Interfacial rheology and relaxation behavior of adsorption layers of the triterpenoid saponin Escin.

HYPOTHESIS: Escin, a monodesmosidic triterpenoid saponin, was shown previously to form viscoelastic interfaces with a very high dilatational and surface shear storage modulus. This is expected to be due to the arrangement of Escin into 2D disordered soft viscoelastic solid interfacial structures, which results in turn in a distribution of relaxation times. EXPERIMENTS: The responses to dilatational and surface shear deformations of Escin-stabilized air-water interfaces were studied, both in the linear viscoelastic (LVE) and non-linear (NLVE) regime. Step relaxation and amplitude sweeps were performed in dilatation experiments. For surface shear, amplitude sweeps and creep recovery experiments were performed. FINDINGS: Escin stabilized-interfaces displayed a highly non-linear behavior in dilatation as seen in the Lissajous plots. In large oscillatory shear the Lissajous curves had a rhomboidal shape, indicating intracycle yielding and recovery, typical of glassy systems. The relaxation of the interface showed stretched exponential behavior, with stretched exponents typical of disordered solids with dynamic heterogeneity. The use of surface rheological measurements beyond the commonly measured LVE regime clearly has provided new insights into the behavior of these interfaces and their microstructure. These results highlight the need to reconsider other complex interfaces as disordered solids and not as 2D homogenous viscoelastic fluids.

Changes in the dimeric state of neuronal nitric oxide synthase affect the kinetics of secretagogue-induced insulin response.

We previously showed that pancreatic beta-cells express a neuronal isoform of nitric oxide synthase (nNOS) that controls insulin secretion by exerting two enzymatic activities: nitric oxide (NO) production and cytochrome c reductase activity. We now bring evidence that two inhibitors of nNOS, N-omega-nitro-l-arginine methyl ester (l-NAME) and 7-nitroindazole (7-NI), increase glucose-induced insulin secretion but affect beta-cell function differently. In the presence of l-NAME, insulin response is monophasic, whereas 7-NI preserves the normal biphasic secretory pattern. In addition, the alterations of beta-cell functional response induced by the inhibitors also differ by their sensitivity to a substitutive treatment with sodium nitroprusside, a chemical NO donor. These differences are probably related to the nature of the two inhibitors. Indeed, using low-temperature SDS-PAGE and real-time analysis of nNOS dimerization by surface plasmon resonance, we could show that 7-NI, which competes with arginine and tetrahydrobiopterin (BH(4)), an essential cofactor for nNOS dimer formation, inhibits dimerization of the enzyme, whereas the substrate-based inhibitor l-NAME stabilizes the homodimeric state of nNOS. The latter effect could be reproduced by the two endogenous inhibitors of NOS, N-omega-methyl-l-arginine and asymmetric dimethylarginine, and resulted interestingly in a reduced ability of the protein inhibitor of nNOS (PIN) to dissociate nNOS dimers. We conclude that intracellular factors able to induce abnormalities in the nNOS monomer/dimer equilibrium could lead to pancreatic beta-cell dysfunction.

Miniglucagon (glucagon 19-29): a novel regulator of the pancreatic islet physiology.

Miniglucagon, the COOH-terminal (19-29) fragment processed from glucagon, is a potent and efficient inhibitor of insulin secretion from the MIN 6 beta-cell line. Using the rat isolated-perfused pancreas, we investigated the inhibitory effect of miniglucagon on insulin secretion and evaluated the existence of an inhibitory tone exerted by this peptide inside the islet. Miniglucagon dose-dependently inhibited insulin secretion stimulated by 8.3 mol/l glucose, with no change in the perfusion flow rate. A concentration of 1 nmol/l miniglucagon had a significant inhibitory effect on a 1 nmol/l glucagon-like peptide 1 (7-36) amide-potentiated insulin secretion. A decrease in extracellular glucose concentration simultaneously stimulated glucagon and miniglucagon secretion from pancreatic alpha-cells. Using confocal and electron microscopy analysis, we observed that miniglucagon is colocalized with glucagon in mature secretory granules of alpha-cells. Perfusion of an anti-miniglucagon antiserum directed against the biologically active moiety of the peptide resulted in a more pronounced effect of a glucose challenge on insulin secretion, indicating that miniglucagon exerts a local inhibitory tone on beta-cells. We concluded that miniglucagon is a novel local regulator of the pancreatic islet physiology and that any abnormal inhibitory tone exerted by this peptide on the beta-cell would result in an impaired insulin secretion, as observed in type 2 diabetes.

Chronic low-back pain modulation is enhanced by hypnotic analgesic suggestion by recruiting an emotional network: a PET imaging study.

This study aimed to characterize the neural networks involved in patients with chronic low-back pain during hypnoanalgesia. PET was performed in 2 states of consciousness, normal alertness and hypnosis. Two groups of patients received direct or indirect analgesic suggestion. The normal alertness state showed activations in a cognitive-sensory pain modulation network, including frontotemporal cortex, insula, somatosensory cortex, and cerebellum. The hypnotic state activated an emotional pain modulation network, including frontotemporal cortex, insula, caudate, accumbens, lenticular nuclei, and anterior cingulate cortex (ACC). Direct suggestion activated cognitive processes via frontal, prefrontal, and orbitofrontal cortices, while indirect suggestion activated a widespread and more emotional network including frontal cortex, anterior insula, inferior parietal lobule, lenticular nucleus, and ACC. Confirmed by visual analog scale data, these results suggest that chronic pain modulation is greater with hypnosis, which enhances both activated networks.

[Pharmaco-proteomic analysis: application of proteomic analysis to the discovery and development of new drugs]. / L'analyse pharmacoprotéomique: application de l'analyse protéomique à la découverte et au développement de nouvelles thérapeutiques.

Pharmacoproteomics may be defined as proteomics applied to the discovery of new therapeutic targets and to the study of drug effects. Proteomics is a powerful technique for analyzing the protein expression profiles in a biological system and its modifications in response to a stimulus or according to the physiological or pathophysiological states. Thus it is a technique of choice for the discovery of new drug targets. It is also an interesting approach for the study of the mode of action of treatments and preclinical drug development. This pharmacoproteomic approach may be particularly useful for the research of new molecular alterations implicated in type 2 diabetes and/or obesity and for the further characterization of existing or new drugs.

Insulinotropic agent ID-1101 (4-hydroxyisoleucine) activates insulin signaling in rat.

ID-1101 (4-hydroxyisoleucine), an amino acid extracted from fenugreek seeds, exhibits an interesting glucose-dependent insulin-stimulating activity. The present study was undertaken to investigate a possible extrapancreatic effect of ID-1101 on insulin signaling and action besides its previously described insulinotropic action. Insulin-sensitizing effects of ID-1101 were investigated in rat in vivo by three different approaches: 1) using euglycemic hyperinsulinemic clamps in two different rat models of insulin resistance, i.e., Zucker fa/fa rats and rats fed a sucrose-lipid diet; 2) measuring liver and muscle phosphatidylinositol (PI) 3-kinase activity after an acute injection of ID-1101 in normal and insulin-resistant diabetic rats; and 3) after chronic treatment in two rat models of insulin resistance. Euglycemic hyperinsulinemic clamp experiments revealed that ID-1101 can improve insulin resistance through an increase of peripheral glucose utilization rate in sucrose-lipid-fed rats and by decreasing hepatic glucose production in Zucker fa/fa rats. Moreover, we demonstrated that a single injection of ID-1101 activates the PI 3-kinase activity in liver and muscle from normal rats but also in muscle from diabetic rats. Finally, chronic ID-1101 treatment significantly reduced insulinemia in type 2 diabetic rats and reduced the progression of hyperinsulinemia in insulin-resistant obese Zucker fa/fa rats. These findings clearly demonstrate that ID-1101 can reduce insulin resistance through activation of the early steps of insulin signaling in peripheral tissues and in liver. In summary, ID-1101, besides its insulinotropic effect, directly improves insulin sensitivity, making it a potentially very valuable therapeutic agent for diabetes treatment.