The dissolution of monosodium urate monohydrate crystals: formulation of a biocompatible buffer solution with potential use in the treatment of gouty arthropathies

The dissolving abilities (DAs) of several aqueous media for microcrystalline monosodium urate monohydrate (MSU, NaC5N4O3H3·H2O) have been investigated using UV spectrophotometry for quantitative analytical determinations and X-ray diffraction, scanning electron microscopy and polarized light optical microscopy to assess structural aspects. High DAs were found for a buffer labeled TMT which contains tris(hydroxymethyl)aminomethane (TRIS), tris(hydroxymethyl)aminomethane hydrochloride (TRIS·HCl), D-mannitol (MAN) and taurine (TAU) and gave DA30=1298(5) mg/L for synthetic MSU after 30 min incubation at 37°C and pH 7.4, most of the dissolution taking place within the first 5-10 min. Semiempirical molecular modelling techniques (ZINDO/1) show a favorable energy balance for the formation of a TRIS-urate-TRIS adduct which might explain the high DA values. Buffers containing linear or dendrimeric polyamines gave DA values which suggest that complex formation toward sodium cations is less important. An ex vivo MSU sample was found to have a significantly lower DA value (DA30=1124(5) mg/L in TMT) as well as a lower crystallinity than its synthetic counterpart, possibly related to the presence of a non-crystalline impurity such as endogenous proteins. Cytotoxicity tests based on the MTT assay were used to check the biocompatibility of the TMT buffer and showed only moderate cell mortality after 24 h contact with the buffer solution

Effect of Free Water Molecules on the Structure of Mg-ATP-Dipyridylamine and Overview on Selected Metal-Adenosine Triphosphate Structures in Model Compounds and in Enzymes

The X-ray diffraction (XRD) structures for new isoforms of [M(H2O)6]·[M(HATP)2]·2(HDPA)·xH2O, ATP = adenosine 5’-triphosphate, DPA = 2,2’-dipyridylamine, M = Mg(II), x = 6H2O, 1, M = Ca(II), x = 8H2O, 2 were determined by using rotating anode on molybdenum target X-ray source and Kappa CCD with confocal focusing mirror. The accuracy of the presently refined structure for 1 is the highest reported so far based on agreement factors (R1 = 0.0579) and estimated standard deviations (esds) on geometrical parameters. The comparative analysis was extended to the structures of other low molecular weight metal-triphosphate complexes, to the structures of metal-triphosphate-protein systems as well as to computed models of metal-triphosphate complexes. The structures of 1 and 2 reported in this work show that on changing the number of co-crystallized water molecules, the interaction of the metal to the phosphate chain (for 1) and the conformation of ribose (for 2) undergo subtle but significant changes. Interestingly, the vast majority of Mg-nucleoside triphosphate (NTP)-enzyme systems have similar pattern of coordination to the phosphate chain when compared to 1 and 2. The three phosphate groups have variable M-O bond distances, depending on the systems. The structures for 1 and 2 have a high significance as general model compounds for experimental solid state and computations for these types of biological systems

Downregulation of the Vitamin D Receptor Regulated Gene Set in the Hippocampus After MDMA Treatment

The active ingredient of ecstasy, ±3,4-methylenedioxymethamphetamine (MDMA), in addition to its initial reinforcing effects, induces selective and non-selective brain damage. Evidences suggest that the hippocampus (HC), a central region for cognition, may be especially vulnerable to impairments on the long-run, nevertheless, transcription factors that may precede and regulate such chronic changes remained uninvestigated in this region. In the current study, we used gene-set enrichment analysis (GSEA) to reveal possible transcription factor candidates responsible for enhanced vulnerability of HC after MDMA administration. Dark Agouti rats were intraperitoneally injected with saline or 15 mg/kg MDMA. Three weeks later HC gene expression was measured by Illumina whole-genome beadarrays and GSEA was performed with MSigDB transcription factor sets. The number of significantly altered genes on the genome level (significance < 0.001) in up/downregulated sets was also counted. MDMA upregulated one, and downregulated 13 gene sets in the HC of rats, compared to controls, including Pax4, Pitx2, FoxJ2, FoxO1, Oct1, Sp3, AP3, FoxO4, and vitamin D receptor (VDR)-regulated sets (q-value <0.05). VDR-regulated set contained the second highest number of significantly altered genes, including among others, Camk2n2, Gria3, and Grin2a. Most identified transcription factors are implicated in the response to ischemia confirming that serious hypoxia/ischemia occurs in the HC after MDMA administration, which may contribute to the selective vulnerability of this brain region. Moreover, our results also raise the possibility that vitamin D supplementation, in addition to the commonly used antioxidants, could be a potential alternative method to attenuate MDMA-induced chronic hippocampal impairments

Chemical characterization and antioxidant properties of products and by‐products from Olea europaea L.

The products and by-products of Olea europaea L.: olive fruits (primary agricultural product), oils (primary agro-industrial product), pomaces (agro-industrial processing by-product), and leaves (agricultural practices by-product), are promising sources of bioactive compounds. In the present study, qualitative and quantitative analyses of selected bioactive components in olive fruits, oils, and pomaces were performed. Total polyphenol content and antioxidant activity were analyzed in all samples (humid pomaces 2015: TPP, 26.0 ± 1.5–43.7 ± 3.0 g(GAEq)/kg DW; TEAC/ABTS, 189.5 ± 3.7–388.1 ± 12.0 mmol(Trx)kg DW). Radical (DPPH) quenching potential was analyzed via photometric and EPR methods, obtaining Vis/EPR signal ratio by 1.05 ± 0.45 and 1.66 ± 0.39 for fruits and pomaces, respectively. Through HPLC-UV and HPLC-MS/MS techniques, oleuropein and hydroxytyrosol, as well as selected hydroxycinnamic acids and flavonoids, were identified and quantified in olive fruits and pomaces. The main components were rutin, luteolin, and chlorogenic acid. Cytotoxic assay on fibroblast cells revealed toxic effects for selected extracts at highest tested concentrations (5%)

Chronic venlafaxine treatment fails to alter the levels of galanin system transcripts in normal rats

It is widely accepted that efficacy and speed of current antidepressants' therapeutic effect are far from optimal. Thus, there is a need for the development of antidepressants with new mechanisms of action. The neuropeptide galanin and its receptors (GalR1, GalR2 and GalR3) are among the promising targets. However, it is not clear whether or not the galanin system is involved in the antidepressant effect exerted by the currently much used inhibitors of the reuptake of serotonin and/or noradrenaline. To answer this question we administered the selective serotonin and noradrenaline reuptake inhibitor (SNRI) venlafaxine (40mg/kg/day via osmotic minipumps) to normal rats and examined the levels of the transcripts for galanin and GalR1-3 after a 3-week venlafaxine treatment in the dorsal raphe, hippocampus and frontal cortex. These areas are known to be involved in the effects of antidepressants and in depression itself. Venlafaxine failed to alter the expression of any of the galanin system genes in these areas. Our results show that one of the most efficient, currently used SNRIs does not alter transcript levels of galanin or its three receptors in normal rats. These findings suggest that the pro- and antidepressive-like effects of galanin reported in animal experiments may employ a novel mechanism(s)

Genes Linking Mitochondrial Function, Cognitive Impairment and Depression are Associated with Endophenotypes Serving Precision Medicine

Mitochondria densely populate cells in central nervous system providing essential energy for neurons and influencing synaptic plasticity. Harm to these organelles can impair cognitive performance through damaged neurotransmission and altered Ca2+ homeostasis. Impaired cognition could be one underlying factor which can characterize major depressive disorder, a huge burden for society marked by depressed mood and anhedonia. A growing body of evidence binds mitochondrial dysfunctions with the disease. Cognitive disturbances with different severity are also observable in several patients, suggesting that damage or inherited alterations of mitochondria may have an important role in depression. Since several different biological and environmental factors can lead to depression, mitochondrial changes may represent a significant subgroup of depressive patients although cognitive correlates can remain undiscovered without a specific focus. Hypothesis driven studies instead of GWAS can pinpoint targets relevant only in a subset of depressed population. This review highlights results mainly from candidate gene studies on nuclear DNA of mitochondrion-related proteins, including TOMM40, MTHFD1L, ATP6V1B2 and MAO genes, also implicated in Alzheimer's disease, and alterations in the mitochondrial genome to argue for endophenotypes where impaired mitochondrial function may be the leading cause for depressive symptomatology and parallel cognitive dysfunction

Ruthenium complexes as nitric oxide donors and scavengers. Synthesis and crystal and molecular structure for mer,trans-[RuIICl3(NO+)(N-4-ethylisonicotinate)2], and mer,trans-[RuIIICl3(N-CH3CN)(N-4-ethylisonicotinate)2] as obtained via UV-photochemical activation of {RuII(NO+)}3+-core parent complex in acetonitrile solution

The synthesis of mer,trans-[(RuCl3)-Cl-II(NO+)(EINT)(2)](EINT = N-4-ethylisonicotinate), 1, was achieved by carefully working under ultrapure nitrogen atmosphere, by mixing (RuCl3)-Cl-III(NO)center dot H2O and EINT (1:2 M ratio in anhydrous ethanol) under stirring and at reflux conditions. Single crystals of 1 suitable for X-ray diffraction XRD techniques were also obtained by slow evaporation of solvent under nitrogen from the mother alcoholic solution. The IR spectrum of the solid (KBr matrixes) showed the characteristic sharp and intense band (1866 cm(-1)) relevant to the N-O stretching vibration for the nitrosyl ligand (Ru-II-NO+ core). Then, on irradiating at 25 degrees C a solution of 1 in ultrapure acetonitrile (contained in quartz cuvette) under an UV source (250 throughout 366 nm) a color turning from pink to yellow occurred. After a prolonged irradiation (250 nm for at least 6 h) the cuvette (yellow solution) was stored in a dry nitrogen atmosphere and allowed to slowly concentrate via spontaneous solvent evaporation. The solution produced brown crystals as parallelepipeds, suitable for XRD data collection, that belong to the monoclinic system, C2/c space group, and the molecular structure (mer,trans-[(RuCl3)-Cl-II(N-NCCH3)(EINT)(2)], 2) consists of complex molecules that are mostly paired via stacking interactions that involve the pyridine moiety and through (ethyl)CH3 center dot center dot center dot Cl(Ru), (pyridine)CH center dot center dot center dot Cl(Ru) and (ethyl)CH3 center dot center dot center dot O(=C) hydrogen bond type interactions. The crystals of the parent nitrosyl complex belong to the orthorhombic Pccn space group and the complex molecule has three chlorido ligands in the equatorial positions and two EINT ligands in the axial positions. The nitrosyl ligand occupy two positions that are trans to each other and have half occupancy each

Biomimetic metal phenolates

The chapter reports on recent studies of metal complexes that have the phenolate group as a ligand. The synthesis and characterization of many low molecular weight complexes is reviewed and commented on. Special attention is devoted to biomimetic models, for a deeper understanding of metalloprotein structures and functions. The chapter is divided into two parts, related to oxidant and antioxidant activities and to the hydrolysis of phospatediesters, respectively

Study of binary and ternary metal complexes containing the sulfato ligand: Molecular models for selected non-catalytic sites in sulfurylase

[CdII(μ2-O2,Oâ\u80², Oâ\u80³-SO4)(terpy)]2·2H2O, 1·2H2O (terpy, 2,2â\u80²:6â\u80²,2â\u80³-terpyridine) was obtained from the reaction of 3 CdSO4·8H2O with terpy and consists of centrosymmetric dimeric units in which the two Cd(terpy)2+ moieties are held together by two tridentate sulfato anions that act as chelators towards the two metal centres, one oxygen being tri-coordinate. This coordination mode for the sulfato ligand has never been reported before in the solid state. [ZnII(μ2-O,Oâ\u80²-SO4) (terpy)]2·2H2O, 2·2H2O, was obtained by using ZnSO4·7H2O through a procedure similar to that followed for 1·2H2O. Semi-empirical quantum mechanics and density functional structure optimisations were performed at the AM1 and Becke3LYP/(6-31 G**, S) levels. The computations reproduced well the main features of the Zn(μ2-O,Oâ\u80²-SO4)2Zn unit as found in 2. A [Zn(imidazole)2(O-OOCCH3)2 (O-SO4)]2- model was also optimised as a model for ATP-sulfurylase from Saccharomices cerevisae