Insights into the Biosynthesis of Cyclic Guanidine Alkaloids from Crambeidae Marine Sponges.

Among the outstanding chemical diversity found in marine sponges, cyclic guanidine alkaloids, present in species of the family Crambeidae, are particularly attractive, not only because of their unique chemical features, but also due to a broad range of biological activities. Despite a growing interest in these natural products as therapeutic agents, their metabolic pathway has not been experimentally investigated. Ex situ feeding experiments using radiolabeled precursors performed on the Mediterranean sponge Crambe crambe suggest arginine and fatty acids as precursors in the metabolic pathway of crambescins. A subsequent bio-inspired approach supported the change of paradigm in the metabolic pathway of cyclic guanidine alkaloids. A large part of the chemical diversity of this family would therefore originate from a tethered Biginelli-like reaction between C-2/C-3 activated fatty acids and a central guanidinylated pyrrolinium.

Metabolome variability for two Mediterranean sponge species of the genus Haliclona: specificity, time, and space.

INTRODUCTION: The study of natural variation of metabolites brings valuable information on the physiological state of the organisms as well as their phenotypic traits. In marine organisms, metabolome variability has mostly been addressed through targeted studies on metabolites of ecological or pharmaceutical interest. However, comparative metabolomics has demonstrated its potential to address the overall and complex metabolic variability of organisms. OBJECTIVES: In this study, the intraspecific (temporal and spatial) variability of two Mediterranean Haliclona sponges (H. fulva and H. mucosa) was investigated through an untargeted and then targeted metabolomics approach and further compared to their interspecific variability. METHODS: Samples of both species were collected monthly during 1 year in the coralligenous habitat of the Northwestern Mediterranean sae at Marseille and Nice. Their metabolomic profiles were obtained by UHPLC-QqToF analyses. RESULTS: Marked variations were noticed in April and May for both species including a decrease in Shannon's diversity and concentration in specialized metabolites together with an increase in fatty acids and lyso-PAF like molecules. Spatial variations across different sampling sites could also be observed for both species, however in a lesser extent. CONCLUSIONS: Synchronous metabolic changes possibly triggered by physiological factors like reproduction and/or environmental factors like an increase in the water temperature were highlighted for both Mediterranean Haliclona species inhabiting close habitats but displaying different biosynthetic pathways. Despite significative intraspecific variations, metabolomic variability remains minor when compared to interspecific variations for these congenerous species, therefore suggesting the predominance of genetic information of the holobiont in the observed metabolome.

Evaluation of the Protective Effects of Sarains on H2O2-Induced Mitochondrial Dysfunction and Oxidative Stress in SH-SY5Y Neuroblastoma Cells.

Sarains are diamide alkaloids isolated from the Mediterranean sponge Haliclona (Rhizoniera) sarai that have previously shown antibacterial, insecticidal and anti-fouling activities. In this study, we examined for the first time the neuroprotective effects of sarains 1, 2 and A against oxidative stress in a human neuronal model. SH-SY5Y cells were co-incubated with sarains at concentrations ranging from 0.01 to 10 µM, and the well-known oxidant hydrogen peroxide at 150 µM for 6 h and the protective effects of the compounds were evaluated. Among the sarains tested, sarain A was the most promising compound, improving mitochondrial function and decreasing reactive oxygen species levels in human neuroblastoma cells treated with the compound at 0.01, 0.1 and 1 µM. This compound was also able to increase the activity of the antioxidant enzymes superoxide dismutases by inducing the translocation of the nuclear factor E2-related factor 2 (Nrf2) to the nucleus at the lower concentrations tested (0.01 and 0.1 µM). Moreover, sarain A at 0.1 and 1 µM blocked the mitochondrial permeability transition pore (mPTP) opening through cyclophilin D inhibition. These results suggest that the protective effects produced by the treatment with sarain A are related with its ability to block the mPTP and to enhance the Nrf2 pathway, indicating that sarain A may be a candidate compound for further studies in neurodegenerative diseases.

Does the Chemical Diversity of the Order Haplosclerida (Phylum Porifera: Class Demospongia) Fit with Current Taxonomic Classification?

Sponges and their associated microbiota are well known to produce a large diversity of natural products, also called specialized metabolites. In addition to their potential use in the pharmaceutical industry, these rather species-specific compounds may help in the classification of some particular sponge groups. We review herein compounds isolated from haplosclerid sponges (Class Demospongia, Order Haplosclerida) in order to help in the revision of this large group of marine invertebrates. We focus only on 3-alkylpyridine derivatives and polyacetylenic compounds, as these two groups of natural products are characteristic of haplosclerid species and are highly diverse. A close collaboration between chemists and biologists is required in order to fully apply chemotaxonomical approaches, and whenever possible biological data should include morphological and molecular data and some insight into their microbial abundance.

Speciation of americium in seawater and accumulation in the marine sponge Aplysina cavernicola.

The fate of radionuclides in the environment is a cause of great concern for modern society, seen especially in 2011 after the Fukushima accident. Among the environmental compartments, seawater covers most of the earth's surface and may be directly or indirectly impacted. The interaction between radionuclides and the marine compartment is therefore essential for better understanding the transfer mechanisms from the hydrosphere to the biosphere. This information allows for the evaluation of the impact on humans via our interaction with the biotope that has been largely undocumented up to now. In this report, we attempt to make a link between the speciation of heavy elements in natural seawater and their uptake by a model marine organism. More specifically, because the interaction of actinides with marine invertebrates has been poorly studied, the accumulation in a representative member of the Mediterranean coralligenous habitat, the sponge Aplysina cavernicola, was investigated and its uptake curve exposed to a radiotracer (241)Am was estimated using a high-purity Ge gamma spectrometer. But in order to go beyond the phenomenological accumulation rate, the speciation of americium(III) in seawater must be assessed. The speciation of (241)Am (and natural europium as its chemically stable surrogate) in seawater was determined using a combination of different techniques: Time-Resolved Laser-Induced Fluorescence (TRLIF), Extended X-ray Absorption Fine Structure (EXAFS) at the LIII edge, Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectroscopy and Scanning Electron Microscopy (SEM) and the resulting data were compared with the speciation modeling. In seawater, the americium(III) complex (as well as the corresponding europium complex, although with conformational differences) was identified as a ternary sodium biscarbonato complex, whose formula can be tentatively written as NaAm(CO3)2·nH2O. It is therefore this chemical form of americium that is accumulated by the sponge A. cavernicola.

Natural paniceins from mediterranean sponge inhibit the multidrug resistance activity of Patched and increase chemotherapy efficiency on melanoma cells.

Multidrug resistance has appeared to mitigate the efficiency of anticancer drugs and the possibility of successful cancer chemotherapy. The Hedgehog receptor Patched is a multidrug transporter expressed in several cancers and as such it represents a new target to circumvent chemotherapy resistance. We report herein that paniceins and especially panicein A hydroquinone, natural meroterpenoids produced by the Mediterranean sponge Haliclona (Soestella) mucosa, inhibit the doxorubicin efflux activity of Patched and enhance the cytotoxicity of this chemotherapeutic agent on melanoma cells in vitro. These results are supported by the molecular docking performed on the structure of the bacterial drug efflux pump AcrB and on the Patched model built from AcrB structure. Docking calculations show that panicein A hydroquinone interacts with AcrB and Patched model close to the doxorubicin binding site. This compound thus appears as the first antagonist of the doxorubicin efflux activity of Patched. The use of inhibitors of Patched drug efflux activity in combination with classical chemotherapy could represent a novel approach to reduce tumor drug resistance, recurrence and metastasis.