DP1 receptor signaling prevents the onset of intrinsic apoptosis in eosinophils and functions as a transcriptional modulator

Prostaglandin (PG) D2 is the ligand for the G‐protein coupled receptors DP1 (D‐type prostanoid receptor 1) and DP2 (also known as chemoattractant receptor homologous molecule, expressed on Th2 cells; CRTH2). Both, DP1 and DP2 are expressed on the cellular surface of eosinophils; although it has become quite clear that PGD2 induces eosinophil migration mainly via DP2 receptors, the role of DP1 in eosinophil responses has remained elusive. In this study, we addressed how DP1 receptor signaling complements the pro‐inflammatory effects of DP2. We found that PGD2 prolongs the survival of eosinophils via a DP1 receptor‐mediated mechanism that inhibits the onset of the intrinsic apoptotic cascade. The DP1 agonist BW245c prevented the activation of effector caspases in eosinophils and protected mitochondrial membranes from depolarization which—as a consequence—sustained viability of eosinophils. DP1 activation in eosinophils enhanced the expression of the anti‐apoptotic gene BCL‐XL, but also induced pro‐inflammatory genes, such as VLA‐4 and CCR3. In HEK293 cells that overexpress recombinant DP1 and/or DP2 receptors, activation of DP1, but not DP2, delayed cell death and stimulated proliferation, along with induction of serum response element (SRE), a regulator of anti‐apoptotic, early‐response genes. We conclude that DP1 receptors promote the survival via SRE induction and induction of pro‐inflammatory genes. Therefore, targeting DP1 receptors, along with DP2, may contribute to anti‐inflammatory therapy in eosinophilic diseases

Understanding the Oxidative Properties of Nickel Oxyhydroxide in Alcohol Oxidation Reactions

The NiOOH electrode is commonly used in electrochemical alcohol oxidations. Yet understanding the reaction mechanism is far from trivial. In many cases, the difficulty lies in the decoupling of the overlapping influence of chemical and electrochemical factors that not only govern the reaction pathway but also the crystal structure of the in situ formed oxyhydroxide. Here, we use a different approach to understand this system: we start with synthesizing pure forms of the two oxyhydroxides, β-NiOOH and γ-NiOOH. Then, using the oxidative dehydrogenation of three typical alcohols as the model reactions, we examine the reactivity and selectivity of each oxyhydroxide. While solvent has a clear effect on the reaction rate of β-NiOOH, the observed selectivity was found to be unaffected and remained over 95% for the dehydrogenation of both primary and secondary alcohols to aldehydes and ketones, respectively. Yet, high concentration of OH- in aqueous solvent promoted the preferential conversion of benzyl alcohol to benzoic acid. Thus, the formation of carboxylic compounds in the electrochemical oxidation without alkaline electrolyte is more likely to follow the direct electrochemical oxidation pathway. Overoxidation of NiOOH from the β- to γ-phase will affect the selectivity but not the reactivity with a sustained >95% conversion. The mechanistic examinations comprising kinetic isotope effects, Hammett analysis, and spin trapping studies reveal that benzyl alcohol is oxidatively dehydrogenated to benzaldehyde via two consecutive hydrogen atom transfer steps. This work offers the unique oxidative and catalytic properties of NiOOH in alcohol oxidation reactions, shedding light on the mechanistic understanding of the electrochemical alcohol conversion using NiOOH-based electrodes

Development and potential role of type-2 sodium-glucose transporter inhibitors for management of type 2 diabetes

There is a recognized need for new treatment options for type 2 diabetes mellitus (T2DM). Recovery of glucose from the glomerular filtrate represents an important mechanism in maintaining glucose homeostasis and represents a novel target for the management of T2DM. Recovery of glucose from the glomerular filtrate is executed principally by the type 2 sodium-glucose cotransporter (SGLT2). Inhibition of SGLT2 promotes glucose excretion and normalizes glycemia in animal models. First reports of specifically designed SGLT2 inhibitors began to appear in the second half of the 1990s. Several candidate SGLT2 inhibitors are currently under development, with four in the later stages of clinical testing. The safety profile of SGLT2 inhibitors is expected to be good, as their target is a highly specific membrane transporter expressed almost exclusively within the renal tubules. One safety concern is that of glycosuria, which could predispose patients to increased urinary tract infections. So far the reported safety profile of SGLT2 inhibitors in clinical studies appears to confirm that the class is well tolerated. Where SGLT2 inhibitors will fit in the current cascade of treatments for T2DM has yet to be established. The expected favorable safety profile and insulin-independent mechanism of action appear to support their use in combination with other antidiabetic drugs. Promotion of glucose excretion introduces the opportunity to clear calories (80–90 g [300–400 calories] of glucose per day) in patients that are generally overweight, and is expected to work synergistically with weight reduction programs. Experience will most likely lead to better understanding of which patients are likely to respond best to SGLT2 inhibitors, and under what circumstances

Development Of New Systems Of Nano-disperse Pt-(2%pt-ce0.9w 0.1o2)/c Electrocatalysts Tolerant To Carbon Monoxide (co) For Pemfc Anodes

The nanophase material (powder) of Ce0.9W0.1O 2 was synthesized via coprecipitation of oxalates of cerium (IV) and tungsten cations. Pt-Ce0.9W0.1O2 (2 wt% Pt) was prepared by an alcohol-reduction process using H2PtCl 6.6H2O as source of Pt, Ce0.9W 0.1O2 as support and ethylene glycol as solvent and reducing agent. Pt-Ce0.9W0.1O2 was physically mixed with commercial Pt/C E-TEK (20 w% Pt) to produce the Pt-(2%Pt-Ce 0.9W0.1O2)/C electrocatalyst. The prepared electrocatalysts were characterized by energy dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD) and CO stripping. The performances of Pt/C E-TEK and Pt-(2%Pt-Ce0.9W0.1O2)/C electrocatalysts were tested in single fuel cell fed with a mixture H2/CO (100 ppm of CO). The results showed that the mixture of 2%Pt-Ce0.9W 0.1O2 and Pt/C E-TEK increases the CO tolerance in a single fuel cell operating at 85°C compared with Pt/C E-TEK. ©The Electrochemical Society.431185189Du Melle, F., The global and urban environment: The need for clean power systems (1998) Journal of Power Sources, 71 (1-2), pp. 7-11Oliveira Neto, A., Farias, A.L., Dias, R.R., Brandalise, M., Linardi, M., Spinacé, E.V., Enhanced electro-oxidation of ethanol using PtSn/CeO2-C electrocatalyst prepared by an alcohol-reduction process (2008) Electrochemistry Communications, 10 (9), pp. 1315-1317Pamqvist, A.E.C., Wirde, M., Gelius, U., Muhammed, M., Surfaces of Doped Nanophase Cerium Oxide Catalysts (1999) NanoStructured Materials, 11 (8), pp. 995-1007Rothenberg, G., De Graaf, E.A., Bliek, A., Solvent-Free Synthesis of Rechargeable Solid Oxygen Reservoirs for Clean Hydrogen Oxidation (2003) Angew. Chem. Int. Ed., (42), pp. 3366-3368. , BartGu, D.M., Chu, Y.Y., Wang, Z.B., Jiang, Z.Z., Yin, G.P., Liu, Y., Methanol oxidation on Pt/CeO2-C electrocatalyst prepared by microwave-assisted ethylene glycol process (2010) Applied Catalysis B: Environmental, 102 (1-2), pp. 9-18Hou, Z., Yi, B., Lin, Z., Zhang, H., CO tolerance of PtRu-HxMeO3/C (Me = W, Mo) made by composite support method (2003) Journal of Power Sources, 123 (2), pp. 116-125Santiago, E.I., Batista, M.S., Assaf, M.E., Ticianelli, E.A., Mechanism of CO tolerance on Molybdenum-Based Electrocatalysts for PEMFC (2004) Journal of the Electrochemical Society, 151 (7), pp. A944-A94

Eotaxin and eotaxin receptor (CCR3) expression in Sephadex particle-induced rat lung inflammation

The β chemokine eotaxin is a potent eosinophil activator and chemoattractant. We examined immunohistochemically eotaxin protein expression in a range of normal rat tissues and in rat lung during Sephadex particle-induced pulmonary inflammation. The time course of eotaxin expression in lung at various time points after Sephadex administration was related to the appearance of eosinophils in the bronchoalveolar lavage fluid and tissue distribution of eotaxin receptor (CCR3) positive cells. Results showed that eotaxin protein was constitutively expressed by both lung airway epithelial cells and gut epithelial cells in normal tissues in the absence of inflammation. During Sephadex induced pulmonary inflammation, eotaxin expression increased in alveolar macrophages prior to the major increase in eosinophil numbers which reached a peak at 72 h. The pattern of eotaxin pulmonary expression and the location of CCR3 receptor positive cells suggest a chemoattractant gradient resulting in migration firstly into the tissue and subsequently through the airway epithelium into the airways. Treatment of rats with the glucocorticoid dexamethasone or the immunosuppressant cyclosporin A reduced eosinophil entry into lung tissue and airways but had no apparent effect on eotaxin expression in vivo, indicating that both these drugs inhibit eosinophil recruitment either by an eotaxin-independent mechanism, or by targetting factors that synergise with eotaxin, or an event post eotaxin expression