Catégorie d'actualités: significant publications

Milk thistle, a plant extract with promising –green- medicinal properties against psoriasis

Considering the relative low efficacy and high toxicity of current drug treatments against psoriasis, new therapeutic strategies are needed.

Scientists from CBM have searched for natural products unable to modulate the TGFb/miRNA-21-5p pathway in keratinocyte cells. This axis of regulation was chosen not only because it plays a pivotal role in epidermal haemostasis but also because its dysregulation is systematically associated with skin disorders including psoriasis.

To identify such bioactive compounds, a library of medicinal plant extracts was screened using the miR-ON RILES screening system placed under the control of the miRNA-21-5p in keratinocytes treated with TGFb. Silymarin, a mixture of flavonolignans extracted from Silybum marianum (L.) Gaertn., was identified as the most potent regulator of miRNA-21-5p expression. RNA-sequencing analysis revealed three unexpected transcriptomic signatures associated with keratinocyte differentiation, cell cycle, and lipid metabolism.

Mechanistically, Silymarin blocks cell cycle progression, inhibits keratinocyte differentiation through repression of Notch3 expression, stimulates lipid synthesis via activation of PPARg signaling and inhibits inflammatory responses by suppressing the transcriptional activity of NF-kB. Notably, the topical application of silymarin alleviates the development of psoriasiform lesions in mice by abrogating the altered expression levels of markers involved in inflammation, proliferation, differentiation, and lipid metabolism without inducing toxicity.

Therefore this plant extract might represent a promising "green" alternative to current pharmacological treatments for the management of this pathology.


Elodie Henriet,Florence Abdallah, Yoan Laurent, Cyril Guimpied, Emily Clement, Michel Simon, Chantal Pichon and Patrick BarilTargeting TGF-β1/miR-21 Pathway in Keratinocytes Reveals Protective Effects of Silymarin on Imiquimod-Induced Psoriasis Mouse ModelVolume 3, ISSUE 3, 100175, May 2023 - DOI:https://doi.org/10.1016/j.xjidi.2022.100175

Raman spectroscopy for detecting biomolecules below surface of Mars

Chlorophyllin, beta-carotene, melanin, chitin, cellulose, naringenin and quercetin: these exotic-sounding compounds are biomolecules that allow certain organisms to live in extreme environments. They are thus prime targets for the search for life on Mars. In order to assess their resistance to Martian conditions, an experiment called BIOMEX, for BIOlogy and Mars EXperiment, was carried out on the exterioir of the International Space Station (ISS).

The molecules were mixed with Martian soil analogs before being exposed to solar radiation outside the ISS for 469 days. Back on Earth, they were   analyzed by Raman spectroscopy at the German Aerospace Center (DLR) in Berlin.

Raman spectroscopy analyses the molecular and mineralogical composition of a sample. Compatible with robotic space missions, it is one of the key techniques for searching for traces of life on Mars. NASA's Perseverance rover currently exploring Jezero Crater is equipped with two Raman spectrometers, and ESA's future ExoMars mission will also use one to aid detection of possible biosignatures on Mars in 2030.

The BIOMEX experiment involved many researchers, including members of the Exobiology team at CBM, Olréans. The results, published in the Science Advances, reveal that these biomolecules are resistant to Mars conditions because the minerals composing the Martian soil have a protective effect against UV. Most importantly, the study shows that these molecules could be identified without difficulty on Mars by Raman spectroscopy.

Biosignature stability in space enables their use for life detection on Mars
Mickael Baqué,Theresa Backhaus et al.
Science Advances, Vol 8 -DOI: 10.1126/sciadv.abn7412

Setting the geological scene for the origin of life and continuing open questions about its emergence

The origin of life is one of the most fundamental questions of humanity. It has been and is still being addressed by a wide range of researchers from different fields, with different approaches and ideas as to how it came about. However, what is missing from the prebiotic chemical experiments is precise information about the environment and the conditions reigning on the early Earth during the Hadean Era (4.5-4.0 Ga). In particular, there is a lack of understanding about the inorganic ingredients that were available, the stability and longevity of the various environments suggested as locations for the emergence of life, as well the kinetics and rates of the prebiotic steps leading to life.

This contribution reviews our current understanding of the geology of the early Earth at the time when life emerged. Having set the geological scenario, we evoke the still open questions about the origin of life: did life start organically or in mineralogical form? If organically, what was the origin of the organic constituents of life? What came first, metabolism or replication? What was the time-scale for the emergence of life? We conclude that the way forward for prebiotic chemistry is an approach merging geology and chemistry, i.e., far-from-equilibrium cycling of organic reactions occurring repeatedly and iteratively at mineral surfaces under hydrothermal-like conditions.

Setting the geological scene for the origin of life and continuing open questions about its emergence
Frances Westall1, André Brack, Alberto G. Fairén and Mitchell D. Schulte
Frontiers in Astronomy and Space Sciences - 05 January 2023 - Volume 9 - doi : 10.3389/fspas.2022.1095701 9:1095701

Bispidines and manganese: a winning couple

As an essential metal ion and an efficient relaxation agent, Mn2+ holds great promise as a substitute for Gd3+ in MRI contrast agent applications, if its stable and inert complexation can be achieved. To achieve this goal, the “Metal complexes and MRI” team of CBM and their collaborators from the University of Heidelberg, Germany, created a Mn2+ selective chelator by introducing four pyridine and one carboxylate donors on a bispidine skeleton. Thanks to a highly rigid and preorganized structure and perfect size-match for Mn2+, the new ligand L provides not only remarkably high thermodynamic stability, but also excellent selectivity over the major biological competitor Zn2+, as well as kinetic inertness. The unusual eight-coordinate structure of the Mn2+ complex, in contrast to the six-coordinate structure of the Zn2+ analogue, underlines that the coordination cavity is perfectly adapted for Mn2+, while it is too large for Zn2+. The MRI efficiency of this MnL complex is about 30% higher than that of typical Mn2+ systems. In vivo MRI experiments realized in control mice at a very low dose (0.02 mmol/kg) indicate good signal enhancement and fast renal clearance. Taken together, MnL is the first chelate that combines such excellent stability, selectivity, inertness and relaxation properties, all of primary importance for MRI use.

D. Ndiaye, P. Cieslik, H. Wadepohl, A. Pallier, S. Même, P. Comba, and É. Tóth, Mn2+ bispidine complex combining exceptional stability, inertness and MRI efficiency, J. Am. Chem. Soc. 2022, doi : 10.1021/jacs.2c10108
JACS spotlight sur cet article : https://pubs.acs.org/doi/pdf/10.1021/jacs.2c12719

A major advance in the understanding of DNA damage repair

The "DNA repair: structure, function and dynamics" team has just revealed, in the prestigious journal Nucleic Acid Research, how archaeal DNA glycosylases are able to recognize and repair, at the molecular level, certain lesions in their DNA.

To know more :
Structural and functional determinants of the archaeal 8-oxoguanine-DNA glycosylase AGOG for DNA damage recognition and processing
Coste Franck, Goffinont Stéphane, Cros Julien, Gaudon Virginie, Guérin Martine, Garnier Norbert, Confalonieri Fabrice, Flament Didier, Suskiewicz Marcin Josef, Castaing Bertrand https://doi.org/10.1093/nar/gkac932

Identification of a ‘double‘ protein post-translational modification

Proteins are the main ‘molecular machines’ of the cell. To efficiently perform their tasks, they have to be dynamically switched on and off, recruited to specific cellular locations, and degraded in a timely manner. One of the main mechanisms that regulate these processes is temporary covalent attachment, to a protein, of extra regulatory elements known as protein post-translational modifications. The modification reaction is catalysed by specific enzymes and can lead to changes in protein activity, localisation, or half-life. Two of the common protein modifications are ubiquitin and ADP-ribose, each of which can be linked directly to a protein substrate.

In the study published in Science Advances, an international team of researchers, including Vincent Aucagne, Marcin Suskiewicz, and Hervé Meudal from the CBM in Orléans, led by Ivan Ahel and Dragana Ahel groups at the University of Oxford, have demonstrated that these two individual modifications can be joined together, producing a ‘double’ protein modification. The enzymes responsible for this process are DELTEX E3 ligases, which can efficiently attach ubiquitin to protein-linked ADP-ribose. A key contribution of Orléans scientists to the project was the analysis of the ubiquitin-ADP-ribose linkage performed using mass spectrometry (MS) and nuclear magnetic resonance (NMR) equipment of the new MOV2ING platform in Orléans.

The study shows that different protein modifications can be joined together to either combine two regulatory signals or produce a third, distinct signal, with a specific function. This shows previously unappreciated level of complexity in protein regulation.

While the role of ubiquitin-ADP-ribose in cells remains unclear, DELTEX enzymes have previously been linked to both development and antiviral response. The authors showed that the SARS-CoV-2 virus possesses enzymes that can remove the new modification, possibly allowing the virus to inhibit the host immune response.

References :
Kang Zhu, Marcin J. Suskiewicz, Hloušek-Kasun, Hervé Meudal, Andreja Mikoč, Vincent Aucagne, Dragana Ahel and Ivan Ahel
DELTEX E3 ligases ubiquitylate ADP-ribosyl modification on protein substrates
Science Advances, 5 Oct 2022, Vol 8, Issue 40 DOI: 10.1126/sciadv.add4253

A versatile new approach to seek constitutive or conditional helicase substrates at global scale

Helicases are ubiquitous ‘molecular motor’ enzymes that disrupt nucleic acid (NA) helices and NA-protein interactions. Despite the key roles of helicases in many cellular processes and diseases, their target repertoires and the determinants of their functional specialization are often unknown. Scientists from the ‘RNA remodeling’ group of CBM have developed a new screening scheme, Helicase-SELEX, to elucidate helicase substrate requirements and find natural or synthetic helicase substrates in large NA sequence libraries. Using the transcription termination Rho helicase as prototype, the CBM scientists have discovered ~3300 functional substrate sequences in Escherichia coli, thereby providing the first detailed map of Rho utilization (Rut) sites at genome scale. Further, they have shown that inclusion of a Rho cofactor (NusG) in the selection scheme can modulate the H-SELEX outcome and help probe specificity determinants at global scale. Finally, they have used H-SELEX to evolve synthetic Rut sequences operating as riboswitches able to elicit Rho activity in vitro and in vivo only in presence of an orthogonal cofactor (serotonin). Thus, Helicase-SELEX is a versatile new approach to characterize or exploit helicases for fundamental or biotechnology purposes.

The CNRS Institute of Chemistry has reported this new original screening approach on its website

Référence

Delaleau M., Eveno E., Simon I., Schwartz A & Boudvillain M.
A scalable framework for the discovery of functional helicase substrates and helicase-driven regulatory switches
PNAS 2022

https://www.pnas.org/doi/10.1073/pnas.2209608119