Algerian Propolis from Distinct Geographical Locations: Chemical Profiles, Antioxidant Capacity, Cytotoxicity and Inhibition of 5-Lipoxygenase Product Biosynthesis.

Propolis was collected from honeybee hives in three geographically distinct Algerian climates and extracts were characterized for composition and bioactivity. Bees were identified as native subspecies using an in-silico DraI mtDNA COI-COII test. Over 20 compounds were identified in extracts by LC-MS. Extracts from the Medea region were more enriched in phenolic content (302±28 mg GAE/g of dry extract) than those from Annaba and Ghardaia regions. Annaba extracts had the highest flavonoid content (1870±385 mg QCE/g of dry extract). Medea extracts presented the highest free-radical scavenging activity (IC50=13.5 µg/mL) using the DPPH radical assay while Ghardaia extracts from the desert region were weak (IC50>100 µg/mL). Antioxidant activities measured using AAPH oxidation of linoleic acid were similar in all extracts with IC50 values ranging from 2.9 to 4.9 µg/mL. All extracts were cytotoxic (MTT assay) and proapoptotic (Annexin-V) against human leukemia cell lines in the low µg/mL range, although the Annaba extract was less active against the Reh cell line. Extracts inhibited cellular 5-lipoxygenase product biosynthesis with IC50 values ranging from 0.6 to 3.2 µg/mL. Overall, examined propolis extracts exhibited significant biological activity that warrant further characterization in cellular and in vivo models.

Time-dependent metabolome and fatty acid profile changes following a high-fat diet exposure in Drosophila melanogaster.

High-fat diets (HFDs) are often used to study metabolic disorders using different animal models. However, the underlying cellular mechanisms pertaining to the concurrent loss of metabolic homeostasis characteristics of these disorders are still unclear mainly because the effects of such diets are also dependent on the time frame of the experiments. Here, we used the fruit fly, Drosophila melanogaster, to investigate the metabolic dynamic effects following 0, 2, 4, 7 and 9 days of an exposure to a HFD (standard diet supplemented with 20% w/v coconut oil, rich in 12:0 and 14:0) by combining NMR metabolomics and GC-FID fatty acid profiling. Our results show that after 2 days, the ingested 12:0 and 14:0 fatty acids are used for both lipogenesis and fatty acid oxidation. After 4 days, metabolites from several different pathways are highly modulated in response to the HFD, and an accumulation of 12:0 is also observed, suggesting that the balance of lipid, amino acid and carbohydrate metabolism is profoundly perturbed at this specific time point. Following a longer exposure to the HFD (and notably after 9 days), an accumulation of many metabolites is observed indicating a clear dysfunction of the metabolic system. Overall, our study highlights the relevance of the Drosophila model to study metabolic disorders and the importance of the duration of the exposure to a HFD to study the dynamics of the fundamental mechanisms that control metabolism following exposure to dietary fats. This knowledge is crucial to understand the development and progression of metabolic diseases.

New Zileuton-Hydroxycinnamic Acid Hybrids: Synthesis and Structure-Activity Relationship towards 5-Lipoxygenase Inhibition.

A novel series of zileuton-hydroxycinnamic acid hybrids were synthesized and screened as 5-lipoxygenase (5-LO) inhibitors in stimulated HEK293 cells and polymorphonuclear leukocytes (PMNL). Zileuton's (1) benzo[b]thiophene and hydroxyurea subunits combined with hydroxycinnamic acid esters' ester linkage and phenolic acid moieties were investigated. Compound 28, bearing zileuton's (1) benzo[b]thiophene and sinapic acid phenethyl ester's (2) α,ß-unsaturated phenolic acid moiety 28, was shown to be equipotent to zileuton (1), the only clinically approved 5-LO inhibitor, in stimulated HEK293 cells. Compound 28 was three times as active as zileuton (1) for the inhibition of 5-LO in PMNL. Compound 37, bearing the same sinapic acid (3,5-dimethoxy-4-hydroxy substitution) moiety as 28, combined with zileuton's (1) hydroxyurea subunit was inactive. This result shows that the zileuton's (1) benzo[b]thiophene moiety is essential for the inhibition of 5-LO product biosynthesis with our hydrids. Unlike zileuton (1), Compound 28 formed two π-π interactions with Phe177 and Phe421 as predicted when docked into 5-LO. Compound 28 was the only docked ligand that showed a π-π interaction with Phe177 which may play a part in product specificity as reported.

First synthesis of "Majoral-Type" glycodendrimers bearing covalently bound alpha-D-mannopyranoside residues onto a hexachlocyclotriphosphazene core.

A short and efficient strategy for the first synthesis of "Majoral-Type" multivalent glycodendrimers bearing covalently bound alpha-D-mannopyranosides onto a cyclotriphosphazene scaffold assembled using single-step Sonogashira and click chemistry is reported. New glycoclusters with valencies ranging from 6 to 18 and different epitope spatial arrangements were obtained. Cross-linking abilities of this series of glycodendrimers were evaluated with the model lectin from Canavalia ensiformis (Concanavalin A). The decameric mannoside 23, built around 19, was shown to be much faster in cross-linking the tetravalent lectin Concanavalin A than the positive control, which is the polysaccharide mannan from yeast. The new glycoconjugates reported may be promising tools as probes or effectors of biological processes involving multivalent carbohydrate-binding proteins.