Summary: While cadmium (Cd) tolerance is a constitutive trait in the Arabidopsis halleri species, Cd accumulation is highly variable. Recent adaptation to anthropogenic metal stress has occurred independently within the genetic units of A. halleri and the evolution of different mechanisms involved in Cd tolerance and accumulation has been suggested. To gain a better understanding of the mechanisms underlying Cd tolerance and accumulation in A. halleri, ionomic inductively coupled plasma mass spectrometry (ICP‐MS), transcriptomic (RNA sequencing) and metabolomic (high‐performance liquid chromatography–mass spectrometry) profiles were analysed in two A. halleri metallicolous populations from different genetic units (PL22 from Poland and I16 from Italy). The PL22 and I16 populations were both hypertolerant to Cd, but PL22 hyperaccumulated Cd while I16 behaved as an excluder both in situ and when grown hydroponically. The observed hyperaccumulator vs excluder behaviours were paralleled by large differences in the expression profiles of transporter genes. Flavonoid‐related transcripts and metabolites were strikingly more abundant in PL22 than in I16 shoots. The role of novel A. halleri candidate genes possibly involved in Cd hyperaccumulation or exclusion was supported by the study of corresponding A. thaliana knockout mutants. Taken together, our results are suggestive of the evolution of divergent strategies for Cd uptake, transport and detoxification in different genetic units of A. halleri.

There is evidence that hyperglycemia results in the generation of reactive oxygen species, leading to oxidative stress in various tissues, including vascular system. An important link between oxidative stress, inflammatory response and insulin activity is now well established. The ability of antioxidants to protect against the deleterious effects of hyperglycemia and also to improve glucose metabolism and intake must be considered as leads of choice in diabetes treatment. In addition to their antioxidative activity, many flavonoids were demonstrated to act on biological targets involved in type 2 diabetes mellitus such as: α-glycosidase, glucose cotransporter or aldose reductase. In this context, flavonoids behaving as antioxidants were studied as potential drugs by acting as biological targets involved in diabetes development. In this review, we propose to shed light on antioxidants flavonoids investigated as antidiabetics. A special focus was made to address the structure-activity relationship related to the effect of these naturally occurring molecules on different targets involved in diabetes development.

Background: Over the past decades, in spite of intensive search, no significant increase in the survival of patients with glioblastoma has been obtained. The role of the blood-brain barrier (BBB) and especially the activity of efflux pumps belonging to the ATP Binding Cassette (ABC) family may, in part, explain this defect.Methods: Thein-vitroactivities of JAI-51 on cell proliferation were assessed by various experimental approaches in four human and a murine glioblastoma cell lines. Using drug exclusion assays and flow-cytometry, potential inhibitory effects of JAI-51 on P-gp and BCRP were evaluated in sensitive or resistant cell lines. JAI-51 activity onin-vitromicrotubule polymerization was assessed by tubulin polymerization assay and direct binding measurements by analytical ultracentrifugation. Finally, a model of C57BL/6 mice bearing subcutaneous GL26 glioblastoma xenografts was used to assess the activity of the title compoundin vivo. An HPLC method was designed to detect JAI-51 in the brain and other target organs of the treated animals, as well as in the tumours.Results: In the four human and the murine glioblastoma cell lines tested, 10 μM JAI-51 inhibited proliferation and blocked cells in the M phase of the cell cycle, via its activity as a microtubule depolymerising agent. This ligand binds to tubulin with an association constant of 2 × 10⁵M^-1, overlapping the colchicine binding site. JAI-51 also inhibited the activity of P-gp and BCRP, without being a substrate of these efflux pumps. Thesein vitrostudies were reinforced by ourin vivoinvestigations of C57BL/6 mice bearing GL26 glioblastoma xenografts, in which JAI-51 induced a delay in tumour onset and a tumour growth inhibition, following intraperitoneal administration of 96 mg/kg once a week. In accordance with these results, JAI-51 was detected by HPLC in the tumours of the treated animals. Moreover, JAI-51 was detected in the brain, showing that the molecule is also able to cross the BBB.Conclusion: Thesein vitroandin vivodata suggest that JAI-51 could be a good candidate for a new treatment of tumours of the CNS. Further investigations are in progress to associate the title compound chemotherapy to radiotherapy in a rat model.