Patrick Dutartre

Paradoxically, iron overload does not potentiate doxorubicin-induced cardiotoxicity in vitro in cardiomyocytes and in vivo in mice

Doxorubicin (DOX) is known to induce serious cardiotoxicity, which is believed to be mediated by oxidative stress and complex interactions with iron. However, the relationship between iron and DOX-induced cardiotoxicity remains controversial and the role of iron chelation therapy to prevent cardiotoxicity is called into question. Firstly, we evaluated in vitro the effects of DOX in combination with dextran-iron on cell viability in cultured H9c2 cardiomyocytes and EMT-6 cancer cells. Secondly, we used an in vivo murine model of iron overloading (IO) in which male C57BL/6 mice received a daily intra-peritoneal injection of dextran-iron (15mg/kg) for 3weeks (D0-D20) and then (D21) a single sub-lethal intra-peritoneal injection of 6mg/kg of DOX. While DOX significantly decreased cell viability in EMT-6 and H9c2, pretreatment with dextran-iron (125-1000μg/mL) in combination with DOX, paradoxically limited cytotoxicity in H9c2 and increased it in EMT-6. In mice, IO alone resulted in cardiac hypertrophy (+22%) and up-regulation of brain natriuretic peptide and β-myosin heavy-chain (β-MHC) expression, as well as an increase in cardiac nitro-oxidative stress revealed by electron spin resonance spectroscopy. In DOX-treated mice, there was a significant decrease in left-ventricular ejection fraction (LVEF) and an up-regulation of cardiac β-MHC and atrial natriuretic peptide (ANP) expression. However, prior IO did not exacerbate the DOX-induced fall in LVEF and there was no increase in ANP expression. IO did not impair the capacity of DOX to decrease cancer cell viability and could even prevent some aspects of DOX cardiotoxicity in cardiomyocytes and in mice.

Cytotoxic steroidal glycosides from Allium flavum.

Three new spirostane-type glycosides (1-3) were isolated from the whole plant of Allium flavum. Their structures were elucidated mainly by 2D NMR spectroscopic analysis and mass spectrometry as (20S,25R)-2α-hydroxyspirost-5-en-3β-yl O-β-D-xylopyranosyl-(1→3)-[β-D-galactopyranosyl-(1→2)]-β-D-galactopyranosyl-(1→4)-β-D-galactopyranoside (1), (20S,25R)-2α-hydroxyspirost-5-en-3β-yl O-β-D-xylopyranosyl-(1→3)-[β-D-glucopyranosyl-(1→2)]-β-D-galactopyranosyl-(1→4)-β-D-galactopyranoside (2), and (20S,25R)-spirost-5-en-3β-yl O-α-L-rhamnopyranosyl-(1→4)-[β-D-glucopyranosyl-(1→2)]-β-D-glucopyranoside (3). The three saponins were evaluated for cytotoxicity against a human cancer cell line (colorectal SW480).

New triterpenoid estersaponins from the root barks of Pittosporum verticillatum subsp. verticillatum and evaluation of cytotoxicities

The phytochemical investigation of the root barks of Pittosporum verticillatum Bojer subsp. verticillatum led to the isolation of three new triterpene saponins, 3-O-[β-D-glucopyranosyl-(1→2)]-[α-L-arabinopyranosyl-(1→3)]-[α-L-arabinofuranosyl-(1→4)]-β-D-glucuronopyranosyl-21-O-(2-acetoxy-2-methylbutanoyl)-R1-barrigenol (1), 3-O-[β-D-glucopyranosyl-(1→2)]-[α-L-arabinopyranosyl-(1→3)]-[α-L-arabinofuranosyl-(1→4)]-β-D-glucuronopyranosyl-21-O-(2-acetoxy-2-methylbutanoyl)-28-O-acetyl-R1-barrigenol (2), 3-O-[β-D-glucopyranosyl-(1→2)]-[α-L-arabinopyranosyl-(1→3)]-[α-L-arabinofuranosyl-(1→4)]-β-D-glucuronopyranosyl-21-O-β,β-dimethylacryloyl-22-O-angeloyl-R1-barrigenol (3), and one known saponin senaciapittoside B (4). Their structures were elucidated mainly by 1D- and 2D-NMR spectroscopy and HRESIMS. Compounds 1-4 were evaluated for their cytotoxicity against one human cancer cell line (SW480) and one rat cardiomyoblast cell line (H9c2).

Steroidal saponins from Chlorophytum deistelianum

Phytochemical investigation of the aerial parts of Chlorophytum deistelianum led to the isolation of four previously undescribed steroidal saponins called chlorodeistelianosides A-D with five known ones. Their structures were established mainly by extensive 1D and 2D NMR spectroscopic techniques and mass spectrometry as (25R)-3β-[(β-D-glucopyranosyl-(1→3)-[α-L-rhamnopyranosyl-(1→4)]-β-D-xylopyranosyl-(1→3)-[β-D-glucopyranosyl-(1→2)]-β-D-glucopyranosyl-(1→4)-β-D-galactopyranosyl)oxy]-5α-spirostan-12-one, (24S,25S)-24-[(β-D-glucopyranosyl)oxy]-3β-[(β-d-glucopyranosyl-(1→2)-[β-D-xylopyranosyl-(1→3)]-β-D-glucopyranosyl-(1→4)-β-D-galactopyranosyl)oxy]-5α-spirostan-12-one, (25R)-26-[(β-D-glucopyranosyl)oxy]-2α-hydroxy-22α-methoxy-5α-furostan-3β-yl β-D-glucopyranosyl-(1→2)-[β-D-xylopyranosyl-(1→3)]-β-D-glucopyranosyl-(1→4)-β-D-galactopyranoside, and (25R)-26-[(β-D-glucopyranosyl)oxy]-3β-[(β-D-glucopyranosyl-(1→2)-[β-D-xylopyranosyl-(1→3)]-β-D-glucopyranosyl-(1→4)-β-D-galactopyranosyl)oxy]-5α-furost-20(22)-en-12-one. Cytotoxicity of most compounds was evaluated against one human cancer cell line (SW480) and one rat cardiomyoblast cell line (H9c2). Among them, three known spirostane-type glycosides exhibited cytotoxicity on both cell lines with IC50 ranging from 8 to 10 μM.

Inflammasomes and Natural Ingredients towards New Anti-Inflammatory Agents

Inflammasomes are a family of proteins in charge of the initiation of inflammatory process during innate immune response. They are now considered major actors in many chronic inflammatory diseases. However, no major drug focusing on this target is currently on the market. Among the various approaches aiming to control this major metabolic pathway, compounds aiming to modify the intracellular antioxidant profile appear to be promising. This can be obtained by “light” antioxidants able to induce natural antioxidant response of the cell itself. This review will give an overview of the current available information on this promising pharmacology approach.

Microwave-assisted synthesis, anti-inflammatory and anti-proliferative activities of new maslinic acid derivatives bearing 1,5- and 1,4-disubstituted triazoles

Abstract In this work, 40 analogs with a natural maslinic acid core (from Olea europaea L.) and various aromatic azides were synthesized. A regiospecific, facile and practical synthesis of 1,5-triazolyl derivatives by Ru(II)-catalyzed azide-alkyne cycloaddition (RuAAC), and mono-, bis- and tri-1,4-triazolyl derivatives by Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) was described. All the reactions were assisted by microwave irradiation avoiding toxic reagents and solvents. The new products were obtained from the reaction mixture by simple purification in almost quantitative yields and the reaction times were in general shorter than those reported in the literature. Their chemical structures were elucidated on the basis of extensive spectroscopic methods including ESI-HRMS, 1D and 2D-NMR. Most of the compounds were evaluated for their anti-inflammatory activity using LPS-stimulated human peripheral blood mononuclear cells (PBMCs) and antiproliferative effects towards cultured murine EMT-6 (Breast) and human SW480 (colon) cancer cell lines.