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Fu, T., Houel, E., Amusant, N., Touboul, D., Genta-Jouve, G., Della-Negra, S., et al. (2019). Biosynthetic investigation of γ-lactones in Sextonia rubra wood using in situ TOF-SIMS MS/MS imaging to localize and characterize biosynthetic intermediates. Sci. Rep., 9, 1928.
Abstract: Molecular analysis by parallel tandem mass spectrometry (MS/MS) imaging contributes to the in situ characterization of biosynthetic intermediates which is crucial for deciphering the metabolic pathways in living organisms. We report the first use of TOF-SIMS MS/MS imaging for the cellular localization and characterization of biosynthetic intermediates of bioactive γ-lactones rubrynolide and rubrenolide in the Amazonian tree Sextonia rubra (Lauraceae). Five γ-lactones, including previously reported rubrynolide and rubrenolide, were isolated using a conventional approach and their structural characterization and localization at a lateral resolution of ~400 nm was later achieved using TOF-SIMS MS/MS imaging analysis. 2D/3D MS imaging at subcellular level reveals that putative biosynthetic γ-lactones intermediates are localized in the same cell types (ray parenchyma cells and oil cells) as rubrynolide and rubrenolide. Consequently, a revised metabolic pathway of rubrynolide was proposed, which involves the reaction between 2-hydroxysuccinic acid and 3-oxotetradecanoic acid, contrary to previous studies suggesting a single polyketide precursor. Our results provide insights into plant metabolite production in wood tissues and, overall, demonstrate that combining high spatial resolution TOF-SIMS imaging and MS/MS structural characterization offers new opportunities for studying molecular and cellular biochemistry in plants. © 2019, The Author(s).
Fu, T., Touboul, D., Della-Negra, S., Houel, E., Amusant, N., Duplais, C., et al. (2018). Tandem Mass Spectrometry Imaging and in Situ Characterization of Bioactive Wood Metabolites in Amazonian Tree Species Sextonia rubra. Anal. Chem., 90(12), 7535–7543.
Abstract: Driven by a necessity for confident molecular identification at high spatial resolution, a new time-of-flight secondary ion mass spectrometry (TOF-SIMS) tandem mass spectrometry (tandem MS) imaging instrument has been recently developed. In this paper, the superior MS/MS spectrometry and imaging capability of this new tool is shown for natural product study. For the first time, via in situ analysis of the bioactive metabolites rubrynolide and rubrenolide in Amazonian tree species Sextonia rubra (Lauraceae), we were able both to analyze and to image by tandem MS the molecular products of natural biosynthesis. Despite the low abundance of the metabolites in the wood sample(s), efficient MS/MS analysis of these γ-lactone compounds was achieved, providing high confidence in the identification and localization. In addition, tandem MS imaging minimized the mass interferences and revealed specific localization of these metabolites primarily in the ray parenchyma cells but also in certain oil cells and, further, revealed the presence of previously unidentified γ-lactone, paving the way for future studies in biosynthesis.
Heu, K., Romoli, O., Schonbeck, J. C., Ajenoe, R., Epelboin, Y., Kircher, V., et al. (2021). The Effect of Secondary Metabolites Produced by Serratia marcescens on Aedes aegypti and Its Microbiota. Frontiers in Microbiology, 12, 645701.
Abstract: Serratia marcescens is a bacterial species widely found in the environment, which very efficiently colonizes mosquitoes. In this study, we isolated a red-pigmented S. marcescens strain from our mosquito colony (called S. marcescens VA). This red pigmentation is caused by the production of prodigiosin, a molecule with antibacterial properties. To investigate the role of prodigiosin on mosquito- S. marcescens interactions, we produced two white mutants of S. marcescens VA by random mutagenesis. Whole genome sequencing and chemical analyses suggest that one mutant has a nonsense mutation in the gene encoding prodigiosin synthase, while the other one is deficient in the production of several types of secondary metabolites including prodigiosin and serratamolide. We used our mutants to investigate how S. marcescens secondary metabolites affect the mosquito and its microbiota. Our in vitro tests indicated that S. marcescens VA inhibits the growth of several mosquito microbiota isolates using a combination of prodigiosin and other secondary metabolites, corroborating published data. This strain requires secondary metabolites other than prodigiosin for its proteolytic and hemolytic activities. In the mosquito, we observed that S. marcescens VA is highly virulent to larvae in a prodigiosin-dependent manner, while its virulence on adults is lower and largely depends on other metabolites
Houel, E., Bertani, S., Bourdy, G., Deharo, E., Jullian, V., Valentin, A., et al. (2009). Quassinoid constituents of Quassia amara L. leaf herbal tea. Impact on its antimalarial activity and cytotoxicity. J. Ethnopharmacol., 126(1), 114–118.
Abstract: Aim of the study: Our objective was to assess whether it could be contemplated to recommend Quassia amara young leaf tea for treatment against malaria. and if yes. set up a standard protocol for preparing the herbal tea. Materials and methods: The leaf tea was extracted with methylene chloride and the organic extract was fractionated with HPLC. Pure compounds were characterized and their in vitro cytotoxicity and antiplasmodial activity was determined. Results and discussion: We discovered that antimalarial Quassia amara young leaf tea contains several quassinoids: simalikalactone D (SkD. 1), picrasin B (2). picrasin H (3), neoquassin (4), quassin (5), picrasin 1(6) and picrasin J (7). These last two compounds are new. In addition. our experiments demonstrate that both biological activity and cytotoxicity of the remedy may be attributed solely to the presence of SkD. Conclusion: In conclusion, this preparation Should not be recommended for treatment of malaria until a clinical Study in humans is performed with SkD. (C) 2009 Elsevier Ireland Ltd. All rights reserved
Keywords: Quassia amara L.; Simaroubaceae; Leaf tea; Antimalarial activity; Cytotoxicity; Simalikalactone D
Houel, E., Fleury, M., Odonne, G., Nardella, F., Bourdy, G., Vonthron-Sénécheau, C., et al. (2015). Antiplasmodial and anti-inflammatory effects of an antimalarial remedy from the Wayana Amerindians, French Guiana: Takamalaimë (Psidium acutangulum Mart. ex DC., Myrtaceae). Journal of Ethnopharmacology, 166, 279–285.
Abstract: Ethnopharmacological relevance:
Field investigations highlighted the use of Psidium acutangulum Mart. ex DC (syn. P. persoonii McVaugh), a small tree used by the Wayana Amerindians in Twenke–Taluhwen and Antecume–Pata, French Guiana, for the treatment of malaria, and administered either orally in the form of a decoction or applied externally over the whole body. This use appears limited to the Wayana cultural group in French Guiana and has never been reported anywhere else. Our goal was to evaluate the antimalarial and anti-inflammatory activities of a P. acutangulum decoction to explain the good reputation of this remedy.
Materials and methods:
Interviews with the Wayana inhabitants of Twenke–Taluhwen and Antecume–Pata were conducted within the TRAMAZ project according to the TRAMIL methodology, which is based on a quantitative and qualitative analysis of medicinal plant uses. A decoction of dried aerial parts of P. acutangulum was prepared in consistency with the Wayana recipe. In vitro antiplasmodial assays were performed on chloroquine-resistant FcB1 ([3H]-hypoxanthine bioassay) and 7G8 (pLDH bioassay) P. falciparum strains and on chloroquine sensitive NF54 ([3H]-hypoxanthine bioassay) P. falciparum strain. In vitro anti-inflammatory activity (IL-1β, IL-6, IL-8, TNFα) was evaluated on LPS-stimulated human PBMC and NO secretion inhibition was measured on LPS stimulated RAW murine macrophages. Cytotoxicity of the decoction was measured on L6 mammalian cells, PBMCs, and RAW cells. A preliminary evaluation of the in vivo antimalarial activity of the decoction, administered orally twice daily, was assessed by the classical four-day suppressive test against P. berghei NK65 in mice.
The decoction displayed a good antiplasmodial activity in vitro against the three tested strains, regardless to the bioassay used, with IC50 values of 3.3 µg/mL and 10.3 µg/mL against P. falciparum FcB1 and NF54, respectively and 19.0 µg/mL against P. falciparum 7G8. It also exhibited significant anti-inflammatory activity in vitro in a dose dependent manner. At a concentration of 50 µg/mL, the decoction inhibited the secretion of the following pro-inflammatory cytokines: TNFα (−18%), IL-1β (−58%), IL-6 (−32%), IL-8 (−21%). It also exhibited a mild NO secretion inhibition (−13%) at the same concentration. The decoction was non-cytotoxic against L6 cells (IC50>100 µg/mL), RAW cells and PBMC. In vivo, 150 µL of the decoction given orally twice a day (equivalent to 350 mg/kg/day of dried extract) inhibited 39.7% average parasite growth, with more than 50% of inhibition in three mice over five. The absence of response for the two remaining mice, however, induced a strong standard deviation.
This study highlighted the in vitro antiplasmodial activity of the decoction of P. acutangulum aerial parts, used by Wayana Amerindians from the Upper-Maroni in French Guiana in case of malaria. Its antioxidant and anti-inflammatory potential, which may help to explain its use against this disease, was demonstrated using models of artificially stimulated cells.
Keywords: Psidium acutangulum; Plasmodium; Cytokines; Antimalarial; French Guiana; Traditional medicine