The Angiogenic Balance and Its Implications in Cancer and Cardiovascular Diseases: An Overview.

Angiogenesis is the process of developing new blood vessels from pre-existing ones. This review summarizes the main features of physiological and pathological angiogenesis and those of angiogenesis activation and inhibition. In healthy adults, angiogenesis is absent apart from its involvement in female reproductive functions and tissue regeneration. Angiogenesis is a complex process regulated by the action of specific activators and inhibitors. In certain diseases, modulating the angiogenic balance can be a therapeutic route, either by inhibiting angiogenesis (for example in the case of tumor angiogenesis), or by trying to activate the process of new blood vessels formation, which is the goal in case of cardiac or peripheral ischemia.

Pathways in the synthesis of functionalized glycolipids for liposomal preparations.

We describe in this paper the synthesis of two glycolipids containing a mannosyl residue functionalized with malonic acid and azide groups at the C6 position. Two synthetic routes have been successfully implemented: the first one involves Schmidt's glycosylation procedure using functionalized carbohydrates, whereas the second one involves nucleophilic substitutions in the C6 position of an iodinated intermediate obtained using Koenigs-Knorr reaction. A comparative discussion of reactions and yields is realized. The two glycolipids served as material for the preparation of liposomes.

Polyphenolic-protein-polysaccharide ternary conjugates from Cystoseira barbata Tunisian seaweed as potential biopreservatives: Chemical, antioxidant and antimicrobial properties.

The present study investigated the antioxidant and antimicrobial activities of naturally occurring Cystoseira barbata seaweed glyco-conjugates (CBGs), with a view to developing safer food preservatives. CBGs were successfully isolated, then chemically and structurally characterized. CBGs contained a high amount of polysaccharides (49.76%) that consisted mainly of neutral sugars (47.67%) and uronic acids (2.09%). The carbohydrate fraction was sulfated (13.81%) and conjugated with proteins (9.86%) and phenolic compounds (4.98%). Infrared spectroscopy of CBGs showed interactions between polyphenols, proteins and polysaccharides, which were characterized by α-type glycosidic bond and sulfate groups in the axial position of sugar residues. Neutral sugars analysis of CBGs by GC-MS revealed that conjugated polysaccharides were mainly composed of galactose (34.02%), fucose (26.25%) and mannitol (21.25%) with few amounts of other sugars such as glucose (5.78%), rhamnose (4.9%), xylose (3.22%) and mannose (2.22%). Analysis of the amino acid composition of CBGs showed a high level of essential amino acids (40.36%), in which threonine was the most relevant (10.28%). LC-QTOF-MS analysis of the phenolic fraction of CBGs showed a variety of phenolic compounds including flavonoids, phlorotannins and anthraquinone glycosides. CBGs exhibited potent antioxidant activities including radical scavenging activity, chelating ability and reducing power, and displayed noticeable antibacterial and antifungal activities, which may open the way to the development of a natural biopreservation strategy based on algae.

New mannose derivatives: The tetrazole analogue of mannose-6-phosphate as angiogenesis inhibitor.

Two novel compounds with mannose-derived structure, bearing a tetrazole (compound 3) and a sulfone group (compound 4) in terminal position, have been prepared from methyl α-d-mannopyranoside in reduced number of steps. The angiogenic activity of 3 and 4 has been screened using the chick chorioallantoic membrane (CAM) method. Tetrazole 3 has been identified to possess a promising bioactivity, being identified as angiogenesis inhibitor, with 68% of neovascular vessels when compared to control (PBS).

Some physicochemical characteristics of pinus (Pinus halepensis Mill., Pinus pinea L., Pinus pinaster and Pinus canariensis) seeds from North Algeria, their lipid profiles and volatile contents.

Physicochemical characteristics of seeds of some pinus species (Pinus halepensis Mill., Pinus pinea L., Pinus pinaster and Pinus canariensis) grown in North Algeria were determined. The results showed that the seeds consist of 19.8-36.7% oil, 14.25-26.62% protein, 7.8-8.6% moisture. Phosphorus, potassium and magnesium were the predominant elements present in seeds. Pinus seed's oil physicochemical properties show acid values (4.9-68.9), iodine values (93.3-160.4) and saponification values (65.9-117.9). Oil analysis showed that the major unsaturated fatty acids for the four species were linoleic acid (30-59%) and oleic acid (17.4-34.6%), while the main saturated fatty acid was palmitic acid (5-29%). Gas Chromatography and Mass Spectrometry analysis of P. halepensis Mill., P. pinaster and P. canariensis volatile oils indicated that the major volatile compound was the limonene with relative percentage of 3.1, 7.5 and 10.8, respectively.

Fucans from a Tunisian brown seaweed Cystoseira barbata: structural characteristics and antioxidant activity.

Sulfated polysaccharides from brown seaweeds are known to be a topic of numerous studies, due to their beneficial biological properties including antioxidant activity. Fucans were isolated from the brown seaweed Cystoseira barbata harvested in Tunisia. ATR-FTIR and (1)H-NMR spectroscopies demonstrated that C. barbata sulfated polysaccharides (CBSPs) consisted mainly of 3-linked-α-l-fucopyranosyl backbone, acetylated and mostly sulfated at C-4. Molar degrees of sulfation and acetylation of CBSPs were 0.79 and 0.27, respectively. Neutral sugars analysis determined by gas chromatography-mass spectrometry (GC-MS) showed that CBSPs were mainly composed of fucose (44.6%) and galactose (34.32%) with few amounts of other sugars such as glucose (7.55%), rhamnose (6.41%), xylose (4.21%) and mannose (2.91%). CBSPs were examined for in vitro antioxidant properties using various antioxidant assays. CBSPs exhibited important DPPH radical-scavenging activity (100% inhibition at a concentration of 1.5mg/ml) and considerable ferric reducing potential (24.62 mg ascorbic acid equivalents). Effective chelating activity and significant protection activity against hydroxyl radical induced DNA breakage were also recorded for CBSPs. However, in the linoleate-ß-carotene system, CBSPs exerted moderate antioxidant activity (62% inhibition at a concentration of 1.5mg/ml). Therefore, CBSPs can be used as a potent natural antioxidant in food industry or in the pharmaceutical field.

Gold nanoparticles decorated with mannose-6-phosphate analogues.

Herein, the preparation of neoglycoconjugates bearing mannose-6-phosphate analogues is described by: (a) synthesis of a cyclic sulfate precursor to access the carbohydrate head-group by nucleophilic displacement with an appropriate nucleophile; (b) introduction of spacers on the mannose-6-phosphate analogues via Huisgen's cycloaddition, the Julia reaction, or the thiol-ene reaction under ultrasound activation. With the resulting compounds in hand, gold nanoparticles could be functionalized with various carbohydrate derivatives (glycoconjugates) and then tested for angiogenic activity. It was observed that the length and flexibility of the spacer separating the sugar analogue from the nanoparticle have little influence on the biological response. One particular nanoparticle system substantially inhibits blood vessel growth in contrast to activation by the corresponding monomeric glycoconjugate, thereby demonstrating the importance of multivalency in angiogenic activity.

Entropy-driven lectin-recognition of multivalent glycovesicles.

Multivalent glycovesicle recognition over lectin layers emphasizes effects on the dynamic lateral fluidity of glycoside clusters upon multivalent binding at the bilayer surface and vice versa.

Water-dispersible sugar-coated iron oxide nanoparticles. An evaluation of their relaxometric and magnetic hyperthermia properties.

Synthesis of functionalized magnetic nanoparticles (NPs) for biomedical applications represents a current challenge. In this paper we present the synthesis and characterization of water-dispersible sugar-coated iron oxide NPs specifically designed as magnetic fluid hyperthermia heat mediators and negative contrast agents for magnetic resonance imaging. In particular, the influence of the inorganic core size was investigated. To this end, iron oxide NPs with average size in the range of 4-35 nm were prepared by thermal decomposition of molecular precursors and then coated with organic ligands bearing a phosphonate group on one side and rhamnose, mannose, or ribose moieties on the other side. In this way a strong anchorage of the organic ligand on the inorganic surface was simply realized by ligand exchange, due to covalent bonding between the Fe(3+) atom and the phosphonate group. These synthesized nanoobjects can be fully dispersed in water forming colloids that are stable over very long periods. Mannose, ribose, and rhamnose were chosen to test the versatility of the method and also because these carbohydrates, in particular rhamnose, which is a substrate of skin lectin, confer targeting properties to the nanosystems. The magnetic, hyperthermal, and relaxometric properties of all the synthesized samples were investigated. Iron oxide NPs of ca. 16-18 nm were found to represent an efficient bifunctional targeting system for theranostic applications, as they have very good transverse relaxivity (three times larger than the best currently available commercial products) and large heat release upon application of radio frequency (RF) electromagnetic radiation with amplitude and frequency close to the human tolerance limit. The results have been rationalized on the basis of the magnetic properties of the investigated samples.

Water-soluble rhamnose-coated Fe3O4 nanoparticles.

Water-soluble biocompatible rhamnose-coated Fe(3)O(4) nanoparticles of 4.0 nm are obtained by covalent anchorage of rhamnose on the nanoparticles surface via a phosphate linker. These nanoparticles present superparamagnetic behavior and nuclear relaxivities in the same order of magnitude as Endorem that make them potential magnetic resonance imaging (MRI) contrast agents of a second generation, where the saccharides represent also specific ligands able to target lectins on skin cells.

Carbonic anhydrase inhibitor coated gold nanoparticles selectively inhibit the tumor-associated isoform IX over the cytosolic isozymes I and II.

An approach for the synthesis of carbonic anhydrase (CA, EC 4.2.1.1) inhibitor coated gold nanoparticles is reported. This nanomaterial selectively inhibited the tumor-associated isoform CA IX overexpressed in hypoxic cancers over the ubiquitous, cytosolic housekeeping isozymes CA I and II and was membrane impermeant. As CA IX has an extracellular active site, the new nanomaterial which is confined to the extracellular space may be useful for imaging and treatment of hypoxic tumors.

Carbonic anhydrase inhibitors: 2-substituted-1,3,4-thiadiazole-5-sulfamides act as powerful and selective inhibitors of the mitochondrial isozymes VA and VB over the cytosolic and membrane-associated carbonic anhydrases I, II and IV.

A series of 2-substituted-1,3,4-thiadiazole-5-sulfamides was prepared and assayed as inhibitors of several carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic CA I and II, the membrane-associated CA IV and the mitochondrial CA VA and VB. The new compounds showed weak inhibitory activity against hCA I (K(I)s of 102 nM-7.42 microM), hCA II (K(I)s of 0.54-7.42 microM) and hCA IV (K(I)s of 4.32-10.05 microM) but were low nanomolar inhibitors of hCA VA and hCA VB, with inhibition constants in the range of 4.2-32 nM and 1.3-74 nM, respectively. Furthermore, the selectivity ratios for inhibiting the mitochondrial enzymes over CA II were in the range of 67.5-415, making these sulfamides the first selective CA VA/VB inhibitors.

Synthesis and biological activity of M6-P and M6-P analogs on fibroblast and keratinocyte proliferation.

A new synthetic route to obtain the carboxylate analog of mannose 6-phosphate (M6-P) is presented. The effects of the M6-P, the carboxylate and two other analogs (the phosphonate and the alpha,beta ethylenic carboxylate) on the proliferation of human keratinocytes and dermal fibroblasts as well as on the proliferation of a murine fibroblast cell line, 3T3-J2 are tested. We observed that M6-P is a potent inhibitor of proliferation of both fibroblasts and keratinocytes. Among its analogs, the phosphonate showed a similar effect on human dermal fibroblasts but not on keratinocytes.

Synthesis and properties of isocannabinoid and cholesterol derivatized rhamnosurfactants: application to liposomal targeting of keratinocytes and skin.

The usefulness of vesicles to cargo material depends on the design of new ligands able to incorporate easily inside the bilayer and also to direct the vesicles to the targeted site. Therefore, the synthesis of two new rhamnose-bearing surfactants is described. The hydrophobic part consists of cholesterol (in compound 3) and citrylidene phloroglucinol (in compound 6). The ability of these two rhamnolipids to incorporate into a DPPC membrane and to form aggregates is investigated, respectively, by differential scanning calorimetry and by surface tension measurements. Those two new surfactants were incorporated in fluorescent liposomes to study their interactions with keratinocytes and skin sections. Intraliposomal delivery to keratinocytes was observed in both cases, even if the kinetics of delivery were different according to the rhamnosurfactant used. Skin sections were stained by both liposomal formulations, and different interactions between the liposomes and skin cells according to the surfactant used were noted.