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International audience; Polycyclic heterocycles such as 1- and 2-aminothioxanthones are important precursors to molecules endowed with different properties and original syntheses are always required. Here, 1-aminothioxanthone was obtained either in four steps from commercially available thioxanthone, or in five steps from 3-fluoroaniline. As for 2-aminothioxanthone, direct N-arylation using commercial 2-chlorothioxanthone gave its Boc-protected derivative. From 1-aminothioxanthone, original 10-methylbenzothiopyrano[4,3,2-de]indolo[2,3-b]quinoline was synthesized by tandem N-arylation-cyclization using 2-iodo-N-methylindole in the presence of copper. However, this approach being less efficient with 2-iodobenzothiophene, we also studied another strategy. Our efforts were next concentrated on the synthesis of benzofuro-, benzothieno- and indolo[2,3-b]benzothiopyrano[4,3,2-de]1,8-naphthyridines which are original hexacycles of helical nature. Different approaches were designed and we achieved our goal from 2-chloro-4-fluoropyridine, in five steps. The original polycyclic compounds obtained were evaluated as protein kinase inhibitors, and the results were rationalized by molecular modeling experiments. Finally, their photophysical properties were measured for the purpose of structure-property relationships.

International audience; An efficient and simple approach has been developed for the synthesis of unprecedented 4,5-diphosphonyldihydropyridazines and 3,4-diphosphonylpyrroles, through the condensation of bisphosphonylallenes with hydrazines and primary amines, respectively. The reactions proceed under operationally simple, mild, and catalyst-free conditions, for a wide substrate scope. The synthesized compounds were screened for their antiproliferative activity against melanoma cancer cells, and they showed promising growth inhibition.

International audience; The regioselective iodination of different 2-mono-, 3-mono- and 2,3-disubstituted 6-aminoquinoxalines, which takes place at their 5-position, was rationalized on the basis of Hückel theory calculations. Oxazolo- and thiazolo[5,4-f]quinoxaline analogues of reported disease-related protein kinases inhibitors were synthesized from the obtained 6-amino-5-iodoquinoxalines by using as key step copper-catalyzed azole ring formation. Pyrazino[b,e]isatins were obtained, for the first time, from the same substrates by recourse to Sonogashira coupling, alkyne hydration, and oxidative cyclization. The absorption and emission properties of the most promising compounds were recorded. In addition, most of the synthesized polycycles were evaluated as protein kinase inhibitors and for their antiproliferative activity towards cancer cells.

Monvoisin, Evariste, Allain, Ronan, Buffetaut, Eric, Picot, Laurent (2022): New data on the theropod diversity from the Middle to Late Jurassic of the Vaches Noires cliffs (Normandy, France). Geodiversitas 44 (12): 385-415, DOI: 10.5252/geodiversitas2022v44a12

In recent years, there has been a considerable increase in interest in the use of transgenic plants as sources of valuable secondary metabolites or recombinant proteins. This has been facilitated by the advent of genetic engineering technology with the possibility for direct modification of the expression of genes related to the biosynthesis of biologically active compounds. A wide range of research projects have yielded a number of efficient plant systems that produce specific secondary metabolites or recombinant proteins. Furthermore, the use of bioreactors allows production to be increased to industrial scales, which can quickly and cheaply deliver large amounts of material in a short time. The resulting plant production systems can function as small factories, and many of them that are targeted at a specific operation have been patented. This review paper summarizes the key research in the last ten years regarding the use of transgenic plants as small, green biofactories for the bioreactor-based production of secondary metabolites and recombinant proteins; it simultaneously examines the production of metabolites and recombinant proteins on an industrial scale and presents the current state of available patents in the field.

The chemical composition and in vitro biological activities of the essential oil (EO) of Micromeria macrosiphon Coss. and M. arganietorum (J. Emb.) R. Morales, two Lamiaceae endemic to south Morocco, were investigated. GC/MS analysis resulted in the identification of 36 metabolites from the EO of M. macrosiphon, 45 from M. arganietorum. Borneol was the major metabolite in both oils and together with related derivatives such as camphor, accounted for 2/3 of the EO of M. macrosiphon, 1/3 of those of M. arganietorum. Pinene and terpinene derivatives were also present in high proportions. From a chemotaxonomic point of view, the composition of the examined samples may be related to those of other species endemic to Macaronesia. Both EOs showed significant toxicity towards liver HepG2 and melanoma B16 4A5 tumor cell lines at 100 mu g/mL; however, they were also cytotoxic towards S17 normal cell lines, with a selectivity index

A phytochemical investigation of cytotoxic extract and fractions of Cnidoscolus quercifolius Pohl led to isolation of five terpenoids, including three lupane-type triterpenes (1-3) and two bis-nor-diterpenes (4-5). Compounds 4 (phyllacanthone) and 5 (favelanone) are commonly found in this species and have unique chemical structure. Although their cytotoxic activity against cancer cells has been previously reported, the anticancer potential of these molecules remains poorly explored. In this paper, the antimelanoma potential of phyllacanthone (PHY) was described for the first time. Cell viability assay showed a promising cytotoxic activity (IC

Since cancer treatment by radio- and chemotherapy has been linked to safety concerns, there is a need for new and alternative anticancer drugs; as such, compounds isolated from plants represent promising candidates. The current study investigates the anticancer features of halimane (11R*,13E)-11-acetoxyhalima-5,13-dien-15-oic acid (HAL) and the labdane diterpenes 1α,6β-diacetoxy-8α,13R*-epoxy-14-labden-11-one (PLEC) and forskolin-like 1:1 mixture of 1,6-di-O-acetylforskolin and 1,6-di-O-acetyl-9-deoxyforskolin (MRC) isolated from Plectranthus ornatus in MCF7 and FaDu cancer cell lines. Cytotoxicity was assessed by MTT assay, ROS production by Di-chloro-dihydro-fluorescein diacetate assay (DCFH) or Red Mitochondrial Superoxide Indicator (MitoSOX) and Mitochondrial Membrane Potential (MMP) by fluorescent probe JC-1 (5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide). In addition, the relative amounts of mitochondrial DNA (mtDNA) were determined using quantitative Real-Time-PCR (qRT-PCR) and damage to mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) by semi-long run quantitative Real-Time-PCR (SLR-qRT-PCR). Gene expression was determined using Reverse-Transcription-qPCR. Caspase-3/7 activity by fluorescence was assessed. Assessment of General In Vivo Toxicity has been determined by Brine Shrimp Lethality Bioassay. The studied HAL and PLEC were found to have a cytotoxic effect in MCF7 with IC50 = 13.61 µg/mL and IC50 = 17.49 µg/mL and in FaDu with IC50 = 15.12 µg/mL and IC50 = 32.66 µg/mL cancer cell lines. In the two tested cancer cell lines, the phytochemicals increased ROS production and mitochondrial damage in the ND1 and ND5 gene regions and reduced MMP (ΔΨm) and mitochondrial copy numbers. They also changed the expression of pro- and anti-apoptotic genes (Bax, Bcl-2, TP53, Cas-3, Cas-8, Cas-9, Apaf-1 and MCL-1). Studies demonstrated increase in caspase 3/7 activity in tested cancer cell lines. In addition, we showed no toxic effect in in vivo test for the compounds tested. The potential mechanism of action may have been associated with the induction of apoptosis in MCF7 and FaDu cancer cells via the mitochondrial pathway; however, further in vivo research is needed to understand the mechanisms of action and potential of these compounds.

Background Arthritis is a syndrome associated with exacerbated inflammation, joint destruction and chronic pain and disability. Chronic treatment of arthritis is associated with several side effects and high abandonment. Therefore, there has been an ongoing search for alternative treatments to overcome these problems. Purpose Natural products, which are already widely used for their biological, cosmetic and pharmacotechnic properties, are a possible source for new drugs. Terpenes, a large class of organic compounds produced mainly by plants and trees, are a promising natural product and have already been shown to be effective in treating chronic pain, particularly of an inflammatory origin. Study Design and Methods This review identifies the main terpenes with anti-arthritic activity reported in the last 10 years. A survey was conducted between December 2017 and June 2018 in the PUBMED, SCOPUS and Science Direct databases using combinations of the descriptors terpenes, arthritis and inflammation. Results The results showed that terpenes have promising biological effects in relation to the treatment of arthritis, with the 24 terpenes identified in our survey being effective in the modulation of inflammatory mediators important to the physiopathology of arthritis, such as IL-6, IL-17, TNF-α, NFκB, and COX-2, among others. It is important to note that most of the studies used animal models, which limits, at least in part, the direct translation to humans of the experimental evidence produced by the studies. Conclusion Together, our finds suggest that terpenes can modulate the immuno-regulatory and destructive tissue events that underlie the clinical presentation and the progression of arthritis and are worthy of further clinical investigation.

Assessments based on monetary valuation of ecosystem services have been increasingly used as a tool to highlight the connection between ecosystems and society. The dissemination of this approach is leading to difficulties and ambiguities related to the use of such assessments in the socio-political realm. Such limits can be stressed using the case study of intertidal bare mudflats. These coastal habitats indeed provide many ecological functions—several being related to the high production of benthic microalgae—but also remain poorly known for some other aspects. The major users of these habitats (i.e. oyster farmers) are still unaware about the trophic role of benthic microalgae, limiting contingent valuation survey methods. Moreover, economic valuation cannot take into account the potentials of mudflats (i.e. undescribed functions) like positive feedbacks related to shellfish farming and provision of bioactive compounds. The lack of physical boundaries in marine systems also strongly reduces the effectiveness of assessments. Lastly, there are concerns that monetary valuation can lead to a commodification of the nature or to the economization of the environment (e.g. appropriation of the environment by users, creation of artificial thresholds). The evaluation of the functions of a socio-ecosystem should not only be restricted to a monetary assessment of its ecosystem services, as this framework may be more reductive than integrative. Some other descriptors—not based on currencies—should be used for ecosystem description.

Rhaponticum carthamoides (Willd.) Iljin (Asteraceae) is an endemic plant species whose roots and rhizomes have been used for many years in traditional Siberian medicine. In this study, the transformed roots of R. carthamoides obtained after Agrobacterium rhizogenes transformation were able to spontaneously regenerate green buds and shoots. Bud and shoot regeneration was observed in more than 90% of the cultures grown in Schenk and Hildebrandt (SH) or Gamborg (B5) liquid medium with full micro- and macronutrient concentrations, under light conditions. The regeneration of shoots from transformed roots may be improved by supplementation of Murashige and Skoog (MS) agar medium with indole-3-acetic acid (IAA) and benzyladenine (BA). The shoots were multiplied on MS medium supplemented with 0.1 mg/L IAA and 0.2 mg/L BA and then rooted successfully. The transformation of the plants derived from transformed roots was confirmed by PCR analysis and Southern hybridization. The three-month-old pRi-transformed plants (TR-plants) were able to biosynthesize caffeoylquinic acid derivatives such as chlorogenic acid, and 3,5- or 4,5-di-O-caffeoylquinic acids. Plants obtained directly from seeds (SD-plants) being in the same age and grown under the same conditions as the transformed plants were used as compared material. The transformed plants demonstrated higher secondary metabolite levels and greater biomass accumulation than SD-plants. It was found that extracts from TR-plants exhibited antioxidant properties in the model of human blood plasma and inhibited the growth of A2058 human melanoma cells depending on the tested concentration. The present study demonstrated that the pRi-transformed plants of R. carthamoides may be an alternative to conventional field crops and these plants can be used as the promising source of the valuable compounds, such as caffeoylquinic acid derivatives.

International audience; Introduction: Cnidoscolus quercifolius Pohl (Euphorbiaceae) is a Brazilian medicinal plant, popularly known as “favela”, “faveleira” and “urtiga-branca”. In folk medicine, its leaves and stem barks are used to treat urinary tract infections. In this study, we report the isolation and characterization of a mixture of two lupane-type triterpenes and one bis-nor-diterpene from the hexane extract of the stem barks. Methods: An aliquot of hexane extract was fractioned by means silica gel chromatography column, yielding a mixture of two compounds (1 and 2). Compound 3 was obtained from the chloroform subfraction through preparative thin layer chromatography (TLC). The compounds were identified by comparison of their spectroscopic data to those reported in the literature. The antibacterial activity of these compounds was evaluated by the microdilution method, through determination of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC), using gram-positive (E. faecalis and S. aureus) and gram-negative (E. coli, K. pneumoniae and S. marcescens) strains. Results: The chemical constituents were identified as a mixture of lupeol-3β-O-cinnamate (1) and lupeol-3β-O-dihydrocinnamate (2) and, phyllacanthone (3). Compounds 1/2 and 3 showed a bacteriostatic effect ten and twenty times higher (MIC = 0.5 and 0.25 mg.ml-1, respectively) than the hexane extract, respectively (MIC = 5.0 mg.ml-1). The molecules also showed a relevant bactericidal effect, mainly compound 3 (MBC = 0.25 mg.ml-1). Conclusion: These results suggest that C. quercifolius may be considered a promising source of new antibacterial agents. In addition, this investigation supports the medicinal use of this plant for the treatment of urinary tract infections.

Limonene (LIM) is a monoterpene, which is abundant in essential oils of Citrus fruits peels (Rutaceae). More recently, LIM, as a potential natural anticancer compound, has attracted major attention and exerted a chemopreventive activity, stimulating the detoxification of carcinogenic compounds and limiting tumor growth and angiogenesis in various cancer models. Twenty-six (26) articles were selected based on previously established criteria. Anticancer activity of LIM was related to the inhibition of tumor initiation, growth, and angiogenesis and the induction of cancer cells apoptosis. LIM was able to increase Bax expression, release cytochrome c, and activate the caspase pathway. In addition, LIM increased the expression of p53 and decreased the activity of Ras/Raf/MEK/ERK and PI3K/Akt pathways. LIM also decreased the expression of VEGF and increased the activities of the Man-6-P / IGF2R and TGF-βIIR receptors. These results highlight LIM as an abundant natural molecule with low toxicity and pleiotropic pharmacological activity in cancer cells, targeting various cell-signaling pathways critically involved in the initiation, growth, and chemoresistance of cancer cells.

N-Arylation of various 2-acylated anilines with different electron-rich heteroaryl iodides (2- and 3-iodothiophenes, 2- and 3-iodobenzothiophenes­, 2-iodobenzofuran) was achieved by using activated copper and potassium carbonate in dibutyl ether at reflux. The reactivity of the different heteroaryl iodides and anilines employed was discussed and rationalized on the basis of their electronic features. Subsequent cyclization by aromatic electrophilic substitution easily took place in the case of C2-free (benzo)thienyl or C3-free (benzo)furyl derivatives­, affording original tri- and tetracycles. The antiproliferative activity of most of them was evaluated in A2058 melanoma cells and revealed four chlorinated tetracycles as effective growth inhibitors.

Complex regional pain syndrome type 1 (CRPS-1) is a painful syndrome without effective treatment. In order to explore possible new treatments, we used an animal model of CRPS-1 to examine the effects of β-Citronellol (βCT), a monoterpene found in a variety of plants that has been shown to have analgesic effects. We aimed to assess its effects alone, and complexed with β-cyclodextrin (βCD), which has been previously used to enhance the effects of a number of medicines. The βCT-βCD was characterized physiochemically using high performance liquid chromatography (HPLC) and differential scanning calorimetry (DSC) and shown to have 80% efficiency. In the animal model, Swiss mice were treated with βCT, βCT-βCD, vehicle, pregabalin or sham and evaluated for hyperalgesia and motor coordination. Inflammatory mediators were measured by Western blot or ELISA and the descending pain pathway by immunofluorescence. βCT was shown to have an anti-hyperalgesic effect (without affecting motor coordination) that reduced inflammatory mediators and activated the descending pain pathway, and these effects were increased with complexation in βCD. Our results showed βCT-βCD to be a promising treatment for CRPS-1.

According to the present knowledge, this is the first report on establishing transformed root cultures of Leonotis nepetifolia after Rhizobium rhizogenes-mediated transformation. The preliminary phytochemical analysis showed differences in the content of phenols and flavonoids in transformed and nontransformed roots. The dominant compounds in the analyzed extracts were (+)-catechin (5464 and 6808 µg/g DW), p-coumaric acid (2549 and 4907 µg/g DW), m-coumaric acid (1508 and 2048 µg/g DW) and rosmarinic acid (1844 and 2643 µg/g DW) for nontransformed (LNNR) and transformed (LNTR4) roots, respectively. Initial biological studies carried out on LNNR, and LNTR4 extracts showed a cytotoxic effect on the A549 lung, HCC1937 breast and leukemia NALM-6 cell lines, antioxidants, as well as repair and protection against DNA damage induced by H2O2 in HUVEC cells. Due to the stronger effect of the LNTR4 root extract, which can be a relatively efficient and cheap source of bioactive secondary metabolites, further biological analyses are needed to discover in detail their potentially valuable biological properties.

MAJIS is part of the science payload of the JUICE mission to be launched in 2022. BIRA-IASB and ROB contribute to MAJIS with the characterization of the VIS-NIR Flight Model (FM) and Spare Model (SM) detectors, including the design, development, and validation of the setup, as well as the data processing pipeline. The VIS-NIR detectors are thermalized within a temperature range from 125 K to 150 K during their characterization campaigns. Moreover, the temperature of their electronic units must always remain above 120 K to avoid any irreparable damage, and below 160 K for operative conditions. Likewise, to avoid any risk of contamination, the detector should preferably be operated below 10-5 mbar of vacuum. To fulfill these requirements, a complete security system was developed; it includes redundant thermal control loops, alarms from every pressure and temperature monitoring devices in use, and a robust semi-automatic control system for the pumping and cryocooling equipment. Moreover, the security system is complemented by the Temperature Ground Support Equipment (TGSE), which provides a LabVIEW user-friendly interface to communicate the status of the detector and the vacuum chamber in real-time. This subsystem was successfully validated in May 2020, before the delivery of the FM detector in June 2020. In this paper, we summarize the design, implementation and validation tests of the security system as well as the thermal and vacuum performances of the facility. We also show the thermal behavior of the detector during acquisitions representative of typical MAJIS observations.

Background Limonene (LIM) and its main metabolite perillyl alcohol (POH) are ingredients found in food with promising chemical entities due to their pharmacological profile. In this study, we hypothesized that LIM and POH are two molecules capable of accelerating the regenerative process and alleviating neuropathic pain. Methods: Animals were treated daily (LIM, POH and saline) for 28 days and during this period evaluated for mechanical hyperalgesia, astrocyte participation by immunofluorescence for GFAP, and ELISA was used to quantify IL-1β and TNF-α in the spinal cord. Western blot analysis of the following proteins was also performed: GFAP, GAP-43, NGF and ERK. For motor deficit analysis, tests were performed to assess hind paw muscle strength and footprints through gait (SFI). Results: Both POH and LIM accelerated the regenerative process and improved motor deficits comparing to positive control; however, POH was more effective, particularly between the 2nd and 3rd week after the nerve injury, increasing GAP-43, NGF and the phosphorylated ERK immunocontent. Moreover, POH and LIM were able to reduce hyperalgesia and astrocytosis. Conclusions: Both substances, LIM and POH, improved the regeneration process and sensory and motor function recovery in the PNI model in mice by mitigating the inflammatory reactions and up-regulating the neurotrophic process.

International audience; By starting from a common substrate, 2-aminobenzaldehyde, both acridines and acridones were prepared. The former were generated in high yields by copper-catalyzed N-arylation followed by acid-mediated cyclization while the latter were obtained by double copper-catalyzed N-arylation followed by cyclization under the same reaction conditions. Moreover, acridine was subjected to deprotometalation by recourse to a lithium-zinc base and converted to the corresponding 4-iodo derivative, which was involved in copper-catalyzed couplings with pyrrolidinone and pyrazole. Finally, addition of pyrazole, indole and carbazole onto the 9 position of bare acridine was improved. While moderate biological activity was noticed in melanoma cells growth inhibition, the newly prepared compounds feature interesting photophysical properties which were evaluated in a preliminary study.

Neuropathic pain develops due to injury to the somatosensory system, affecting the patient's quality of life. In view of the ineffectiveness of the current pharmacotherapy, substances obtained from natural products (NPs) are a promising alternative. One NP that has been discussed in the literature is hecogenin acetate (HA), a steroidal sapogenin with anti-inflammatory and antinociceptive activity. However, HA has low water solubility, which affects its bioavailability. Thus, the objective of this study was to evaluate the anti-hyperalgesic activity of pure and complexed hecogenin acetate (HA/βCD) in an animal model of chronic neuropathic and inflammatory pain. The inclusion complex was prepared at a molar ratio of 1:2 (HA:βCD) by the lyophilization method. For the induction of chronic inflammatory pain, the mice received an intraplantar injection of CFA (complete Freund's adjuvant), and were evaluated for mechanical hyperalgesia and for the levels of myeloperoxidase (MPO) in the skin of the paw after eight days of treatment. HA and HA/βCD reduced mechanical hyperalgesia in relation to the vehicle group until the fourth and fifth hours, respectively, in the acute evaluation, with a superior effect of the complexed form over the pure form in the second and third hour after treatment (p 0.001). In the chronic evaluation, HA and HA/βCD reduced hyperalgesia in relation to the vehicle in the eight days of treatment (p 0.001). Both pure (p 0.01) and complexed (p 0.001) forms reduced myeloperoxidase activity in the skin of the animals' paw. Groups of animals subjected to the same pharmacological protocol were submitted to the partial sciatic nerve ligation (PSNL) model and evaluated for mechanical and thermal hyperalgesia, and cold allodynia. HA and HA/βCD reduced mechanical hyperalgesia until the fourth and sixth hours, respectively, and both reduced hyperalgesia in relation to the vehicle in the chronic evaluation (p 0.001). HA and HA/βCD also reduced thermal hyperalgesia and cold allodynia (p 0.05 and p 0.001, respectively). The analysis of the spinal cord of these animals showed a decrease in the levels of the pro-inflammatory cytokines TNF-α, IL-1β and IL-6 and a reduction in the phosphorylation of NFκB and p38MAPK, as well as a decrease in microglioses compared to the vehicle group. In addition, HA/βCD reduced the nociception induced by intraplantar injection of agonist TRPA1 (p 0.01) and TRPM8 (p 0.05). Treatment for eight days with HA and HA/βCD showed no signs of gastric or liver damage. HA and HA/βCD were, therefore, shown to have antinociceptive effects in chronic pain models. Based on our exploration of the mechanisms of the action of HA, these effects are likely to be related to inhibited leukocyte migration, interaction with the TRPA1 and TRPM8 receptors, reduced pro-inflammatory cytokines levels, microglial expression and suppression of NF-κB p65 and p38 MAPK pathway signaling. Therefore, HA/βCD has great potential for use in the treatment of chronic pain.

A series of 10 natural and semisynthetic flavonoids (1 to 10) were obtained from Gardenia oudiepe (Rubiaceae), an endemic plant from New Caledonia. Most of them were polymethoxylated flavones (PMFs) of rare occurrence. After a cell viability screening test, PMFs 2 and 3 showed significant cytotoxic activity against A2058 human melanoma cells (IC50 = 3.92 and 8.18 μM, respectively) and were selected for in-depth pharmacological assays. Both compounds inhibited cell migration and induced apoptosis and cell cycle arrest after 72h of treatment. Immunofluorescence assays indicated that these outcomes were possibly related to the induction of cytoskeleton disruption associated to actin and tubulin depolymerization. These data were confirmed by molecular docking studies, which showed a good interaction between PMFs 2 and 3 and tubulin, particularly at the colchicine binding site. As A2058 are considered as chemoresistant to conventional chemotherapy, compounds 2 and 3 (½IC50) were associated to clinically-used antimelanoma drugs (vemurafenib and dacarbazine) and combined therapies efficacy was assessed by the MTT assay. PMFs 2 restored the sensitivity of A2058 cells to dacarbazine treatment (IC50 = 49.38 μM vs. >100 μM). Taken together, these data suggest that PMFs from G. oudiepe could be potential leaders for the design of new antimelanoma drugs.

Phytol is a diterpene constituent of chlorophyll and has been shown to have several pharmacological properties, particularly in relation to the management of painful inflammatory diseases. Arthritis is one of the most common of these inflammatory diseases, mainly affecting the synovial membrane, cartilage, and bone in joints. Proinflammatory cytokines, such as TNF-α and IL-6, and the NFκB signaling pathway play a pivotal role in arthritis. However, as the mechanisms of action of phytol and its ability to reduce the levels of these cytokines are poorly understood, we decided to investigate its pharmacological effects using a mouse model of complete Freund's adjuvant (CFA)-induced arthritis. Our results showed that phytol was able to inhibit joint swelling and hyperalgesia throughout the whole treatment period. Moreover, phytol reduced myeloperoxidase (MPO) activity and proinflammatory cytokine release in synovial fluid and decreased IL-6 production as well as the COX-2 immunocontent in the spinal cord. It also downregulated the p38MAPK and NFκB signaling pathways. Therefore, our findings demonstrated that phytol can be an innovative antiarthritic agent due to its capacity to attenuate inflammatory reactions in joints and the spinal cord, mainly through the modulation of mediators that are key to the establishment of arthritic pain.

Melanoma is an aggressive tumor with invasive and metastatic potential, frequently exhibiting multidrug resistance mechanisms. In our continuous search for antimelanoma molecules, we have identified some effective marine compounds capable of not only inducing cell death, but also of sensitizing chemoresistant tumor cells to clinically used anticancer drugs. In this report, the cryptophyte Rhodomonas salina (Wislouch) D.R.A.Hill & R.Wetherbee, Pyrenomonadaceae, was chemically investigated in order to identify pigments efficiently inhibiting melanoma cells proliferation. All pharmacological tests were performed on A2058 cells expressing the oncogenic BRAF V600E mutation and resistant to dacarbazine treatment. Flash chromatography of R. salina ethanol extract led to purification of alloxanthin and crocoxanthin, which showed significant antiproliferative activity against A2058 cells, exhibiting IC50 = 29 and 50 μM, respectively. These carotenoids promoted growth inhibition, decreased cell migration, and induced apoptosis and sub-G1 cells accumulation after 72 h of treatment. In addition, alloxanthin potentiated the cytotoxic activity of vemurafenib (a BRAF inhibitor) and restored the sensitivity of A2058 cells to dacarbazine treatment.

Many biologically-active plant-derived compounds have therapeutic or chemopreventive effects. The use of plant in vitro cultures in conjunction with modern genetic engineering techniques allows greater amounts of valuable secondary metabolites to be obtained without interfering with the natural environment. This work presents the first findings concerning the acquisition of transgenic hairy roots of Senna obtusifolia overexpressing the gene encoding squalene synthase 1 from Panax ginseng (PgSS1) (SOPSS hairy loot lines) involved in terpenoid biosynthesis. Our results confirm that one of PgSS1-overexpressing hairy root line extracts (SOPSS2) possess a high cytotoxic effect against a human acute lymphoblastic leukemia (NALM6) cell line. Further analysis of the cell cycle, the expression of apoptosis-related genes (TP53, PUMA, NOXA, BAX) and the observed decrease in mitochondrial membrane potential also confirmed that the SOPSS2 hairy root extract displays the highest effects, similar results were also obtained for this extract combined with doxorubicin. The high cytotoxic activity, observed both alone or in combination with doxorubicin, may be due to the higher content of betulinic acid as determined by HPLC analysis. Our results suggest synergistic effects of tested extract (betulinic acid in greater amount) with doxorubicin which may be used in the future to develop new effective strategies of cancer chemosensitization.

A bibliographic database of scientific papers published by authors affiliated worldwide, especially focused in Europe and in the European Atlantic Area, and containing the keywords “microalga(e)” or “phytoplankton” was built. A corpus of 79,020 publications was obtained and analyzed using the Orbit Intellixir software to highlight the evolution of the research domain. Publication rates from 1960 to 2019, organization of the research, collaboration networks between countries and organizations, emerging and fading research concepts, major studied species, and associated concepts, as well as journals publishing microalgae research were considered. As a result, of the 79,020 papers published worldwide, 26,137 included authors from Europe (33% of world production) and 6989 from the European Atlantic Area (AA) (27% of European production, 9% of world production). The main worldwide scientific research topics found in this study were phytoplankton, community, bloom, diatoms, distribution, ecosystem, coastal, chlorophyll, zooplankton, photosynthesis, and primary production. At the European scale, the most studied topics were related to the environment, food, chemicals, pigments, protein, feed, and drugs. The highest scientific trends and market opportunities analysis identified bioplastics and biostimulants as top emerging concepts at the European level and agricultural, animal feed, and blue biotechnology at the European AA level.

Teleosauridae and Metriorhynchidae were thalattosuchian crocodylomorph clades that secondarily adapted to marine life and coexisted during the Middle to Late Jurassic. While teleosaurid diversity collapsed at the end of the Jurassic, most likely as a result of a global cooling of the oceans and associated marine regressions, metriorhynchid diversity was largely unaffected, although the fossil record of Thalattosuchia is poor in the Cretaceous. In order to investigate the possible differences in thermophysiologies between these two thalattosuchian lineages, we analysed stable oxygen isotope compositions (expressed as δ18O values) of tooth apatite from metriorhynchid and teleosaurid specimens. We then compared them with the δ18O values of coexisting endo-homeothermic ichthyosaurs and plesiosaurs, as well as ecto-poikilothermic chondrichthyans and osteichthyans. The distribution of δ18O values suggests that both teleosaurids and metriorhynchids had body temperatures intermediate between those of typical ecto-poikilothermic vertebrates and warm-blooded ichthyosaurs and plesiosaurs, metriorhynchids being slightly warmer than teleosaurids. We propose that metriorhynchids were able to raise their body temperature above that of the ambient environment by metabolic heat production, as endotherms do, but could not maintain a constant body temperature compared with fully homeothermic ichthyosaurs and plesiosaurs. Teleosaurids, on the other hand, may have raised their body temperature by mouth-gape basking, as modern crocodylians do, and benefited from the thermal inertia of their large body mass to maintain their body temperature above the ambient one. Endothermy in metriorhynchids might have been a by-product of their ecological adaptations to active pelagic hunting, and it probably allowed them to survive the global cooling of the Late Jurassic, thus explaining the selective extinction affecting Thalattosuchia at the Jurassic–Cretaceous boundary.This article is part of the theme issue ‘Vertebrate palaeophysiology'.

International audience; Original 1-amino substituted thioxanthone derivatives were easily prepared from the bare heterocycle by a deprotometalation-iodolysis-copper-catalyzed CeN bond formation sequence. This last reaction delivered mono-or/and diarylated products depending on the aniline involved. 1-Amino-9-thioxanthone was also prepared and reacted with 2-iodoheterocycles. Interestingly, while 1-(arylamino)-9-thioxanthones could be isolated, their subsequent cyclization was found to deliver original hexacyclic derivatives of helicoidal nature. Evaluation of their photophysical properties revealed high fluorescence in polar media, indicating potential applications for biological imaging. These compounds being able to inhibit PIM1 kinase, their putative binding mode was examined through molecular modeling experiments. Altogether, these results tend to suggest the discovery of a new family of fluorescent PIM inhibitors and pave the way for their future rational optimization.

International audience; Fast-growing transgenic root cultures of Leonurus sibiricus transformed with the AtPAP1 transcriptional factor may be used as a base for potential large-scale phenolic acid production. The present study investigates the effect of different volumes of medium (300 mL, 1 L, 3 L, 5L flasks) and a 5 L bioreactor on biomass increase and phenolic acid production by transgenic roots of L. sibiricus. Of these cultures, those from the 5 L bioreactor demonstrated the greatest increase in dry weight (20.83g/L) and highest yields of phenolic acids (chlorogenic acid 448 mg/L and caffeic acid 302 mg/L). Additionally, they also displayed a cytotoxic effect on melanoma cells across the range of tested concentrations, as well as antioxidant activity on human blood plasma. This approach may serve as an alternative to conventional field crops for enabling large-scale production of the active constituents of AtPAP1 root extract, which would be of great value for pharmaceutical production.

International audience; The X-ray crystal structure of 6,7-dihydro-5a,7a,13,14-tetraaza-pentaphene-5,8-dione, a potential antiproliferative agent on A2058 melanoma cells, was established. It crystallizes in the monoclinic space group P21/c with cell parameters a = 24.879(3)Å, b = 6.868(2)Å, c = 26.068(4Å, α = 90, β = 110.49(2), γ = 90, V = 4172.4(15)Å3 and Z = 12. The crystal structure was refined to final values of R1 = 0.1353 and wR2 = 0.1936. An X-ray crystal structure analysis revealed that each molecule features intermolecular CArom.–H···O hydrogen bonds to form trimers.