Comparison of the anti-diabetic effects of GIP- and GLP-1-receptor activation in obese diabetic (ob/ob) mice: studies with DPP IV resistant N-AcGIP and exendin(1-39)amide

Background The two major incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are being actively explored as anti-diabetic agents because they lower blood glucose through multiple mechanisms. The rapid inactivation of GIP and GLP-1 by the ubiquitous enzyme, dipeptidyl peptidase IV (DPP IV) makes their biological actions short-lived, but stable agonists such as N-acetylated GIP (N-AcGIP) and exendin(1-39)amide have been advocated as stable and specific GIP and GLP-1 analogues.

Beneficial effects of sub-chronic activation of glucagon-like peptide-1 (GLP-1) receptors on deterioration of glucose homeostasis and insulin secretion in aging mice

Aging is associated with an increased incidence of glucose intolerance and type 2 diabetes. Glucagon-like peptide-1 (GLP-1) is an important insulinotropic peptide secreted from the gastrointestinal tract in response to nutrient absorption. The present study was designed to assess the sub-chronic glucose regulatory effects of the potent long-acting GLP-1 receptor agonist, (Val(8))GLP-1, in aging 45-49 week old mice. Daily injection of (Val$)GLP-1 (25 nmol/kg body weight) for 12 days had no significant effect on food intake, body weight, non-fasting plasma glucose and insulin concentrations. However, after 12 days, the glycaemic response to intraperitoneal glucose was improved (P <0.05) in (Val(8))GLP-1 treated mice. In keeping with this, glucose-mediated insulin secretion was enhanced (P <0.05) and insulin sensitivity improved (P <0.05) compared to controls. These data indicate that sub-chronic activation of the GLP-1 receptor by daily treatment with (Val(8))GLP-1 counters aspects of the age-related impairment of pancreatic beta-cell function and insulin sensitivity. 2006 Elsevier Inc. All rights reserved.

Interleukin-8 signaling promotes androgen-independent proliferation of prostate cancer cells via induction of androgen receptor expression and activation

The aim of our study was to assess the importance of the CXC chemokine and interleukin (IL)-8 in promoting the transition of prostate cancer (CaP) to the androgen-independent state. Stimulation of the androgen-dependent cell lines, LNCaP and 22Rv1, with exogenous recombinant human interleukin-8 (rh-IL-8) increased androgen receptor (AR) gene expression at the messenger RNA (mRNA) and protein level, assessed by quantitative polymerase chain reaction and immunoblotting, respectively. Using an androgen response element-luciferase construct, we demonstrated that rh-IL-8 treatment also resulted in increased AR transcriptional activity in both these cell lines, and a subsequent upregulation of prostate-specific antigen and cyclin-dependent kinase 2 mRNA transcript levels in LNCaP cells. Blockade of CXC chemokine receptor-2 signaling using a small molecule antagonist (AZ10397767) attenuated the IL-8-induced increases in AR expression and transcriptional activity. Furthermore, in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, coadministration of AZ10397767 reduced the viability of LNCaP and 22Rv1 cells exposed to bicalutamide. Our data show that IL-8 signaling increases AR expression and promotes ligand-independent activation of this receptor in two androgen-dependent cell lines, describing two mechanisms by which this chemokine may assist in promoting the transition of CaP to the androgen-independent state. In addition, our data show that IL-8-promoted regulation of the AR attenuates the effectiveness of the AR antagonist bicalutamide in reducing CaP cell viability.

C-H bond activation over metal oxides: A new insight into the dissociation kinetics from density functional theory

The C-H activation on metal oxides is a fundamental process in chemistry. In this paper, we report a density functional theory study on the process of the C-H activation of CH4 on Pd(111), Pt(111), Ru(0001), Tc(0001), Cu(111), PdO(001), PdO(110), and PdO(100). A linear relationship between the C-H activation barrier and the chemisorption in the dissociation final state on the metal surfaces is obtained, which is consistent with the work in the literature. However, the relationship is poor on the metal oxide surfaces. Instead, a strong linear correlation between the barrier and the lattice O-H bond strength is found on the oxides. The new linear relationship is analyzed and the physical origin is identified. (c) 2008 American Institute of Physics.

The possibility of single C-H bond activation in CH4 on a MoO3-supported Pt catalyst: A density functional theory study

Methane activation is a crucial step in the conversion of methane to valuable oxygenated products. In heterogeneous catalysis, however, methane activation often leads to complete dissociation: If a catalyst can activate the first C-H bond in CH4, it can often break the remaining C-H bonds. In this study, using density functional theory, we illustrate that single C-H bond activation in CH4 is possible. We choose a model system which consists of isolated Pt atoms on a MoO3(010) surface. We find that the Pt atoms on this surface can readily activate the first C-H bond in methane. The reaction barrier of only 0.3 eV obtained in this study is significantly lower than that on a Pt(111) surface. We also find, in contrast to the processes on pure metal surfaces, that the further dehydrogenation of methyl (CH3) is very energetically unfavorable on the MoO3-supported Pt catalyst. (C) 2002 American Institute of Physics.

Activation of waste MDF sawdust charcoal and its reactive dye adsorption characteristics

This paper reports an experimental investigation of converting waste medium density fibreboard (MDF) sawdust into chars and activated carbon using chemical activation and thermal carbonisation processes. The MDF sawdust generated during the production of architectural mouldings was characterised and found to have unique properties in terms of fine particle size and high particle density. It also has a high content of urea formaldehyde resin used as a binder in the manufacturing of MDF board. Direct thermal carbonisation and chemical activation of the sawdust by metal impregnation and acid (phosphoric acid) treatment prior to pyrolysis treatment were carried out. The surface morphology of the raw dust, its chars and activated carbon were examined using scanning electron microscopy (SEM). Adsorptive properties and total pore volume of the materials were also analysed using the BET nitrogen adsorption method. Liquid adsorption of a reactive dye (Levafix Brilliant red E-4BA) by the derived sawdust carbon was investigated in batch isothermal adsorption process and the results compared to adsorption on to a commercial activated carbon (Filtrasorb F400). The MDF sawdust carbon exhibited in general a very low adsorption capacity towards the reactive dye, and physical characterisation of the carbon revealed that the conventional chemical activation and thermal carbonisation process were ineffective in developing a microporous structure in the dust particles. The small size of the powdery dust, the high particle density, and the presence of the urea formaldehyde resin all contributed to the difficulty of developing a proper porous structure during the thermal and chemical activation process. Finally, activation of the dust material in a consolidated form (cylindrical pellet) only achieved very limited improvement in the dye adsorption capacity. This original study, reporting some unexpected outcomes, may serve as a stepping-stone for future investigations of recycle and reuse of the waste MDF sawdust which is becoming an increasing environmental and cost liability. (C) 2004 Elsevier Ltd. All rights reserved.

Substitution of pseudokinase domain residue Val-617 by large non-polar amino acids causes activation of JAK2

Explaining the uniqueness of the acquired somatic JAK2 V617F mutation, which is present in more than 95% of polycythemia vera patients, has been a challenge. The V617F mutation in the pseudokinase domain of JAK2 renders the unmutated kinase domain constitutively active. We have performed random mutagenesis at position 617 of JAK2 and tested each of the 20 possible amino acids for ability to induce constitutive signaling in Ba/F3 cells expressing the erythropoietin receptor. Four JAK2 mutants, V617W, V617M, V617I, and V617L, were able to induce cytokine independence and constitutive downstream signaling. Only V617W induced a level of constitutive activation comparable with V617F. Also, only V617W stabilized tyrosine-phosphorylated suppressor of cytokine signaling 3 ( SOCS3), a mechanism by which JAK2 V617F overcomes inhibition by SOCS3. The V617W mutant induced a myeloproliferative disease in mice, mainly characterized by erythrocytosis and megakaryocytic proliferation. Although JAK2 V617W would predictably be pathogenic in humans, the substitution of the Val codon, GTC, by TTG, the codon for Trp, would require three base pair changes, and thus it is unlikely to occur. We discuss how the predicted conformations of the activated JAK2 mutants can lead to better screening assays for novel small molecule inhibitors.

Age-related differences in rapid muscle activation after rate of force development training of the elbow flexors

In young adults, improvements in the rate of force development as a result of resistance training are accompanied by increases in neural drive in the very initial phase of muscle activation. The purpose of this experiment was to determine if older adults also exhibit similar adaptations in response to rate of force development (RFD) training. Eight young (21-35 years) and eight older (60-79 years) adults were assessed during the production of maximum rapid contractions, before and after four weeks of progressive resistance training for the elbow flexors. Young and older adults exhibited significant increases (P<0.01) in peak RFD, of 25.6% and 28.6% respectively. For both groups the increase in RFD was accompanied by an increase in the root mean square (RMS) amplitude and in the rate of rise (RER) in the electromyogram (EMG) throughout the initial 100 ms of activation. For older adults, however, this training response was only apparent in the brachialis and brachioradialis muscles. This response was not observed in surface EMG recorded from the biceps brachii muscle during either RFD testing or throughout training, nor was it observed in the pronator teres muscle. The minimal adaptations observed for older adults in the bifunctional muscles biceps brachii and pronator teres are considered to indicate a compromise of the neural adaptations older adults might experience in response to resistance training.

Bimanual coordination: constraints imposed by the relative timing of homologous muscle activation

It has often been supposed that patterns of rhythmic bimanual coordination in which homologous muscles are engaged simultaneously, are performed in a more stable manner than those in which the same muscles are activated in an alternating fashion. In order to assess the efficacy of this constraint, the present study investigated the effect of forearm posture (prone or supine) on bimanual abduction-adduction movements of the wrist in isodirectional and non-isodirectional modes of coordination. Irrespective of forearm posture, non-isodirectional coordination was observed to be more stable than isodirectional coordination. In the latter condition, there was a more severe deterioration of coordination accuracy/stability as a function of cycling frequency than in the former condition. With elevations in cycling frequency, the performers recruited extra mechanical degrees of freedom, principally via flexion-extension of the wrist, which gave rise to increasing motion in the vertical plane. The increases in movement amplitude in the vertical plane were accompanied by decreasing amplitude in the horizontal plane. In agreement with previous studies, the present findings confirm that the relative timing of homologous muscle activation acts as a principal constraint upon the stability of interlimb coordination. Furthermore, it is argued that the use of manipulations of limb posture to investigate the role of other classes of constraint (e.g. perceptual) should be approached with caution because such manipulations affect the mapping between muscle activation patterns, movement dynamics and kinematics.