochondria). ROS generation was monitored by confocal microscopy of MitoSox Red and plate reader fluorimetry of chloromethyldihydrodichlorofluorescein diacetate (cmH2DCF-DA). Administered 1h before APAP (10mM), the lysosomally targeted iron chelator, starch-desferal (1mM), and the MCFU inhibitors, Ru360 (100nM) and minocycline (4µM), decreased cell killing from 83% to 41%, 57% and 53%, respectively, after 10h. Progressive quenching of calcein and MFF began after ~4h, signifying increased cytosolic and mitochondrial chelatable Fe(2+). Mitochondria then depolarized after ~10h. Dipyridyl, a membrane-permeable iron chelator, dequenched calcein and MFF fluorescence after APAP. Starch-desferal, but not Ru360 and minocycline, suppressed cytosolic calcein quenching, whereas starch-desferal, Ru360 and minocycline all suppressed mitochondrial MFF quenching and mitochondrial depolarization. Starch-desferal, Ru360 and minocycline also each decreased ROS formation. Moreover, minocycline 1h after APAP decreased cell killing by half. In conclusion, release of Fe(2+) from lysosomes followed by uptake into mitochondria via MCFU occurs during APAP hepatotoxicity. Mitochondrial iron then catalyzes toxic hydroxyl radical formation, which triggers the MPT and cell killing. The efficacy of minocycline post-treatment shows minocycline as a possible therapeutic agent against APAP hepatotoxicity.

Solid Electrolyte Lithium Phosphous Oxynitride as a Protective Nanocladding Layer for 3D High-Capacity Conversion Electrodes.

Materials that undergo conversion reactions to form different materials upon lithiation typically offer high specific capacity for energy storage applications such as Li ion batteries. However, since the reaction products often involve complex mixtures of electrically insulating and conducting particles and significant changes in volume and phase, the reversibility of conversion reactions is poor, preventing their use in rechargeable (secondary) batteries. In this paper, we fabricate and protect 3D conversion electrodes by first coating multiwalled carbon nanotubes (MWCNT) with a model conversion material, RuO2, and subsequently protecting them with conformal thin-film lithium phosphous oxynitride (LiPON), a well-known solid-state electrolyte. Atomic layer deposition is used to deposit the RuO2 and the LiPON, thus forming core double-shell MWCNT@RuO2@LiPON electrodes as a model system. We find that the LiPON protection layer enhances cyclability of the conversion electrode, which we attribute to two factors. (1) The LiPON layer provides high Li ion conductivity at the interface between the electrolyte and the electrode. (2) By constraining the electrode materials mechanically, the LiPON protection layer ensures electronic connectivity and thus conductivity during lithiation/delithiation cycles. These two mechanisms are striking in their ability to preserve capacity despite the profound changes in structure and composition intrinsic to conversion electrode materials. This LiPON-protected structure exhibits superior cycling stability and reversibility as well as decreased overpotentials compared to the unprotected core-shell structure. Furthermore, even at very low lithiation potential (0.05 V), the LiPON-protected electrode largely reduces the formation of a solid electrolyte interphase.

trans-Hydrogenation: application to a concise and scalable synthesis of brefeldin†A.

The important biochemical probe molecule brefeldin A (1) has served as an inspirational target in the past, but none of the many routes has actually delivered more than just a few milligrams of product, where documented. The approach described herein is clearly more efficient; it hinges upon the first implementation of ruthenium-catalyzed trans-hydrogenation in natural products total synthesis. Because this unorthodox reaction is selective for the triple bond and does not touch the transannular alkene or the lactone site of the cycloalkyne, it outperforms the classical Birch-type reduction that could not be applied at such a late stage. Other key steps en route to 1 comprise an iron-catalyzed reductive formation of a non-terminal alkyne, an asymmetric propiolate carbonyl addition mediated by a bulky amino alcohol, and a macrocyclization by ring-closing alkyne metathesis catalyzed by a molybdenum alkylidyne.

The ruthenium nitric oxide donor, [Ru(HEDTA)NO], inhibits acute nociception in mice by modulating oxidative stress, cytokine production and activating the cGMP/PKG/ATP-sensitive potassium channel signaling pathway.

Nitric oxide plays an important role in various biological processes including antinociception. The control of its local concentration is crucial for obtaining the desired effect and can be achieved with exogenous nitric oxide-carriers such as ruthenium complexes. Therefore, we evaluated the analgesic effect and mechanism of action of the ruthenium nitric oxide donor [Ru(HEDTA)NO] focusing on the role of cytokines, oxidative stress and activation of the cyclic guanosine monophosphate/protein kinase G/ATP-sensitive potassium channel signaling pathway. It was observed that [Ru(HEDTA)NO] inhibited in a dose-dependent (1-10 mg/kg) manner the acetic acid-induced writhing response. At the dose of 1 mg/kg, [Ru(HEDTA)NO] inhibited the phenyl-p-benzoquinone-induced writhing response, and formalin- and complete Freund's adjuvant-induced licking and flinching responses. Systemic and local treatments with [Ru(HEDTA)NO] also inhibited the carrageenin-induced mechanical hyperalgesia and increase of myeloperoxidase activity in paw skin samples. Mechanistically, [Ru(HEDTA)NO] inhibited carrageenin-induced production of the hyperalgesic cytokines tumor necrosis factor-α and interleukin-1ß, and decrease of reduced glutathione levels. Furthermore, the inhibitory effect of [Ru(HEDTA)NO] in the carrageenin-induced hyperalgesia and myeloperoxidase activity was prevented by the treatment with ODQ (soluble guanylyl cyclase inhibitor), KT5823 (protein kinase G inhibitor) and glybenclamide (ATP-sensitive potassium channel inhibitor), indicating that [Ru(HEDTA)NO] inhibits inflammatory hyperalgesia by activating the cyclic guanosine monophosphate/protein kinase G/ATP-sensitive potassium channel signaling pathway, respectively. These results demonstrate that [Ru(HEDTA)NO] exerts its analgesic effect in inflammation by inhibiting pro-nociceptive cytokine production, oxidative imbalance and activation of the nitric oxide/cyclic guanosine monophosphate/protein kinase G/ATP-sensitive potassium channel signaling pathway in mice.

Nanoformulation improves activity of the (pre)clinical anticancer ruthenium complex KP1019.

Ruthenium anticancer drugs belong to the most promising non-platinum anticancer metal compounds in clinical evaluation. However, although the clinical results are promising regarding both activity and very low adverse effects, the clinical application is currently hampered by the limited solubility and stability of the drug in aqueous solution. Here, we present a new nanoparticle formulation based on polymer-based micelles loaded with the anticancer lead ruthenium compound KP1019. Nanoprepared KP1019 was characterised by enhanced stability in aqueous solutions. Moreover, the nanoparticle formulation facilitated cellular accumulation of KP1019 (determined by ICP-MS measurements) resulting in significantly lowered IC50 values. With regard to the mode of action, increased cell cycle arrest in G2/M phase (PI-staining), DNA damage (Comet assay) as well as enhanced levels of apoptotic cell death (caspase 7 and PARP cleavage) were found in HCT116 cells treated with the new nanoformulation of KP1019. Summarizing, we present for the first time evidence that nanoformulation is a feasible strategy for improving the stability as well as activity of experimental anticancer ruthenium compounds.

'True' bosonic coupling strength in strongly correlated superconductors.

Clarifying the coupling between electrons and bosonic excitations (phonons or magnetic fluctuations) that mediate the formation of Cooper pairs is pivotal to understand superconductivity. Such coupling effects are contained in the electron self-energy, which is experimentally accessible via angle-resolved photoemission spectroscopy (ARPES). However, in unconventional superconductors, identifying the nature of the electron-boson coupling remains elusive partly because of the significant band renormalization due to electron correlation. Until now, to quantify the electron-boson coupling, the self-energy is most often determined by assuming a phenomenological 'bare' band. Here, we demonstrate that the conventional procedure underestimates the electron-boson coupling depending on the electron-electron coupling, even if the self-energy appears to be self-consistent via the Kramers-Kronig relation. Our refined method explains well the electron-boson and electron-electron coupling strength in ruthenate superconductor Sr2RuO4, calling for a critical revision of the bosonic coupling strength from ARPES self-energy in strongly correlated electron systems.

Incorporation mechanisms of a branched nonylphenol isomer in soil-derived organo-clay complexes during a 180-day experiment.

The incorporation process of a defined (13)C- and (14)C-labeled nonylphenol isomer (4-(3,5-dimethylhept-3-yl)phenol) into soil-derived organo-clay complexes was investigated. Isolated organo-clay complexes were separated into humic subfractions. Noninvasive ((13)C-CP/MAS NMR) and invasive methods (sequential chemical degradation, pyrolysis) were applied to obtain detailed information about the mode of incorporation, chemical structure, and change of the incorporation character of nonextractable residues in course of incubation. (13)C-CP/MAS NMR measurements of humic acids revealed an increasing incorporation of phenolic compounds during the experimental time which was referred to residues of the introduced (13)C-labeled NP isomer. Detailed investigations by means of sequential chemical degradation indicated a predominant incorporation of nonextractable NP isomer residues via reversible ester (amide) bonds. In course of time, the amount of releasable compounds decreased, pointing to altering processes which affected the mode of incorporation. BBr3-treatment, RuO4 oxidation, and thermochemolysis released only low portions of nonextractable radioactivity giving evidence of strongly incorporated residues. With the comprehensive application of complementary methods (e.g., humic matter fractionation, (13)C-CP/MAS NMR, sequential chemical degradation) it was possible to provide a comparatively detailed insight into the incorporation behavior of the applied NP isomer.

The ruthenium NO donor, [Ru(bpy)2(NO)SO3](PF6), inhibits inflammatory pain: involvement of TRPV1 and cGMP/PKG/ATP-sensitive potassium channel signaling pathway.

The activation of nitric oxide (NO) production is an analgesic mechanism shared by drugs such as morphine and diclofenac. Therefore, the controlled release of low amounts of NO seems to be a promising analgesic approach. In the present study, the antinociceptive effect of the ruthenium NO donor [Ru(bpy)2(NO)SO3](PF6) (complex I) was investigated. It was observed that complex I inhibited in a dose (0.3-10mg/kg)-dependent manner the acetic acid-induced writhing response. At the dose of 1mg/kg, complex I inhibited the phenyl-p-benzoquinone-induced writhing response and formalin- and complete Freund's adjuvant-induced licking and flinch responses. Additionally, complex I also inhibited transient receptor potential cation channel subfamily V member 1 (TRPV1)-dependent overt pain-like behavior induced by capsaicin. Complex I also inhibited the carrageenin-induced mechanical hyperalgesia and increase of myeloperoxidase activity (MPO) in paw skin samples. The inhibitory effect of complex I in the carrageenin-induced hyperalgesia, MPO activity and formalin was prevented by the treatment with ODQ, KT5823 and glybenclamide, indicating that complex I inhibits inflammatory hyperalgesia by activating the cGMP/PKG/ATP-sensitive potassium channel signaling pathway. The present study demonstrates the efficacy of a novel ruthenium NO donor and its analgesic mechanisms.

Magnetic ground state and electronic structure of CeRu(2)Al(10).

We present a combined theoretical and experimental study of the electronic structure for CeRu(2)Al(10) based on ab initio band structure calculations and x-ray photoemission spectroscopy (XPS) data. Our calculations were performed for the base unit cell and for the hypothetical unit cell which enables antiferromagnetic ordering. The stability of the magnetic phase was investigated within fixed spin moment calculations. When additional 4f correlations are not included in the LSDA C U approach, CeRu(2)Al(10) exhibits an unstable magnetic configuration with the difference in total energy per unit cell between the weakly magnetic state and the non-magnetic one of the order ~0.3 meV. We found that Coulomb correlations among 4f electrons, when they are included in the LSDA C U approach, stabilize the magnetic structure. In the weakly correlated system (small U) an antiferromagnetic (AFM) ground state with the lowest total energy is preferred. The situation is, however, the opposite when the 4f correlations are strong. In this case the ferromagnetic (FM) ground state is preferred. By comparing our calculations with the experimental data we conclude that the 4f correlations in CeRu(2)Al(10) are weak. We also carried out a structural relaxation of atomic positions within the Cmcm unit cell and we found that the Al atoms exhibit noticeable displacement from their positions known from x-ray diffraction (XRD) analysis.

The ruthenium complex cis-(dichloro)tetrammineruthenium(III) chloride induces apoptosis and damages DNA in murine sarcoma 180 cells.

Ruthenium (III) complexes are increasingly attracting the interest of researchers due to their promising pharmacological properties. Recently, we reported that the cis-(dichloro)tetrammineruthenium (III) chloride compound has cytotoxic effects on murine sarcoma 180 (S-180) cells. In an effort to understand the mechanism responsible for their cytotoxicity, study we investigated the genotoxicity, cell cycle distribution and induction of apoptosis caused by cis- (dichloro) tetrammineruthenium (III) chloride in S-180 tumour cells. cis-(dichloro) tetrammineruthenium (III) chloride treatment induced significant DNA damage in S-180 cells, as detected by the alkaline comet assay. In the cell cycle analysis, cis-(dichloro) tetrammineruthenium (III) chloride caused an increase in the number of cells in G1 phase, accompanied by a decrease in the S and G2 phases after 24 h of treatment. In contrast, the cell cycle distribution of S-180 cells treated with cis-(dichloro) tetrammineruthenium (III) chloride for 48 h showed a concentration-dependent increase in the sub-G1 phase (indicating apoptosis), with a corresponding decrease in cells in the G1, S and G2 phases. In addition, cis-(dichloro) tetrammineruthenium(III) chloride treatment induced apoptosis in a time-dependent manner,as observed by the increased numbers of annexin V-positive cells. Taken together, these findings strongly demonstrate that DNA damage, cell cycle changes and apoptosis may correlate with the cytotoxic effects of cis-(dichloro) tetrammineruthenium (III) chloride on S-180 cells.