Mitochondrial ATP-Mg/phosphate carriers transport divalent inorganic cations in complex with ATP

The ATP-Mg/phosphate carriers (APCs) modulate the intramitochondrial adenine nucleotide pool size. In this study the concentration-dependent effects of Mg²⁺ and other divalent cations (Me²⁺) on the transport of [³H]ATP in liposomes reconstituted with purified human and Arabidopsis APCs (hAPCs and AtAPCs, respectively, including some lacking their N-terminal domains) have been investigated. The transport of Me²⁺ mediated by these proteins was also measured. In the presence of a low external concentration of [³H]ATP (12 μM) and increasing concentrations of Me²⁺, Mg²⁺ stimulated the activity (measured as initial transport rate of [³H]ATP) of hAPCs and decreased that of AtAPCs; Fe²⁺ and Zn²⁺ stimulated markedly hAPCs and moderately AtAPCs; Ca²⁺ and Mn²⁺ markedly AtAPCs and moderately hAPCs; and Cu²⁺ decreased the activity of both hAPCs and AtAPCs. All the Me²⁺-dependent effects correlated well with the amount of ATP-Me complex present. The transport of [¹⁴C]AMP, which has a much lower ability of complexation than ATP, was not affected by the presence of the Me²⁺ tested, except Cu²⁺. Furthermore, the transport of [³H]ATP catalyzed by the ATP/ADP carrier, which is known to transport only free ATP and ADP, was inhibited by all the Me²⁺ tested in an inverse relationship with the formation of the ATP-Me complex. Finally, direct measurements of Mg²⁺, Mn²⁺, Fe²⁺, Zn²⁺ and Cu²⁺ showed that they are cotransported with ATP by both hAPCs and AtAPCs. It is likely that in vivo APCs transport free ATP and ATP-Mg complex to different degrees, and probably trace amounts of other Me²⁺ in complex with ATP.     

Interaction of tumour cells with their microenvironment: ion channels and cell adhesion molecules. A focus on pancreatic cancer

Cancer must be viewed as a ‘tissue’, constituted of both transformed cells and a heterogeneous microenvironment, the ‘tumour microenvironment’ (TME). The TME undergoes a complex remodelling during the course of multistep tumourigenesis, hence strongly contributing to tumour progression. Ion channels and transporters (ICTs), being expressed on both tumour cells and in the different cellular components of the TME, are in a strategic position to sense and mediate signals arising from the TME. Often, this transmission is mediated by integrin adhesion receptors, which are the main cellular receptors capable of mediating cell-to-cell and cell-to-matrix bidirectional signalling. Integrins can often operate in conjunction with ICT because they can behave as functional partners of ICT proteins. The role of integrin receptors in the crosstalk between tumour cells and the TME is particularly relevant in the context of pancreatic cancer (PC), characterized by an overwhelming TME which actively contributes to therapy resistance. We discuss the possibility that this occurs through integrins and ICTs, which could be exploited as targets to overcome chemoresistance in PC.     

The identification of structurally novel,selective, orally bioavailable positive modulators of mGluR2

The optimisation of an HTS hit series (1) leading to the identification of structurally novel, selective, orally bioavailable mGluR2 positive modulators GSK1331258 and GSK1331268 is described. Structure–activity relationships, attenuation of dopaminergic activity, and potentiation of mGluR2 responses in rat hippocampal MPP-DG synapses are also reported.     

Cisplatin and its dibromido analogue: a comparison of chemical and biological profiles

The dibromido analogue of cisplatin, cis-PtBr₂(NH₃)₂ (cisPtBr₂ hereafter), has been prepared and characterised. Its solution behaviour in standard phosphate buffer, at pH 7.4, was investigated spectrophotometrically and found to reproduce quite closely that of cisplatin; indeed, progressive sequential release of the two halide ligands typically occurs as in the case of cisplatin, with a roughly similar kinetics. Afterward, patterns of reactivity toward model proteins and standard ctDNA were explored and the nature of the resulting interactions elucidated. The antiproliferative properties were then evaluated in four representative cancer cell lines, namely A549 (human lung cancer), HCT116 (human colon cancer), IGROV-1 (human ovarian cancer) and FLG 29.1 (human acute myeloid leukaemia). Cytotoxic properties in line with those of cisplatin were highlighted. From these studies an overall chemical and biological profile emerges for cisPtBr₂ closely matching that of cisplatin; the few slight, but meaningful differences that were underscored might be advantageously exploited for clinical application.     

Enzymatic activity under tangential flow conditions of photochemically grafted membranes containing immobilized catalase

Catalase has been immobilized within sandwich membranes prepared by the photoinduced grafting of an epoxy-diacrylate prepolymer onto commercial asymmetric cellulose membranes. The enzymatic activity of the membrane composite of hydrogen peroxide decomposition has been studied in a recirculation apparatus under tangential flow conditions without ultrafiltration. The enzymatic membranes were exposed to very low mechanical stresses and showed a very good catalytic performance and durability. Initial reaction rates, measured at 25 degrees C as a function of both substrate concentration and enzyme amount immobilized per unit membrane surface, indicate that the mechanism of action of catalase is not altered after immobilization, although substrate diffusion through the original thin layer of membranes may become rate controlling. (c) 1993 John Wiley & Sons, Inc.     

Aphyllophorales della Pineta di is Arenas (Oristano)

Abstract

L'autore riferisce sui primi ritrovamenti di Aphyllophorales ad Is Arenas, pineta litoranea che si estende sulla costa occidentale della Sardegna, in provincia di Oristano. Le specie segnalate sono 48 e tra queste: Crustoderma dryinum (Berk. & Curt.) Parm., Hyphoderma malençonii (Manjón & Moreno) Manjón, Moreno & Hjortstam, Peniophora tamaricicola Boid. & Malençon, Phanerochaete magnoliae (Berk. & Curt.) Burds., Thanatephorus cucumeris (A.B. Frank) Donk, sono risultate nuove per la micoflora italiana.     

Deregulated Sphingolipid Metabolism and Membrane Organization in Neurodegenerative Disorders

Sphingolipids are polar membrane lipids present as minor components in eukaryotic cell membranes. Sphingolipids are highly enriched in nervous cells, where they exert important biological functions. They deeply affect the structural and geometrical properties and the lateral order of cellular membranes, modulate the function of several membrane-associated proteins, and give rise to important intra- and extracellular lipid mediators. Sphingolipid metabolism is regulated along the differentiation and development of the nervous system, and the expression of a peculiar spatially and temporarily regulated sphingolipid pattern is essential for the maintenance of the functional integrity of the nervous system: sphingolipids in the nervous system participate to several signaling pathways controlling neuronal survival, migration, and differentiation, responsiveness to trophic factors, synaptic stability and synaptic transmission, and neuron–glia interactions, including the formation and stability of central and peripheral myelin. In several neurodegenerative diseases, sphingolipid metabolism is deeply deregulated, leading to the expression of abnormal sphingolipid patterns and altered membrane organization that participate to several events related to the pathogenesis of these diseases. The most impressive consequence of this deregulation is represented by anomalous sphingolipid–protein interactions that are at least, in part, responsible for the misfolding events that cause the fibrillogenic and amyloidogenic processing of disease-specific protein isoforms, such as amyloid β peptide in Alzheimer’s disease, huntingtin in Huntington’s disease, α-synuclein in Parkinson’s disease, and prions in transmissible encephalopathies. Targeting sphingolipid metabolism represents today an underexploited but realistic opportunity to design novel therapeutic strategies for the intervention in these diseases.     

Single‐Step Preparation of Large Area TiO2 Photoelectrodes for Water Splitting

The fast, single‐step and easily scalable production by plasma electrolytic oxidation (PEO) of large area TiO₂ electrodes with excellent photoactivity in water splitting under simulated solar light is systematically investigated here. In particular, the effects that the cell voltage (100–180 V) and the processing time (0.5–15 min) have on the electrode properties are studied. The PEO‐produced oxide layers are porous, the predominant crystalline structure shifting from anatase, to an anatase‐rutile mixture, and finally to rutile by rising the cell voltage. The electrodes show a double‐layered structure, with a more compact layer at the interface with the titanium substrate and a thick porous layer on the external surface. The photocurrent density versus wavelength reflects the phase composition, with a maximum incident photon‐to‐current efficiency of 90% at 320 nm. The highest H₂ production rate is attained with the mixed anatase‐rutile electrode prepared by 300 s‐long PEO at 150 V.