Common variants in P2RY11 are associated with narcolepsy.

l e t t e r s Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genomewide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3′ untranslated region of P2RY11, the purinergic receptor subtype P2Y 11 gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10 −10 , odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The diseaseassociated allele is correlated with reduced expression of P2RY11 in CD8 + T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases

Common variants in P2RY11 are associated with narcolepsy.

Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3' untranslated region of P2RY11, the purinergic receptor subtype P2Y₁₁ gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10⁻¹⁰, odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8(+) T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.journal articleresearch support, n.i.h., extramuralresearch support, non-u.s. gov'tresearch support, u.s. gov't, p.h.s.2011 Jan2010 12 19importedErratum in : Nat Genet. 2011 Oct;43(10):1040

Stabilizing Alginate Confinement and Polymer Coating of CO-Releasing Molecules Supported on Iron Oxide Nanoparticles To Trigger the CO Release by Magnetic Heating

Maghemite (Fe2O3) iron oxide nanoparticles (IONPs) were synthesized, modified with covalent surface-bound CO-releasing molecules of a tri(carbonyl)-chlorido-phenylalaninato-ruthenium(II) complex (CORM), and coated with a dextran polymer. The time- and temperature-dependent CO release from this CORM-3 analogue was followed by a myoglobin assay. A new measurement method for the myoglobin assay was developed, based on confining water-soluble polymer-coated Dextran500k@CORM@IONP particles in hollow spheres of nontoxic and easily prepared calcium alginate. Dropping a mixture of Dextran500k@CORM@IONP and sodium alginate into a CaCl2 solution leads to stable hollow spheres of Ca2+ cross-linked alginate which contain the Dextran500k@CORM@IONP particles. This alginate-method (i) protects CORM-3 analogues from rapid CO-displacement reactions with a protein, (ii) enables a spatial separation of the CORM from its surrounding myoglobin assay with the alginate acting as a CO-permeable membrane, and (iii) allows the use of substances with high absorptivity (such as iron oxide nanopartides) in the myoglobin assay without interference in the optical path of the UV cell. Embedding the CORM@IONP nanopartides in the alginate vessel represents a compartmentation of the reactive component and allows for close contact with, yet facile separation from, the surrounding myoglobin assay. The half-life of the CO release from Dextran500k@CORM@IONP particles surrounded by alginate was determined to be 890 +/- 70 min at 20 degrees C. An acceleration of the CO release occurs at higher temperature with a half-life of 172 +/- 27 min at 37 degrees C and 45 +/- 7 min at 50 degrees C. The CO release can be triggered in an alternating current magnetic field (31.7 kA m(-1), 247 kHz, 39.9 mT) through local magnetic heating of the susceptible iron oxide nanopartides. With magnetic heating at 20 degrees C in the bulk solution, the half-life of CO release from Dextran500k@CORM@IONP particles decreased to 155 +/- 18 min without a noticeable temperature increase in the dispersion. At 37 and 50 degrees C, the half-life for the CO release triggered by local magnetic heating was 65 +/- 5 min and 30 +/- 3 min, respectively. Thus, at a physiological temperature of 37 degrees C, magnetic heating accelerates the CO release of the IONP-bound CORM by a factor of similar to 2.6 The activation energy for CO release from a CORM-3 analogue was determined to be E-A = 78 kJ/mol

The Novel Class IIa Selective Histone Deacetylase Inhibitor YAK540 Is Synergistic with Bortezomib in Leukemia Cell Lines

The treatment of leukemias, especially acute myeloid leukemia (AML), is still a challenge as can be seen by poor 5-year survival of AML. Therefore, new therapeutic approaches are needed to increase the treatment success. Epigenetic aberrations play a role in pathogenesis and resistance of leukemia. Histone deacetylase (HDAC) inhibitors (HDACIs) can normalize epigenetic disbalance by affecting gene expression. In order to decrease side effects of so far mainly used pan-HDACIs, this paper introduces the novel highly selective class IIa HDACI YAK540. A synergistic cytotoxic effect was observed between YAK540 and the proteasome inhibitor bortezomib (BTZ) as analyzed by the Chou-Talalay method. The combination of YAK540 and BTZ showed generally increased proapoptotic gene expression, increased p21 expression, and synergistic, caspase 3/7-mediated apoptosis. Notably, the cytotoxicity of YAK540 is much lower than that of pan-HDACIs. Further, combinations of YAK540 and BTZ are clearly less toxic in non-cancer HEK293 compared to HL-60 leukemia cells. Thus, the synergistic combination of class IIa selective HDACIs such as YAK540 and proteasome inhibitors represents a promising approach against leukemias to increase the anticancer effect and to reduce the general toxicity of HDACIs

Synthesis of oxime-based CO-releasing molecules, CORMs and their immobilization on maghemite nanoparticles for magnetic-field induced CO release

Oxime-based CO-releasing molecules (oximeCORMs) were immobilized with a catechol-modified backbone on maghemite iron oxide nanoparticles (IONPs) to give oximeCORM@IONP. The CO release from the free and immobilized oximeCORMs was measured using the standard myoglobin assay. The oxime-CORM-nanoparticles were coated with dextran for improved water solubility and confined into an alginate shell for protection and separation from the surrounding myoglobin assay to allow for CO release studies by UV/Vis absorption without interference from highly-absorptive oximeCORM@IONP. Half-lifes of the oxime-based polymer-confined alginate@dextran@oximeCORM@IONPs were estimated at 20 degrees C to 814 +/- 23 min, at 37 degrees C to 346 +/- 83 min and at 50 degrees C to 73 +/- 1 min. The alginate@dextran@oximeCORM@IONP composite showed a further decrease of the half-life of CO release to 153 +/- 27 min at 37 degrees C through local magnetic heating of the susceptible iron oxide nanoparticles with application of an external alternating magnetic field (31.7 kA m(-1), 247 kHz, 39.9 mTesla). The activation energy for the CO release from molecular dicarbonylchlorido(imidazole-2-carbaldehydeoxime)(alkoxycarbonyl)ruthenium(II) complexes is determined to be similar to 100 kJ mol(-1) for five different imidazole-oxime derivatives

Discovery of a potent and selective free fatty acid receptor 1 agonist with low lipophilicity and high oral bioavailability

The free fatty acid receptor 1 (FFA1, also known as GPR40) mediates enhancement of glucosestimulated insulin secretion and is emerging as a new target for the treatment of type 2 diabetes. Several FFA1 agonists are known, but the majority of these suffer from high lipophilicity. We have previously reported the FFA1 agonist 3 (TUG-424). We here describe the continued structure−activity exploration and optimization of this compound series, leading to the discovery of the more potent agonist 40, a compound with low lipophilicity, excellent in vitro metabolic stability and permeability, complete oral bioavailability, and appreciable efficacy on glucose tolerance in mice