Molecular docking studies on InhA, MabA and PanK enzymes from Mycobacterium tuberculosis of ellagic acid derivatives from Ludwigia adscendens and Trewia nudiflora

There is an urgent need to discover and develop new drugs to combat Mycobacterium tuberculosis, the causative agent of tuberculosis (TB) in humans. In recent years, there has been a renewed interest in the discovery of new anti-TB agents from natural sources. In the present investigation, molecular docking studies were carried out on two ellagic acid derivatives, namely pteleoellagic acid (1) isolated from Ludwigia adscendens, and 3,3′-di-O-methyl ellagic acid 4-O-α-rhamnopyranoside (2) isolated from Trewia nudiflora, to investigate their binding to two enzymes involved in M. tuberculosis cell wall biogenesis, namely 2-trans-enoyl-ACP reductase (InhA) and β-ketoacyl-ACP reductase (MabA), and to pantothenate kinase (PanK type I) involved in the biosynthesis of coenzyme A, essential for the growth of M. tuberculosis. Molecular docking experiments were performed using AutoDock Vina. The crystal structures of InhA, MabA and PanK were retrieved from the RCSB Protein Data Bank (PDB). Isonicotinic-acyl-NADH for InhA and MabA, and triazole inhibitory compound for PanK, were used as references. Pteleoellagic acid showed a high docking score, estimated binding free energy of −9.4 kcal/mol, for the MabA enzyme comparable to the reference compound isonicotinic-acyl-NADH.Knowledge on the molecular interactions of ellagic acid derivatives with essential M. tuberculosis targets could prove a useful tool for the design and development of future anti-TB drugs

Clinical outcomes of 130 patients with primary and secondary lung tumors treated with Cyberknife robotic stereotactic body radiotherapy

Background: Authors report clinical outcomes of patients treated with robotic stereotactic body radiotherapy (SBRT) for primary, recurrent and metastatic lung lesions. Patients and methods: 130 patients with 160 lesions were treated with Cyberknife SBRT, including T1-3 primary lung cancers (54%), recurrent tumors (22%) and pulmonary metastases (24%). The mean biologically equivalent dose (BED10Gy) was 151 Gy (72–180 Gy). Median prescribed dose for peripheral and central lesions was 3x20 Gy and 3x15 Gy, respectively. Local control (LC), overall survival (OS), and cause-specific survival (CSS) rates, early and late toxicities are reported. Statistical analysis was performed to identify factors influencing local tumor control. Results: Median follow-up time was 21 months. In univariate analysis, higher dose was associated with better LC and a cut-off value was detected at BED10Gy ≤ 112.5 Gy, resulting in 1-, 2-, and 3-year actuarial LC rates of 93%, vs 73%, 80% vs 61%, and 63% vs 54%, for the high and low dose groups, respectively (p = 0.0061, HR = 0.384). In multivariate analysis, metastatic origin, histological confirmation and larger Planning Target Volume (PTV) were associated with higher risk of local failure. Actuarial OS and CSS rates at 1, 2, and 3 years were 85%, 74% and 62%, and 93%, 89% and 80%, respectively. Acute and late toxicities ≥ Gr 3 were observed in 3 (2%) and 6 patients (5%), respectively. Conclusions: Our favorable LC and survival rates after robotic SBRT, with low rates of severe toxicities, are coherent with the literature data in this mixed, non-selected study population

Involvement of KCa3.1 channel activity in immediate perioperative cognitive and neuroinflammatory outcomes.

peer reviewed[en] BACKGROUND: Potassium channels (KCa3.1; Kv1.3; Kir2.1) are necessary for microglial activation, a pivotal requirement for the development of Perioperative Neurocognitive Disorders (PNDs). We previously reported on the role of microglial Kv1.3 for PNDs; the present study sought to determine whether inhibiting KCa3.1 channel activity affects neuroinflammation and prevents development of PND. METHODS: Mice (wild-type [WT] and KCa3.1-/-) underwent aseptic tibial fracture trauma under isoflurane anesthesia or received anesthesia alone. WT mice received either TRAM34 (a specific KCa3.1 channel inhibitor) dissolved in its vehicle (miglyol) or miglyol alone. Spatial memory was assessed in the Y-maze paradigm 6 h post-surgery/anesthesia. Circulating interleukin-6 (IL-6) and high mobility group box-1 protein (HMGB1) were assessed by ELISA, and microglial activitation Iba-1 staining. RESULTS: In WT mice surgery induced significant cognitive decline in the Y-maze test, p = 0.019), microgliosis (p = 0.001), and increases in plasma IL-6 (p = 0.002) and HMGB1 (p = 0.001) when compared to anesthesia alone. TRAM34 administration attenuated the surgery-induced changes in cognition, microglial activation, and HMGB1 but not circulating IL-6 levels. In KCa3.1-/- mice surgery neither affected cognition nor microgliosis, although circulating IL-6 levels did increase (p < 0.001). CONCLUSION: Similar to our earlier report with Kv1.3, perioperative microglial KCa3.1 blockade decreases immediate perioperative cognitive changes, microgliosis as well as the peripheral trauma marker HMGB1 although surgery-induced IL-6 elevation was unchanged. Future research should address whether a synergistic interaction exists between blockade of Kv1.3 and KCa3.1 for preventing PNDs

Serum Neurotrophin Profile in Systemic Sclerosis

International audienceBACKGROUND: Neurotrophins (NTs) are able to activate lymphocytes and fibroblasts; they can modulate angiogenesis and sympathic vascular function. Thus, they can be implicated in the three pathogenic processes of systemic sclerosis (SSc). The aims of this study are to determine blood levels of Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF) and Neurotrophin-3 (NT-3) in SSc and to correlate them with clinical and biological data.METHODS: Serum samples were obtained from 55 SSc patients and 32 control subjects to measure NTs levels by ELISA and to determine their relationships with SSc profiles. FINDINGS: Serum NGF levels were higher in SSc patients (288.26 ± 170.34 pg/mL) than in control subjects (170.34 ± 50.8 pg/mL, p<0.001) and correlated with gammaglobulins levels and the presence of both anti-cardiolipin and anti-Scl-70 antibodies (p<0.05). In contrast, BDNF levels were lower in SSc patients than in controls (1121.9 ± 158.1 vs 1372.9 ± 190.9 pg/mL, p<0.0001), especially in pulmonary arterial hypertension and diffuse SSc as compared to limited forms (all p<0.05). NT-3 levels were similar in SSc and in the control group (2657.2 ± 2296 vs 2959.3 ± 2555 pg/mL, NS). BDNF levels correlated negatively with increased NGF levels in the SSc group (and not in controls). CONCLUSION: Low BDNF serum levels were not previously documented in SSc, particularly in the diffuse SSc subset and in patients with pulmonary hypertension or anti-Scl-70 antibodies. The negative correlation between NGF and BDNF levels observed in SSc and not in healthy controls could be implicated in sympathic vascular dysfunction in SSc

Initial and bulk extraction of natural products isolation

Currently, there is a growing interest in the study of natural products, especially as part of drug discovery programs. Secondary metabolites can be extracted from a variety of natural sources, including plants, microbes, marine animals, insects, and amphibians. This chapter focuses principally on laboratory-scale processes of initial and bulk extraction from plant and microbial sources. With regard to plant natural products, the steps required for the preparation of the material prior to extraction, including aspects concerning plant selection, collection, identification, drying, and grinding, are detailed. The various extraction methods available (maceration, ultrasound-assisted solvent extraction, percolation, Soxhlet extraction, pressurized solvent extraction, extraction under reflux, steam distillation, and acid/based extraction) are reviewed. Regarding microbial natural products, this chapter covers issues relating to the isolation and culture of microorganisms and presents the extraction methods available for the recovery of microbial metabolites. Methods of minimizing compound degradation, artifacts formation, extract contamination with external impurities, and enrichment of extracts with desired metabolites are also examined

Anti-methicillin resistant Staphylococcus aureus (MRSA) activity of 'Pacific propolis' and isolated prenylflavanones

The need to discover and develop alternative therapies to treat methicillin-resistant Staphylococcus aureus (MRSA) infections is timely. This study was undertaken to purify and identify some anti-MRSA constituents from propolis, a natural product from the beehive traditionally used in folk medicine for its antimicrobial properties. A crude extract of propolis originating from the Solomon Islands ('Pacific propolis') was screened, using an agar dilution assay, in vitro against 15 MRSA clinical isolates. Results revealed activity worthy of further investigation, and subsequent purification work on this crude extract afforded 23 fractions. Further purification of active fractions led to the isolation of compounds 1–4, characterized upon analysis of their spectroscopic data (1D- and 2D-NMR, MS) and by comparison with the literature, as the prenylflavanones propolin H (1), propolin G (2), propolin D (3), and propolin C (4). This study is the first to report the anti-MRSA activity of 'Pacific propolis' and the presence of prenylflavanones in the propolis sample selected. The anti-MRSA activity of propolin D (3) (MIC 8–16 mg/L) and propolin C (4) (MIC 8–32 mg/L) is reported for the first time

L’hydrogéologie karstique : des premiers concepts aux avancées récentes

International audienceDepuis les premières idées nées il y a plus de 3 000 ans en Chine ou sur le pourtour de la Méditerranée, l’hydrogéologie karstique s’est enrichie des avancées des sciences en général. La pluridisciplinarité nécessaire pour aborder la singularité des aquifères karstiques lui confère une place particulière au sein des géosciences et explique l’origine de la diversité de la communauté qui s’y intéresse. Elle dispose à présent de nombreux outils d’investigation in situ, de calcul ou de modélisation qui ne se prêtent pas toujours à l’ingénierie opérationnelle. Dans les années 1970, deux courants de pensées complémentaires ont émergé. Le premier est basé sur une vision « fonctionnelle » du karst perçu comme un système transformant une entrée (précipitation) en une sortie (débit), alors que le second est basé sur une représentation « structurelle » constituée d’une matrice rocheuse fissurée recoupée par des fractures karstifiées et/ou conduits karstiques. Si ces deux visions s’accordent sur la coexistence de compartiments à écoulements lents et d’autres à écoulements rapides, elles sont à l’origine de différents modèles numériques de fonctionnement. Le développement de modèles robustes est un défi majeur pour répondre aux problématiques de volumes prélevables, de gestion des crues ou de protection de la ressource et ainsi à la demande sociétale croissante face aux pressions climatiques ou anthropiques. Le système karstique du Lez (Hérault) est pris comme exemple de la complémentarité des méthodes d’investigation et de modélisation

Hydrochemical characterization of a complex Mediterranean karstic system (Thau lagoon area, Montpellier, France) for the regional management of the groundwater resources

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Characterization and Origin of karstic thermal waters of the Northeast of Algeria.

International audienceThe northeastern part of Algeria has numerous thermal karstic springs which present an economicalinterest for the national office of the Algerian tourism. This organization considers the setting-up ofinfrastructures dedicated to the thermal tourism. The springs are located in a region of a 535 000 kmCwhich extends from Bejaïa to El-Kala (Tunisian border). The geological context is marked by ageological structure inherited of the alpine tectonic episodes Priabonia n to Tortonian at the origin oflarge faults and thrust systems. An analysis of the hydrochemical char acteristics of these waters, hasbe realised, at the regional scale, mainly to determine the geotectonic factors being the cause of thechemical facies and rising, but also to identify one or several deep geothermal reservoirs. Twosampling campaigns were realized on 52 sites, one during low waters (September, 2014) and theother during high waters (May, 2015). The analysis concerned major and trace elements, and isotopes(O18, H2, H3, Sr87 Sr86). From binary diagrams and from ACP treatments, results allowed todiscriminate 4 geochemical groups of waters. (1) a HCO3-Ca type, slightly mineralized andcharacterizing hypothermal waters with fast circulations, (2) a HCO3-Na type, more mineralized andcharacterizing mesothermal waters with deeper circulations, marked by phenomena of base exchangebetween water and clay levels, (3) a Cl-Na type, characterizing hyperthermal waters with deepcirculations attested by chemical exchanges with sedimentary evaporite levels, finally (4) a SO4-Catype having acquired its mineralization in triassic formations. Furthermore, a high percentage (75%) ofhyper or mesothermal springs, with chloride or sulphate facies, are located along the large regionalfaults identified by geophysical investigation. These results will be clarified by the use of silicium andalkaline geothermometers and temperature estimation using saturation index

Eléments de caractérisation des flux de recharge à différentes échelles de temps et d’observations en milieu karstique

International audienceLes systèmes karstiques se caractérisent par des processus de recharge et de transferts complexes, très variables dans le temps et dans l’espace, résultant notamment de la combinaison de différents types d’hétérogénéités du milieu. Dans ce type de contexte, les transferts d’eau au sein de la zone critique peuvent être étudiés en considérant les relations entre les différents éléments et compartiments constitutifs du karst: - épikarst, zone non saturée, zone saturée ; - matrice, fractures, conduits et chemins d'écoulements préférentiels, associées aux structures géologiques (successions lithostratigraphiques et zones de failles notamment). Les réponses hydrodynamiques et hydrogéochimiques observées aux exutoires des hydrosystèmes karstiques traduisent la complexité des échanges qui, pour être correctement caractérisée, nécessite des réseaux d’observations à différentes échelles. Le système karstique du Lez, rattaché à l’observatoire Multi Echelle de la DYnamique des Crues et de hYdrodynamique Souterraine en milieu karStiqUE (Observatoire MEDYCYSS), fait l'objet d'un monitoring hydrodynamique et hydrogéochimique depuis 2006 en différents points (forages, réseau karstique, sources temporaires et pérennes) afin de mieux apprécier le taux de renouvellement de la ressource en eau, mais également le rôle des différents éléments et compartiments du karst dans les crues de surface. Sur ce site, un forage CRITEX de 335 m, localisé à 500m en amont de l’exutoire principal (Source du Lez) et à proximité d’une rivière intermittente, a été équipé du système "Multi-level monitoring PMPS" (SolExperts ®) de façon à suivre en continu la pression/température dans le karst, au niveau de 5 intervalles isolés par des obturateurs et équipés pour le prélèvement d'eau souterraine. Ce dispositif, couplé au suivi hydrodynamique et hydrochimique effectué à l’exutoire principal de ce karst méditerranéen, offre un nouvel éclairage sur les mécanismes de la recharge à l’échelle du cycle hydrologique et/ou de l’évènement, ainsi que sur les interactions entre les écoulements de surface et souterrain. Les premiers résultats montrent (1) le rôle complexe des différents compartiments géologiques constitutifs de la zone critique sur la recharge de l’aquifère, (2) la nécessité de combiner les informations obtenues à différentes échelles d’observation pour préciser l’hétérogénéité, et notamment les variations latérales et verticales, des mécanismes de recharge en milieu karstique