Biological activities of nitidine, a potential anti-malarial lead compound

International audienceAbstract Background Nitidine is thought to be the main active ingredient in several traditional anti-malarial remedies used in different parts of the world. The widespread use of these therapies stresses the importance of studying this molecule in the context of malaria control. However, little is known about its potential as an anti-plasmodial drug, as well as its mechanism of action. Methods In this study, the anti-malarial potential of nitidine was evaluated in vitro on CQ-sensitive and -resistant strains. The nitidine's selectivity index compared with cancerous and non-cancerous cell lines was then determined. In vivo assays were then performed, using the four-day Peter's test methodology. To gain information about nitidine's possible mode of action, its moment of action on the parasite cell cycle was studied, and its localization inside the parasite was determined using confocal microscopy. The in vitro abilities of nitidine to bind haem and to inhibit β-haematin formation were also demonstrated. Results Nitidine showed similar in vitro activity in CQ-sensitive and resistant strains, and also a satisfying selectivity index (> 10) when compared with a non-cancerous cells line. Its in vivo activity was moderate; however, no sign of acute toxicity was observed during treatment. Nitidine's moment of action on the parasite cycle showed that it could not interfere with DNA replication; this was consistent with the observation that nitidine did not localize in the nucleus, but rather in the cytoplasm of the parasite. Nitidine was able to form a 1-1 complex with haem in vitro and also inhibited β-haematin formation with the same potency as chloroquine. Conclusion Nitidine can be considered a potential anti-malarial lead compound. Its ability to complex haem and inhibit β-haematin formation suggests a mechanism of action similar to that of chloroquine. The anti-malarial activity of nitidine could therefore be improved by structural modification of this molecule to increase its penetration of the digestive vacuole in the parasite, where haemoglobin metabolization takes place

How Adsorption Affects the Gas-Ice Partitioning of Organics Erupted from Enceladus

International audienceWe study the effect of adsorption of volatile organic compounds (VOCs) in Enceladus’ geysers, both onto the ice grains ejected in the plumes, and onto the ice walls of the cracks connecting Enceladus’ internal ocean to its surface. We use a model of adsorption/desorption based on the Polanyi-Wiegner equation and experimental values of binding energies (energy of desorption E des) of the adsorbed compounds to water ice. We find that under conditions expected at Enceladus, the process of adsorption tends to ensure that the VOCs with the highest binding energy are over-represented on the ice surface, even if their abundance is comparatively lower than those of other compounds. We find that VOCs with E des ≤ 0.5 eV are insignificantly affected by adsorption while compounds with E des ≥ 0.7 eV are readily retained on the surface and compete to occupy most of the adsorption sites. We also deduce that ice grains falling back onto the surface are likely to retain most of the molecules adsorbed on their surface. The implication is that remote observation or sampling of the ice in the cracks or of the surface around it would show a mixture of VOCs that would not be representative of the gas phase of the plumes, with the high E des VOCs dominating the adsorbed phase

Expected effect of atomic oxygen of Europa's exosphere on the MAss Spectrometer for Planetary EXploration

International audienceThe future Europa Clipper NASA mission to Europa will carry the MAss Spectrometer for Planetary EXploration (MASPEX), which will analyze the compounds making up Europa's exosphere, and plumes, if present. Europa's exosphere is likely to feature abundant atomic oxygen, a product of sputtering of Europa's surface by energetic particles from Jupiter's radiation belts, or photolysis of oxygen-bearing molecules in the exosphere. Due to its very high reactivity, this atomic oxygen could induce chemical processes within MASPEX. These processes could involve materials composing the instrument, or other compounds from Europa's exosphere. In both cases, the possible effect on the instrument's measurements is a concern. In this work we first review previous relevant experiments on the effect of atomic oxygen on several candidate metals and conclude that stainless steel with a gold coating is the most satisfactory choice for MASPEX's antechamber walls, and alumina for the impact plate. We then perform simulations of adsorption/desorption processes within the instrument's antechamber to bound the effect of atomic oxygen on other compounds from Europa's exosphere. We find that the accumulation of atomic oxygen during a flyby would lead to a reduction of the apparent abundance of water by as much as 0.125% (Δ[H2O]/[H2O] = -1.25 × 10-3). Evaluating the exact extent of this effect during data post-processing would require constraining the atomic oxygen abundance, which would have to be achieved with other instruments, such as the ultraviolet spectrometer

On the distribution of volatiles in the Galilean moons' primordial hydrospheres

Virtual meetingInternational audienceThe accretion of the Galilean icy moons within the Jovian circumplanetary disk (hereafter CPD) and the subsequent overturn of their cores led to their differentiation and the disposal of the hydrospheres at the top of the denser rocky mantles. In the most extreme cases, when the accretional energy is high enough to sublimate the icy material, volatiles are expected to settle in a liquid-vapor equilibrium between the ocean and the atmosphere. Here, we present an equilibrium model that investigates the effect of the variation of the initial oceanic compositions on the thermodynamic equilibrium between primordial oceans and their coexisting atmospheres. This model will be applied to ultimately derive links between the current compositions of Europa, Ganymede, and Callisto's surfaces and those of their primordial hydrospheres.Given a starting concentration of volatiles in a primordial ocean and the expected temperature of the system, our model outputs the equilibrium composition of the species involved in the vapor and liquid phase, and the atmospheric pressure with the contribution of each species (partial pressure). Using different initial concentrations, we can compare the impact of the initial ratio among the volatiles, in their final distribution in the hydrospheres. Furthermore, the model evaluates the clathrate formation, which is expected depending on the concentration of species such CO2 and CH4, and the high pressure (HP) ices formation.The liquid-Vapor equilibrium is reached when the fugacities of both phases are equal. This translates into the following expression:where \ensuremathΦi is the fugacity coefficient of component i, yiisthe molar fraction of i in the vapor phase, P is the pressure, \ensuremathγi is the activity coefficient of i, xi is the molar fraction of i in the liquid phase and fi0 is the reference state.Fugacity coefficients (\ensuremathΦi) are obtained using the approximation from Peng-Robinson equation of state [1]:Where a is the attraction parameter of the mixture, b is the covolume parameter of the mixture and bk of component k, P is the pressure, T the temperature, R the gas constant and Z the compressibility factor. Activity coefficients (\ensuremathγi) are obtained using the ex-tended UNIQUAC-Debye-Huckel model [2], and the reference state is approximated to the saturation pressure in the case of water and to Henry's constant for the solutes (Eq. 3): Some of the dissolved species can self-dissociate in the liquid phase and change the contribution of other species to the final thermodynamic state [3]. Therefore, we model the ocean as an electrolytic solution taking into account the acid/base equilibrium and the subsequent formation of new ions.The highlights of the model include:\textbullet An extended list of molecules based on cometarycomposition and CPD origin for the starting composition, such CO, CO2, CH4, NH3, H2O, CH3OH, H2S, HCN, SO2, H2O2, Kr, Ar, Xe.\textbullet A precise estimate of clathrates formation conditionsand composition via the use of a thermodynamic statistical model [4,5]. This model provides a description of clathrates properties including structure, density and determination of whether they would sink or float and form a crust.\textbullet Description of the thermodynamic properties of HP ices that might form at the base of the ocean, usingthe SeaFreeze EOS package [6].References[1] Peng, D.-Y., and Robinson, D. B., ``A new two-constantequation of state,''Industrial & Engineering Chemistry Fun-damentals, Vol. 15, No. 1, 1976, pp. 59-64.[2] Sander, B., Rasmussen, P., and Fredenslund, A., ``Calculationof vapour-liquid equilibria in nitric acid-water-nitrate saltsystems using an extended UNIQUAC equation,''Chemicalengineering science, Vol. 41, No. 5, 1986, pp. 1185-1195.[3] Marounina, N., Grasset, O., Tobie, G., and Carpy, S., ``Roleof the global water ocean on the evolution of Titan's primitiveatmosphere,''Icarus, Vol. 310, 2018, pp. 127-139.[4] Bouquet, A., Mousis, O., Glein, C. R., Danger, G., and Waite,J. H., ``The role of clathrate formation in Europa's oceancomposition,''The Astrophysical Journal, Vol. 885, No. 1,2019, p. 14.[5] Mousis, O., Lakhlifi, A., Picaud, S., Pasek, M., and Chas-sefiere, E., ``On the abundances of noble and biologicallyrelevant gases in Lake Vostok, Antarctica,''Astrobiology,Vol. 13, No. 4, 2013, pp. 380-390.[6] Journaux, B., Brown, J. M., Pakhomova, A., Collings, I. E.,Petitgirard, S., Espinoza, P., Boffa Ballaran, T., Vance, S. D.,Ott, J., Cova, F., et al., ``Holistic approach for studyingplanetary hydrospheres: Gibbs representation of ices thermo-dynamics, elasticity, and the water phase diagram to 2,300MPa,''Journal of Geophysical Research: Planets, Vol. 125,No. 1, 2020, p. e2019JE00617

Limits on the contribution of early endogenous radiolysis to oxidation in carbonaceous chondrites’ parent bodies

International audienceContext. Carbonaceous chondrites have undergone alteration in their parent bodies and display oxidized secondary phases, including sulfates in CI and CM chondrites. The cause of the formation of these sulfates is yet to be determined.Aims. This study investigates the potential of endogenous radiolysis of water (i.e., radiolysis caused by radionuclides present in the rock) on the parent bodies of carbonaceous chondrites. Radiolysis may have contributed to the enhanced degree of oxidation of CI and CM chondrites, and we also examined CV chondrites as a case with no measured sulfates.Methods. We quantified the oxidants produced by radiolysis and how much of the sulfur content could be oxidized to form sulfates by this method. The amount of oxidants was calculated using a radiolytic production model developed and used for Earth and planetary applications that takes into account relevant physical parameters (water-to-rock ratio, grain density) and composition (amount of radionuclides, sulfur content).Results. For CM and CI parent bodies, even using a very favorable set of assumptions, only slightly more than 1% of the available sulfur can be oxidized into sulfates by this process, significantly below the amount of sulfates observed in these chondrites.Conclusions. Endogenous radiolysis is unlikely to have significantly contributed to the abundance of sulfate in CI and CM meteorites. The hypothesis of oxidation of sulfur by large quantities of O2 accreted with primitive ice, on the other hand, is quantitatively supported by measurements of O2 in comet 67P/Churyumov-Gerasimenko

Effect of the UV flux and temperature on the formation of complex organic molecules in astrophysical ices

Virtual meetingInternational audienceI. Introduction Ices throughout the ISM are exposed to different energetic processes that trigger several reactions and change the com- position of the ice [1-3]. Particularly, ices in stars- forming regions can be subjected to the ultraviolet radiation that comes from the new born stars and triggers reactions in the ice. These ices are normally composed of H2O, CO, CO2, NH3 , methanol (CH3OH), and traces of other molecules. Irradiation- induced reactions in these ices are a source of complex organic molecules (COM) that might later feed the building blocks of planets or other bodies that are being formed. Methanol is one of the main constituents of interstel- lar ices, where its abundance can go up to 30% (with respect to water) [1, 3, 4]. With this in mind, we irradiated pure methanol ice deposited at 20 and 80 K, with UV radiation during different periods of time to evaluate the effect of fluence and temperature in the abundance of volatile COMs that formed. II. Methods All experiments were carried out in the VAHIIA set-up [5]. Briefly, the system consist of an ultrahigh vacuum chamber connected to a GC-MS through a pre-condensation loop. The latter consist of a stainless steel loop that is immersed in liquid nitrogen for the recovery of the volatile COMs coming from the vacuum chamber. This is connected to a custom-made group of valves that allows to recover volatile COMs for their injection in the GS-MS for identification. Species recovered were identified by comparing the chromatographic peak and mass spectra with the standard database, whose retention time and mass spectrum were obtained in the system under the same conditions as the experiments. Pure methanol was deposited in a copper plated surface attached to the tip of the cryostat in the chamber at 20 K. Six periods of time were used: 15 and 30 min, 1, 3, 8 and 24 h, for evaluating different UV fluence. Each experiment consists of five layers of 0.2 mbar of pure methanol ice each, one on top of the other. Each of these layers is irradiated during the period of time under evaluation, with a UV flux of \ensuremath∼1e13 photons s-1 cm-2, using a flowing H2 microwave-discharge lamp. Layers have been verified to be opaque to the UV photons, ensuring the layer(s) underneath the one being irradiated are not affected further. Once five layers are irradiated, under the same conditions, the chamber is warmed up to \ensuremath∼ 300 K and volatiles are recovered with the injection of Argon for transferring the sample to the pre-condensation loop. Each experiment consist of 5 layers having received the same irradiation dose to obtain a larger quantity of products, and facilitate their detection and identification with the GC-MS. In addition, experiments were carried out at 80 K to evaluate the effect of the temperature on the abundance of volatiles formed. In this case we evaluated 30 min, 1 h and 24 h of irradiation. III. Effect of fluence 23 molecules were identified after UV- irradiation of methanol ice. Figure 1 shows the absolute area under the total ion content curve of the molecules identified, as a function of the irradiation time. This quantity is a function of the abundance of the compound and is hereafter referred to as integrated TIC. Within functional groups, the same pattern is seen for molecules with different numbers of carbons. Aldehydes are the main functional group that forms. With the exception of formaldehyde, all of them have a similar increase up to 8h of irradiation and then even though the integrated TIC increases, the slope is smaller. Alcohols have a low yield and have a steady integrated TIC. Ethers are produced rapidly and reach high integrated TIC during the first 3-8 h but then, their formation is lower than its usage for the formation of more complex molecules and its integrated TIC drops. Dimethyl Ether (DME) has the highest integrated TIC throughout all experiments. Ketones are the main products with 4 and 5 carbons, and maintain a constant increase with the time of irradiation. Esters and ketones are the only two functional groups identified with up to 5 carbons in the chain. With the exception of methyl formate, esters have a similar pattern. During the first 3 h of irradiation the integrated TIC increases rapidly but between 3-8 h there is a recession. After, the increase is the highest. At 8 h of irradiation several molecules display an inflection point. Aldehydes's rate of production decreases (the integrated TIC is lower than expected), while the integrated TIC of esters and ketones is higher. Special cases are formaldehyde, DME and dimetoxymethane, who fall under the detection threshold after 24 h of irradiation tends to zero, which indicates they are the main reactants to form the more complex molecules. Fig. 1. Integrated TIC of volatiles formed after UV-irradiation at 20 K. Aldehydes: blue, ethers: yellow, alcohol: black, ketones: green, esters: red. IV. Effect of temperature At 80 K there is a reduction in diversity and integrated TIC of products, and there is no common pattern to describe the functional groups as in section III. Propanol, DME and 1,3,5-trioxane are not identified at anytime. Aldehydes are identified only after 24 h of irradiation, except for isobutyraldeyde that appears at all times. Alcohols and Ethers have a lower yield. Ketones are still produced at all times with constant yield, which suggest an efficient mechanism of formation. References [1] S. Maity, R. I. Kaiser, and B. M. Jones, Physical Chemistry Chemical Physics, vol. 17,no. 5, pp. 3081-3114, 2015. [2] P. de Marcellus, C. Meinert, I. Myrgorodska, L. Nahon, T. Buhse, L. L. S.d'Hendecourt, and U. J. Meierhenrich, PNAS, vol. 112, no. 4, pp. 965-970, 2015. [3] D. Paardekooper, J.-B. Bossa, and H. Linnartz, Astronomy & Astrophysics, vol. 592, p. A67, 2016. [4] A. Bergantini, S. Góbi, M. J. Abplanalp, and R. I. Kaiser, The Astrophysical Journal, vol. 852, no. 2,p. 70, 2018. [5] N. Abou Mrad, F. Duvernay, P. Theulé, T. Chiavassa, and G. Danger, Analytical chemistry, vol. 86, no. 16, pp. 8391-8399, 201

The Role of Clathrate Formation in Europa’s Ocean Composition

International audienceWe use a thermodynamic statistical model to evaluate how the composition of Europa’s internal ocean may have been affected by clathrate hydrate formation. Assuming an input of the observed O2 and CO2 from the surface into a mildly acidic ocean (pH 4 and H2S) or oxidized (CO2-bearing) hydrothermal fluids, we calculate the fractional occupancies in clathrate and deduce the effect on the ocean’s composition. The structure of the clathrate formed, and therefore its density and composition is influenced by the relative amount of O2 compared to the other compounds present. We also include a mixture of noble gases—argon, krypton, and xenon—based on cometary abundances measured at comet 67P and find that the Ar/Kr ratio can be affected by almost two orders of magnitude. In most cases, the formed clathrate is likely to become part of the icy crust, with guest molecules possibly accessible to future in situ measurements by the Europa Clipper and JUICE missions

Biological activities of nitidine, a potential anti-malarial lead compound

Abstract Background Nitidine is thought to be the main active ingredient in several traditional anti-malarial remedies used in different parts of the world. The widespread use of these therapies stresses the importance of studying this molecule in the context of malaria control. However, little is known about its potential as an anti-plasmodial drug, as well as its mechanism of action. Methods In this study, the anti-malarial potential of nitidine was evaluated in vitro on CQ-sensitive and -resistant strains. The nitidine's selectivity index compared with cancerous and non-cancerous cell lines was then determined. In vivo assays were then performed, using the four-day Peter's test methodology. To gain information about nitidine's possible mode of action, its moment of action on the parasite cell cycle was studied, and its localization inside the parasite was determined using confocal microscopy. The in vitro abilities of nitidine to bind haem and to inhibit β-haematin formation were also demonstrated. Results Nitidine showed similar in vitro activity in CQ-sensitive and resistant strains, and also a satisfying selectivity index (> 10) when compared with a non-cancerous cells line. Its in vivo activity was moderate; however, no sign of acute toxicity was observed during treatment. Nitidine's moment of action on the parasite cycle showed that it could not interfere with DNA replication; this was consistent with the observation that nitidine did not localize in the nucleus, but rather in the cytoplasm of the parasite. Nitidine was able to form a 1-1 complex with haem in vitro and also inhibited β-haematin formation with the same potency as chloroquine. Conclusion Nitidine can be considered a potential anti-malarial lead compound. Its ability to complex haem and inhibit β-haematin formation suggests a mechanism of action similar to that of chloroquine. The anti-malarial activity of nitidine could therefore be improved by structural modification of this molecule to increase its penetration of the digestive vacuole in the parasite, where haemoglobin metabolization takes place.</p

Sulfur ion irradiation experiments simulating space weathering of Solar System body surfaces: Organosulfur compound formation

International audienceContext. Sulfur (S) is of prime interest in the context of (astro)chemical evolution and habitability. However, the origin of S-bearing organic compounds in the Solar System is still not well constrained.Aims. We carried out laboratory experiments to test whether complex organosulfur compounds can be formed when surfaces of icy Solar System bodies are subject to high-energy S ions.Methods. Non-S-bearing organic residues, formed during the processing of astrophysical H2O:CH3OH:NH3-bearing ice analogs, were irradiated with 105 keV-S7+ ions at 10 K and analyzed by high-resolving FT-ICR-MS. The resulting data were comprehensively analyzed, including network analysis tools.Results. Out of several thousands of detected compounds, 16% contain at least one sulfur atom (organosulfur (CHNOS) compounds), as verified via isotopic fine structures. These residue-related organosulfur compounds are different from those formed during the S ion irradiation of ices at 10 K. Furthermore, insoluble, apolar material was formed during the sulfur irradiation of residues. Potential organosulfur precursors (CHNO molecules) were identified by means of molecular networks.Conclusions. This evidence of organosulfur compounds formed by sulfur irradiation of organic residues sheds new light onto the rich and complex scope of pristine organosulfur chemistry in the Solar System, presented in the context of current and future space missions. These results indicate that the space weathering of Solar System bodies may lead to the formation of organosulfur compounds