Antifungal Activity of Guiera senegalensis: From the Chemical Composition to the Mitochondrial Toxic Effects and Tyrosinase Inhibition.

Pest resistance against fungicides is a widespread and increasing problem, with impact on crop production and public health, making the development of new fungicides an urgent need. Chemical analyses of a crude methanol extract (CME) of Guiera senegalensis leaves revealed the presence of sugars, phospholipids, phytosterols, guieranone A, porphyrin-containing compounds, and phenolics. To connect chemical composition with biological effects, solid-phase extraction was used to discard water-soluble compounds with low affinity for the C18 matrix and obtain an ethyl acetate fraction (EAF) that concentrates guieranone A and chlorophylls, and a methanol fraction (MF) dominated by phenolics. While the CME and MF exhibited poor antifungal activity against Aspergillus fumigatus, Fusarium oxysporum and Colletotrichum gloeosporioides, the EAF demonstrated antifungal activity against these filamentous fungi, particularly against C. gloeosporioides. Studies with yeasts revealed that the EAF has strong effectiveness against Saccharomyces cerevisiae, Cryptococcus neoformans and Candida krusei with MICs of 8, 8 and 16 µg/mL, respectively. A combination of in vivo and in vitro studies shows that the EAF can function as a mitochondrial toxin, compromising complexes I and II activities, and as a strong inhibitor of fungal tyrosinase (Ki = 14.40 ± 4.49 µg/mL). Thus, EAF appears to be a promising candidate for the development of new multi-target fungicides.

Echium plantagineum L. honey: Search of pyrrolizidine alkaloids and polyphenols, anti-inflammatory potential and cytotoxicity.

For a long time, honey has been recognized for its health-promoting properties and, consequently, has been used in traditional medicine worldwide. Apart from the beneficial bioactive compounds found in this food (e.g. polyphenols), molecules with potentially harmful effects may also be present, such as pyrrolizidine alkaloids. Aiming the quality assessment of honeys produced from Echium plantagineum L., a species known for its content in pyrrolizidine alkaloids, this work was focused in the search of these alkaloids and of polyphenols in one monofloral and two multifloral honeys, using chromatographic techniques. Additionally, their cytotoxicity and anti-inflammatory potential were assessed in cellular models. Several polyphenols were determined, but no pyrrolizidine alkaloid was detected in the analysed honey samples. Honey extracts exhibited capacity to decrease NO levels in lipopolysaccharide-stimulated murine macrophage-like cells (RAW 264.7) up to 40% at concentrations of 0.25 mg/mL. Therefore, this work highlights the health benefits of these honey samples.

Biological Evaluation of Naproxen-Dehydrodipeptide Conjugates with Self-Hydrogelation Capacity as Dual LOX/COX Inhibitors.

The use of peptide-drug conjugates is emerging as a powerful strategy for targeted drug delivery. Previously, we have found that peptides conjugated to a non-steroidal anti-inflammatory drug (NSAID), more specifically naproxen-dehydrodipeptide conjugates, readily form nanostructured fibrilar supramolecular hydrogels. These hydrogels were revealed as efficacious nano-carriers for drug delivery applications. Moreover, the incorporation of superparamagnetic iron oxide nanoparticles (SPIONs) rendered the hydrogels responsive to external magnetic fields, undergoing gel-to-solution phase transition upon remote magnetic excitation. Thus, magnetic dehydrodipeptide-based hydrogels may find interesting applications as responsive Magnetic Resonance Imaging (MRI) contrast agents and for magnetic hyperthermia-triggered drug-release applications. Supramolecular hydrogels where the hydrogelator molecule is endowed with intrinsic pharmacological properties can potentially fulfill a dual function in drug delivery systems as (passive) nanocariers for incorporated drugs and as active drugs themselves. In this present study, we investigated the pharmacological activities of a panel of naproxen-dehydrodipeptide conjugates, previously studied for their hydrogelation ability and as nanocarriers for drug-delivery applications. A focused library of dehydrodipeptides, containing N-terminal canonical amino acids (Phe, Tyr, Trp, Ala, Asp, Lys, Met) N-capped with naproxen and linked to a C-terminal dehydroaminoacid (ΔPhe, ΔAbu), were evaluated for their anti-inflammatory and anti-cancer activities, as well as for their cytotoxicity to non-cancer cells, using a variety of enzymatic and cellular assays. All compounds except one were able to significantly inhibit lipoxygenase (LOX) enzyme at a similar level to naproxen. One of the compounds 4 was able to inhibit the cyclooxygenase-2 (COX-2) to a greater extent than naproxen, without inhibiting cyclooxygenase-1 (COX-1), and therefore is a potential lead in the search for selective COX-2 inhibitors. This hydrogelator is a potential candidate for dual COX/LOX inhibition as an optimised strategy for treating inflammatory conditions.

Dehydropeptide-based plasmonic magnetogels: a supramolecular composite nanosystem for multimodal cancer therapy.

Supramolecular hydrogels are highly promising candidates as biomedical materials owing to their wide array of properties, which can be tailored and modulated. Additionally, their combination with plasmonic/magnetic nanoparticles to form plasmonic magnetogels further improves their potential in biomedical applications through the combination of complementary strategies, such as photothermia, magnetic hyperthermia, photodynamic therapy and magnetic-guided drug delivery. Here, a new dehydropeptide hydrogelator, Npx-l-Met-Z-ΔPhe-OH, was developed and combined with two different plasmonic/magnetic nanoparticle architectures, i.e., core/shell manganese ferrite/gold nanoparticles and gold-decorated manganese ferrite nanoparticles with ca. 55 nm and 45 nm sizes, respectively. The magnetogels were characterized via HR-TEM, FTIR spectroscopy, circular dichroism and rheological assays. The gels were tested as nanocarriers for a model antitumor drug, the natural compound curcumin. The incorporation of the drug in the magnetogel matrices was confirmed through fluorescence-based techniques (FRET, fluorescence anisotropy and quenching). The curcumin release profiles were studied with and without the excitation of the gold plasmon band. The transport of curcumin from the magnetogels towards biomembrane models (small unilamellar vesicles) was assessed via FRET between the fluorescent drug and the lipid probe Nile Red. The developed magnetogels showed promising results for photothermia and photo-triggered drug release. The magnetogels bearing gold-decorated nanoparticles showed the best photothermia properties, while the ones containing core/shell nanoparticles had the best photoinduced curcumin release.

Pyrrolizidine Alkaloids: Chemistry, Pharmacology, Toxicology and Food Safety.

Pyrrolizidine alkaloids (PA) are widely distributed in plants throughout the world, frequently in species relevant for human consumption. Apart from the toxicity that these molecules can cause in humans and livestock, PA are also known for their wide range of pharmacological properties, which can be exploited in drug discovery programs. In this work we review the current body of knowledge regarding the chemistry, toxicology, pharmacology and food safety of PA.