Chemical composition and anti-arthritic activity of Anacyclus valentinus extract on adjuvant-induced arthritis in rats

Anacyclus valentinus L. is a common annual plant in Algeria, known for her various therapeutic effects. In addition, the plant is used as a food condiment. We reported our investigations on the chemical compositions and the antiarthritic activity of methanolic extract of A. valentinus (MEAV). The polyphenol extraction by maceration with methanol (80%) gave yields of 17.82%. The identification by LC-MS and colorimetric assays revealed the wealth of methanolic extracts on phenolic compounds including flavonoids (52.15 mg Equ/g) and lactones. Acute oral toxicity of extract was performed in line with OECD guidelines and the lethal dose 50 was assessed greater than 2500 mg/Kg. Regarding the anti-arthritic power, rheumatoid arthritis was induced by Freund\u27s adjuvant in rats. The methanolic extract of A. valentinus presented a largest effect with weight gain, an arthritic score, thymus indices; spleen and serum parameters close to those of the control. The extract also inhibited edema and restored cartilage structure

Enantiomerically pure amino-alcohol quinolines: in vitro anti-malarial activity in combination with dihydroartemisinin, cytotoxicity and in vivo efficacy in a Plasmodium berghei mouse model

International audienceBackground: As resistance to marketed anti-malarial drugs continues to spread, the need for new molecules active on Plasmodium falciparum-resistant strains grows. Pure (S) enantiomers of amino-alcohol quinolines previously displayed a good in vitro anti-malarial activity. Therefore, a more thorough assessment of their potential clinical use through a rodent model and an in vitro evaluation of their combination with artemisinin was undertaken. Methods: Screening on a panel of P. falciparum clones with varying resistance profiles and regional origins was performed for the (S)-pentyl and (S)-heptyl substituted quinoline derivatives, followed by an in vitro assessment of their combination with dihydroartemisinin (DHA) on the 3D7 clone and an in vivo assay in a mouse model infected with Plasmodium berghei. Their haemolytic activity was also determined. Results: A steady anti-malarial activity of the compounds tested was found, whatever the resistance profile or the regional origin of the strain. (S)-quinoline derivatives were at least three times more potent than mefloquine (MQ), their structurally close parent. The in vitro combination with DHA yielded an additive or synergic effect for both that was as good as that of the DHA/MQ combination. In vivo, survival rates were similar to those of MQ for the two compounds at a lower dose, despite a lack of clearance of the parasite blood stages. A 50% haemolysis was observed for concentrations at least 1,000-fold higher than the antiplasmodial IC 50 s. Conclusions: The results obtained make those two (S)-amino-alcohol quinoline derivatives good candidates for the development of new artemisinin-based combination therapy (ACT), hopefully with fewer neurologic side effects than those currently marketed ACT, including MQ

Selectivity of pyoverdine recognition by the FpvA receptor of Pseudomonas aeruginosa from molecular dynamics simulations

International audienceThe Gram-negative bacterium Pseudomonas aeruginosa, a ubiquitous human opportunistic pathogen, has developed resistances to multiple antibiotics. It uses its primary native siderophore, pyoverdine, to scavenge the iron essential to its growth in the outside medium and transport it back into its cytoplasm. The FpvA receptor on the bacterial outer membrane recognizes and internalizes pyoverdine bearing its iron payload, but can also bind pyoverdines from other Pseudomonads or synthetic analogues. Pyoverdine derivatives could therefore be used as vectors to deliver antibiotics into the bacterium. In this study, we use molecular dynamics and free energy calculations to characterize the mechanisms and thermodynamics of the recognition of the native pyoverdines of P. aeruginosa and P. fluorescens by FpvA. Based on these results, we delineate the features that pyoverdines with high affinity for FpvA should possess. In particular, we show that (i) the dynamics and interaction of the unbound pyoverdines with water should be optimized with equal care as the interface contacts in the complex with FpvA; (ii) the C-terminal extremity of the pyoverdine chain, which appears to play no role in the bound complex, is involved in the intermediate stages of recognition; and (iii) the length and cyclicity of the pyoverdine chain can be used to fine-tune the kinetics of the recognition mechanism

Chemical composition, in vitro antioxidant and anti-inflammatory activities of Juniperus oxycedrus subsp. oxycedrus extracts from Algeria

This study was conducted to examine chemical compositions, the anti-oxidant and anti-inflammatory properties of methanolic and aqueous extracts from aerial parts of Juniperus oxycedrus subsp oxycedrus growing in Mascara, Algeria. The quantitative assessment indicated that methanol extract was the most concentrated in phenolic, flavonoid and tannin contents (167.77±5.12 mg GAE/g DW, 90.56±2.23 mg QE/g DE and 110.21±2.38 mg CE/g DE respectively). The chromatographic analysis by HPLC showed quantitative differences in phenolic constutents, noting that Chlorogenic acid was the major compound of both extracts. Moreover, methanolic extract exhibited the highest antioxidant activity than the aqueous extract when tested by the 1,1-diphenyl-2-picrylhydrazyl (IC50 4.45±0.001 μg/mL) and phosphomolybdenum (328.52±0.071 mg of GAE/g DW) assays. Furthermore, the in vitro anti-inflammatory activity showed a strong inhibition of albumin denaturation by the methanolic extract at different concentrations when compared to standard drug diclofenac sodium. These findings confirm the richness of Algerian Juniperus oxycedrus extracts in bioactive compounds with antioxidant and anti-inflammatory capacities. These results are compatible with the use of the plant in traditional medicine. DOI: http://dx.doi.org/10.5281/zenodo.713528

Differences in anti-malarial activity of 4-aminoalcohol quinoline enantiomers and investigation of the presumed underlying mechanism of action

International audienc

Synthesis and Antiplasmodial Activity of Betulinic Acid and Ursolic Acid Analogues

More than 40% of the World population is at risk of contracting malaria, which affects primarily poor populations in tropical and subtropical areas. Antimalarial pharmacotherapy has utilised plant-derived products such as quinine and artemisinin as well as their derivatives. However, worldwide use of these antimalarials has caused the spread of resistant parasites, resulting in increased malaria morbidity and mortality. Considering that the literature has demonstrated the antimalarial potential of triterpenes, specially betulinic acid (1) and ursolic acid (2), this study investigated the antimalarial activity against P. falciparum chloroquine-sensitive 3D7 strain of some new derivatives of 1 and 2 with modifications at C-3 and C-28. The antiplasmodial study employed flow cytometry and spectrofluorimetric analyses using YOYO-1, dihydroethidium and Fluo4/AM for staining. Among the six analogues obtained, compounds 1c and 2c showed excellent activity (IC50 = 220 and 175 nM, respectively) while 1a and b demonstrated good activity ( IC50 = 4 and 5 mu M, respectively). After cytotoxicity evaluation against HEK293T cells, 1a was not toxic, while 1c and 2c showed IC50 of 4 mu M and a selectivity index (SI) value of 18 and 23, respectively. Moreover, compound 2c, which presents the best antiplasmodial activity, is involved in the calcium-regulated pathway(s).Instituto Nacional de Ciencia e Tecnologia para Inovacao Farmaceutica (INCTif, Brazil)Instituto Nacional de Ciencia e Tecnologia para Inovacao Farmaceutica (INCT-if, Brazil)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), BrazilConselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq-Brazil)Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), BrazilCoordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES-Brazil)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP), BrazilFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP, Brazil)Fundacao de Amparo a Pesquisa do Estado do Rio Grande do Sul (FAPERGS, Brazil)Fundacao de Amparo a Pesquisa do Estado do Rio Grande do Sul (FAPERGS, Brazil)FAPESPFAPES

Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia.

BACKGROUND: Genetic mutations underlying familial Alzheimer\u27s disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression of mutated transgenes have yielded key insights in mechanisms of disease, those models are subject to artifacts, including random genetic integration of the transgene, ectopic expression and non-physiological protein levels. The genetic engineering of novel mouse models using knock-in approaches addresses some of those limitations. With mounting evidence of the role played by microglia in AD, high-dimensional approaches to phenotype microglia in those models are critical to refine our understanding of the immune response in the brain. METHODS: We engineered a novel App knock-in mouse model (App RESULTS: Leveraging multi-omics approaches, we discovered profound alteration of diverse lipids and metabolites as well as an exacerbated disease-associated transcriptomic response in microglia with high intracellular Aβ content. The App DISCUSSION: Our findings demonstrate that fibrillar Aβ in microglia is associated with lipid dyshomeostasis consistent with lysosomal dysfunction and foam cell phenotypes as well as profound immuno-metabolic perturbations, opening new avenues to further investigate metabolic pathways at play in microglia responding to AD-relevant pathogenesis. The in-depth characterization of pathological hallmarks of AD in this novel and open-access mouse model should serve as a resource for the scientific community to investigate disease-relevant biology

A TREM2-activating antibody with a blood-brain barrier transport vehicle enhances microglial metabolism in Alzheimer's disease models

van Lengerich et al. developed a human TREM2 antibody with a transport vehicle (ATV) that improves brain exposure and biodistribution in mouse models. ATV:TREM2 promotes microglial energetic capacity and metabolism via mitochondrial pathways. Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer's disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy. Here we describe a high-affinity human TREM2-activating antibody engineered with a monovalent transferrin receptor (TfR) binding site, termed antibody transport vehicle (ATV), to facilitate blood-brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced signaling compared to a standard anti-TREM2 antibody. In human induced pluripotent stem cell (iPSC)-derived microglia, ATV:TREM2 induced proliferation and improved mitochondrial metabolism. Single-cell RNA sequencing and morphometry revealed that ATV:TREM2 shifted microglia to metabolically responsive states, which were distinct from those induced by amyloid pathology. In an AD mouse model, ATV:TREM2 boosted brain microglial activity and glucose metabolism. Thus, ATV:TREM2 represents a promising approach to improve microglial function and treat brain hypometabolism found in patients with AD