Unprecedented incorporation of α-emitter radioisotope 213Bi into porphyrin chelates with reference to a daughter isotope mediated assistance mechanism.

International audienceFor the first time, α-emitter radioisotope (213)Bi has been incorporated into porphyrin chelates, with rates matching with the short period of the radionuclide. An in situ transmetalation mechanism involving the daughter isotope (209)Pb is expected to boost the (213)Bi radiolabeling process

RIPK1 protects from TNF-α-mediated liver damage during hepatitis

Cell death of hepatocytes is a prominent characteristic in the pathogenesis of liver disease, while hepatolysis is a starting point of inflammation in hepatitis and loss of hepatic function. However, the precise molecular mechanisms of hepatocyte cell death, the role of the cytokines of hepatic microenvironment and the involvement of intracellular kinases, remain unclear. Tumor necrosis factor alpha (TNF-alpha) is a key cytokine involved in cell death or survival pathways and the role of RIPK1 has been associated to the TNF-alpha-dependent signaling pathway. We took advantage of two different deficient mouse lines, the RIPK1 kinase dead knock-in mice (Ripk1K45A) and the conditional knockout mice lacking RIPK1 only in liver parenchymal cells (Ripk1LPC-KO), to characterize the role of RIPK1 and TNF-alpha in hepatitis induced by concanavalin A (ConA). Our results show that RIPK1 is dispensable for liver homeostasis under steady-state conditions but in contrast, RIPK1 kinase activity contributes to caspase-independent cell death induction following ConA injection and RIPK1 also serves as a scaffold, protecting hepatocytes from massive apoptotic cell death in this model. In the Ripk1LPC-KO mice challenged with ConA, TNF-alpha triggers apoptosis, responsible for the observed severe hepatitis. Mechanism potentially involves both TNF-independent canonical NF-kappa B activation, as well as TNF-dependent, but canonical NF-kappa B-independent mechanisms. In conclusion, our results suggest that RIPK1 kinase activity is a pertinent therapeutic target to protect liver against excessive cell death in liver diseases

Del Pezzo surfaces of degree 55 over perfect fields

We classify del Pezzo surfaces of degree $5$ over a perfect field $\mathbf{k}$ according to the actions of the Galois group $\operatorname{Gal}(\overline{\mathbf{k}}/\mathbf{k})$ on the graph of $(-1)$-curves, and we explicitely describe their automorphism groups

A role for lipid rafts in the protection afforded by docosahexaenoic acid against ethanol toxicity in primary rat hepatocytes.

International audience: Previously, we demonstrated that eicosapentaenoic acid enhanced ethanol-induced oxidative stress and cell death in primary rat hepatocytes via an increase in membrane fluidity and lipid raft clustering. In this context, another n-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA), was tested with a special emphasis on physical and chemical alteration of lipid rafts. Pretreatment of hepatocytes with DHA reduced significantly ethanol-induced oxidative stress and cell death. DHA protection could be related to an alteration of lipid rafts. Indeed, rafts exhibited a marked increase in membrane fluidity and packing defects leading to the exclusion of a raft protein marker, flotillin. Furthermore, DHA strongly inhibited disulfide bridge formation, even in control cells, thus suggesting a disruption of protein-protein interactions inside lipid rafts. This particular spatial organization of lipid rafts due to DHA subsequently prevented the ethanol-induced lipid raft clustering. Such a prevention was then responsible for the inhibition of phospholipase C-γ translocation into rafts, and consequently of both lysosome accumulation and elevation in cellular low-molecular-weight iron content, a prooxidant factor. In total, the present study suggests that DHA supplementation could represent a new preventive approach for patients with alcoholic liver disease based upon modulation of the membrane structures

Protective action of n-3 fatty acids on benzo[a]pyrene-induced apoptosis through the plasma membrane remodeling-dependent NHE1 pathway

International audiencePlasma membrane is an early target of polycyclic aromatic hydrocarbons (PAH). We previously showed that the PAH prototype, benzo[a]pyrene (B[a]P), triggers apoptosis via DNA damage-induced p53 activation (genotoxic pathway) and via remodeling of the membrane cholesterol-rich microdomains called lipid rafts, leading to changes in pH homeostasis (non-genotoxic pathway). As omega-3 (n-3) fatty acids can affect membrane composition and function or hamper in vivo PAH genotoxicity, we hypothesized that addition of physiologically relevant levels of polyunsaturated n-3 fatty acids (PUFAs) might interfere with B[a]P-induced toxicity. The effects of two major PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), were tested on B[a]P cytotoxicity in the liver epithelial cell line F258. Both PUFAs reduced B[a]P-induced apoptosis. Surprisingly, pre-treatment with DHA increased the formation of reactive B[a]P metabolites, resulting in higher levels of B[a]P-DNA adducts. EPA had no apparent effect on B[a]P metabolism or related DNA damage. EPA and DHA prevented B[a]P-induced apoptotic alkalinization by affecting Na(+)/H(+) exchanger 1 activity. Thus, the inhibitory effects of omega-3 fatty acids on B[a]P-induced apoptosis involve a non-genotoxic pathway associated with plasma membrane remodeling. Our results suggest that dietary omega-3 fatty acids may have marked effects on the biological consequences of PAH exposure

Importance of the difference in surface pressures of the cell membrane in doxorubicin resistant cells that do not express Pgp and ABCG2

P-glycoprotein (Pgp) represents the archetypal mechanism of drug resistance. But Pgp alone cannot expel drugs. A small but growing body of works has demonstrated that the membrane biophysical properties are central to Pgp-mediated drug resistance. For example, a change in the membrane surface pressure is expected to support drug–Pgp interaction. An interesting aspect from these models is that under specific conditions, the membrane is predicted to take over Pgp concerning the mechanism of drug resistance especially when the surface pressure is high enough, at which point drugs remain physically blocked at the membrane level. However it remains to be determined experimentally whether the membrane itself could, on its own, affect drug entry into cells that have been selected by a low concentration of drug and that do not express transporters. We demonstrate here that in the case of the drug doxorubicin, alteration of the surface pressure of membrane leaflets drive drug resistance

Carbon Nanotube and Porphyrins:Materials for Optics and Energy Applications

International audienceThe fabrication of functional hybrid materials that preserves and combines the properties of their building blocks is a central issue of nanosciences. Among the different classes of nanomaterials, carbon nanotubes are promising for electronics, opto-electronics, catalysis and composite applications. In this context the combination of nanotubes with porphyrins has been widely explored for catalytic or electron transfer purposes. Here I present two results obtained recently on the nanotube/porphyrincomposites, the first deals with the supramolecular organization in micelles of porphyrins around the nanotubes. In this work we were able to explain the Davidoff splitting observed on the absorption bands of the porphyrins by their organization around the nanotubes. The second deals with the synergic effect on catalytic activity of carbon nanotubes and strapped iron porphyrin hybrids for Oxygen Reduction Reaction (ORR). In particular, we demonstrated that the combination of both components - MWNTs and porphyrin - leads to a better catalytic activity than those of the nanotubes or the porphyrins taken separately.This study highlights the importance of the carbon support for the catalysis. The nanotubes ensure the availability of electrons to the porphyrin catalysts and allow the ORR to occur via the 4-electron pathway, avoiding the production of hydrogen peroxide

2-(2-Pyrid­yl)pyridinium (2,2′-bipyridine-κ2 N,N′)tetra­kis­(nitrato-κ2 O,O′)bis­muthate(III)

The structure of the title compound, (C10H9N2)[Bi(NO3)4(C10H8N2)], consists of 2-(2-pyrid­yl)pyridinium cations and anions [Bi(NO3)4(C10H8N2)]−. The Bi3+ ion lies on the twofold axis. It is coordinated by two nitro­gen atoms from one 2,2′-bipyridine ligand and eight oxygen atoms from four NO3 − anions. The disordered cation is positioned at the inversion centre. The [Bi(NO3)4(C10H8N2)]− anions and 2-(2-pyrid­yl)pyridinium cations are connected via N—H⋯O hydrogen bonds into chains. Moreover, these chains are further linked into a two-dimensional layered structure through π–π stacking inter­actions between bipyridine ligands along the c axis [centroid–centroid distance = 2.868 (4) Å]

Identification of the couple GSK3α/c-Myc as a new regulator of hexokinase II in benzo[a]pyrene-induced apoptosis.

International audienceThe early apoptotic events induced by environmental pollutants with carcinogenic properties are poorly understood. Here, we focus on the early cytotoxic effects of benzo[a]pyrene (B[a]P). In F258 rat hepatic epithelial cells, B[a]P induces intrinsic apoptosis via a mitochondrial dysfunction characterized by the release of hexokinase II (HKII) from the mitochondria. Cancer cells often have an anomalous cell energy metabolism; since HKII dysfunction regulates B[a]P-induced apoptosis in F258 cells, but may also alter cell energy metabolism, HKII release from the mitochondria may represent an important B[a]P-related carcinogenic issue. Thus in the present study, we aimed at deciphering the mechanisms underlying HKII dysfunction upon B[a]P exposure. We show that while glycogen synthase kinase 3 beta (GSK3β) regulated the expression of HKII at the transcriptional level, glycogen synthase kinase 3 alpha (GSK3α) was involved in B[a]P-induced apoptosis via a decrease in c-Myc expression. The reduced level of c-Myc caused the relocation of HKII from the mitochondria to the cytosol, thereby being involved in the formation of reactive oxygen species and apoptosis. In conclusion, we show that the couple GSK3α/c-Myc plays a key role in B[a]P-induced early apoptotic cell signaling via HKII dysfunction