(De)stabilization of Alpha-Synuclein Fibrillary Aggregation by Charged and Uncharged Surfactants

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. An important hallmark of PD involves the pathological aggregation of proteins in structures known as Lewy bodies. The major component of these proteinaceous inclusions is alpha (α)-synuclein. In different conditions, α-synuclein can assume conformations rich in either α-helix or β-sheets. The mechanisms of α-synuclein misfolding, aggregation, and fibrillation remain unknown, but it is thought that β-sheet conformation of α-synuclein is responsible for its associated toxic mechanisms. To gain fundamental insights into the process of α-synuclein misfolding and aggregation, the secondary structure of this protein in the presence of charged and non-charged surfactant solutions was characterized. The selected surfactants were (anionic) sodium dodecyl sulphate (SDS), (cationic) cetyltrimethylammonium chloride (CTAC), and (uncharged) octyl β-D-glucopyranoside (OG). The effect of surfactants in α-synuclein misfolding was assessed by ultra-structural analyses, in vitro aggregation assays, and secondary structure analyses. The α-synuclein aggregation in the presence of negatively charged SDS suggests that SDS-monomer complexes stimulate the aggregation process. A reduction in the electrostatic repulsion between N- and C-terminal and in the hydrophobic interactions between the NAC (non-amyloid beta component) region and the C-terminal seems to be important to undergo aggregation. Fourier transform infrared spectroscopy (FTIR) measurements show that β-sheet structures comprise the assembly of the fibrils.     

The geology and mineralogy of a range of kaolins from the Santa Cruz and Chubut Provinces, Patagonia (Argentina)

In the Santa Cruz and Chubut provinces, Patagonia, Argentina, kaolin deposits were formed by “in situ” alteration of volcaniclastic rocks, such as the Bajo Grande, Chon Aike or Marifil Formations, or by erosion, transportation, and deposition of residual clays in small basins. This paper describes the genesis; geology; mineralogy; major, minor, and trace element geochemistry; grain size distribution; and specific surface area of natural and washed kaolins in an attempt to understand their behavior in the ceramic process. The sedimentary clays of the Baqueró Fm Lower Member, related to the Bajo Grande basement, are kaolinitic–smectitic, very fine-grained, and with a very high specific surface area. The clays related to the Chon Aike or Marifil Fms are kaolinitic, showing intermediate values of specific surface area and a coarser particle size distribution, associated with quite a fine-grained texture. The Baqueró Fm Upper Member received a considerable pyroclastic supply, fostering the development of a fine-grained clay in which kaolinite (± halloysite) with higher values of kaolinite crystal order prevailed. Primary kaolins – derived from weathering of pyroclastic sequences of Chon Aike and Marifil Fms – are coarse-grained, composed of kaolinite + quartz ± halloysite and exhibit a very low specific surface area. Alteration of mostly crystalline pyroclastics yielded ordered kaolinite and illite (+ halloysite) with a fine particle size distribution and intermediate values of specific surface area. Alteration of mainly vitreous pyroclastics produced halloysite (+ kaolinite) with a fine-grained texture and moderately high values of specific surface area. A supergene origin of primary kaolins is inferred on the basis of palaeoclimatic and geochemical evidence that corroborates stable isotopic data. The mineralogy, grain size, and textural characteristics of clays are controlled by parent rock composition (primary kaolins) or by provenance and proximity to source areas (sedimentary kaolins).     

Modulatory Effects of Polyphenols on Apoptosis Induction: Relevance for Cancer Prevention

Polyphenols, occurring in fruit and vegetables, wine, tea, extra virgin olive oil, chocolate and other cocoa products, have been demonstrated to have clear antioxidant properties in vitro, and many of their biological actions have been attributed to their intrinsic reducing capabilities. However, it has become clear that, in complex biological systems, polyphenols exhibit several additional properties which are yet poorly understood. Apoptosis is a genetically controlled and evolutionarily conserved form of cell death of critical importance for the normal embryonic development and for the maintenance of tissue homeostasis in the adult organism. The malfunction of the death machinery may play a primary role in various pathological processes, since too little or too much apoptosis can lead to proliferative or degenerative diseases, respectively. Cancer cells are characterized by a deregulated proliferation, and/or an inability to undergo programmed cell death. A large body of evidence indicates that polyphenols can exert chemopreventive effects towards different organ specific cancers, affecting the overall process of carcinogenesis by several mechanisms: inhibition of DNA synthesis, modulation of ROS production, regulation of cell cycle arrest, modulation of survival/proliferation pathways. In addition, polyphenols can directly influence different points of the apoptotic process, and/or the expression of regulatory proteins. Although the bulk of data has been obtained in in vitro systems, a number of clinical studies suggesting a preventive and therapeutic effectiveness of polyphenols in vivo is available. However, a deeper knowledge of the underlying mechanisms responsible for the modulation of apoptosis by polyphenols, and their real effectiveness, is necessary in order to propose them as potential chemopreventive and chemotherapeutic candidates for cancer treatment.     

A potent integrin antagonist from a small library of cyclic RGD pentapeptide mimics including benzyl-substituted azabicycloalkane amino acids

A small library of cyclic RGD pentapeptide mimics, including benzyl-substituted azabicycloalkane amino acids, was synthesized with the aim of developing active and selective integrin antagonists. In vitro binding assays established one particular compound with affinity for both the alpha(v)beta(3) and the alpha(v)beta(5) integrins. The synthesis in solution and the in vitro screening of these RGD derivatives, as well as the determination of the conformational properties of the integrin ligands by spectroscopic and computational methods are described.     

Peptide-containing aggregates as selective nanocarriers for therapeutics

New nanocarriers are obtained by assembling two amphiphilic monomers: one containing the bioactive peptide CCK8 spaced, by a polydisperse poly(ethylene glycol), from two hydrophobic tails ((C18)2PEG2000CCK8), and the other containing a chelating agent able to give stable radiolabeled indium-111 complexes linked to the same hydrophobic moiety ((C18)2DTPAGlu). The size and shape of the supramolecular aggregates were structurally characterized by dynamic light scattering, small-angle neutron scattering, and cryogenic transmission electronic microscopy. Under the experimental conditions we investigated (pH 7.4 and molar ratio between monomers 30:70), there is the presence of high polydisperse aggregates: rod-like micelles with a radius of approximately 40 A and length >700 A, open bilayer fragments with thickness approximately 65 A, and probably vesicles. The presence of the bioactive peptide well exposed on the external surface of the aggregate allows selective targeting of nanocarriers towards the cholecystokinin receptors overexpressed by the cancerous cells. In vitro binding assays and in vivo biodistribution studies by nuclear medicine experiments using indium-111 are reported. Moreover, preliminary data concerning the drug loading capability of the aggregates and their drug efficiency on the target cells is reported by using the cytotoxic drug doxorubicin. Incubation of receptor-positive and control cells with peptide-containing aggregates filled with doxorubicin shows significantly lower cell survival in receptor-expressing cells relative to the control, for samples incubated in the presence of doxorubicin.     

LLDPE with Exclusively Ethyl Branches by Tandem Catalysis with Single-Site Zr(IV)/Co(II) Catalysts

Semicrystalline linear low density polyethylenes (LLDPEs) with exclusively ethyl branching (from 7 to 56 branches per 1,000 carbon atoms) were prepared from ethylene by homogeneous tandem catalytic systems comprising (imino)pyridine cobalt(II) dichlorides as oligomerization precursors, bis(cyclopentadienyl)zirconium(IV) dichloride as copolymerization precursor and methyaluminoxane as activator. The activity of the tandem systems was evaluated by varying either the molar fraction of the cobalt precursors or the ethylene pressure. The latter parameter was of crucial importance to control both the productivity and the extent of 1-butene incorporation. In particular, increasing the ethylene pressure from 2 bar to 4 bar changed the “comonomer effect” from positive to negative.     

Remarkable Efficiency Improvement in the Preparation of Insoluble Polymer‐Bound (IPB) Enantioselective Catalytic Systems by the Use of Silicone Chemistry

The use of platinum‐catalyzed hydrosilylation chemistry of silicones greatly simplifies the preparation of bis‐oxazoline (box) ligands covalently bound to an insoluble polymeric support. The use of such immobilized chiral ligands in different copper‐catalyzed asymmetric transformations (carbonyl‐ene, Mukaiyama aldol and olefin cyclopropanation reactions) allows the attainment of high levels of enantioselectivity (91–99 % ee).     

Caffeic Acid Enhances the Anti-Leukemic Effect of Imatinib on Chronic Myeloid Leukemia Cells and Triggers Apoptosis in Cells Sensitive and Resistant to Imatinib

Among the phenolic acids tested on the K562 cell line, a model of chronic myeloid leukemia (CML), caffeic acid (CA) was biologically active on sensitive and imatinib (IM)-resistant cells at micro-molar concentration, either in terms of reduction of cell proliferation or triggering of apoptosis. The CA treatment provoked mitochondrial membrane depolarization, genomic DNA fragmentation and phosphatidylserine exposure, hallmarks of apoptosis. Cell cycle analysis following the treatment with comparable cytotoxic concentrations of IM or CA showed marked differences in the distribution profiles. The reduction of cell proliferation by CA administration was associated with increased expression of two cell cycle repressor genes, CDKN1A and CHES1, while IM at a cytotoxic concentration increased the CHES1 but not the CDKN1A expression. In addition, CA treatment affected the proliferation and triggered the apoptosis in IM-resistant cells. Taken together, these data suggested that CA induced the anti-proliferative effect and triggered apoptosis of CML cells by a different mechanism than IM. Finally, the combined administration of IM and CA at suboptimal concentrations evidenced a synergy of action in determining the anti-proliferative effect and triggering apoptosis. The ability of CA to potentiate the anti-leukemic effect of IM highlighted the nutraceutical potential of CA in CML.