Neuroprotective actions of a histidine analogue in models of ischemic stroke.

Histidine is a naturally occurring amino acid with antioxidant properties, which is present in low amounts in tissues throughout the body. We recently synthesized and characterized histidine analogues related to the natural dipeptide carnosine, which selectively scavenge the toxic lipid peroxidation product 4-hydroxynonenal (HNE). We now report that the histidine analogue histidyl hydrazide is effective in reducing brain damage and improving functional outcome in a mouse model of focal ischemic stroke when administered intravenously at a dose of 20 mg/kg, either 30 min before or 60 min and 3 h after the onset of middle cerebral artery occlusion. The histidine analogue also protected cultured rat primary neurons against death induced by HNE, chemical hypoxia, glucose deprivation, and combined oxygen and glucose deprivation. The histidine analogue prevented neuronal apoptosis as indicated by decreased production of cleaved caspase-3 protein. These findings suggest a therapeutic potential for HNE-scavenging histidine analogues in the treatment of stroke and related neurodegenerative conditions.

Characterisation and glucoregulatory actions of a novel acylated form of the (Pro(3))GIP receptor antagonist in type 2 diabetes

In this study, we tested the biological activity of a novel acylated form of (Pro(3))glucose-dependent insulinotropic polypetide [(Pro3)GIP] prepared by conjugating palmitic acid to Lys(16) to enhance its efficacy in vivo by promoting binding to albumin and extending its biological actions. Like the parent molecule (Pro(3))GIP, (Pro(3))GIPLys(16)PAL was completely stable to the actions of DPP-IV and significantly (p <0.01 to p <0.001) inhibited GIP-stimulated cAMP production and cellular insulin secretion. Furthermore, acute administration of (Pro(3))GIPLys(16)PAL also significantly (p <0.05 to p <0.001) countered the glucose-lowering and insulin-releasing actions of GIP in ob/ob mice. Daily injection of (Pro(3))GIPLys(16)PAL (25 nmol/kg bw) in 14-18-week-old ob/ob mice over 14 days had no effect on body weight, food intake or non-fasting plasma glucose and insulin concentrations. (Pro(3))GIPLys(16)PAL treatment also failed to significantly alter the glycaemic response to an i.p. glucose load or test meal, but insulin concentrations were significantly reduced (1.5-fold; p <0.05) after the glucose load. Insulin sensitivity was enhanced (1.3-fold; p <0.05) and pancreatic insulin was significantly reduced (p <0.05) in the (Pro(3))GIPLys(16)PAL-treated mice. These data demonstrate that acylation of Lys(16) with palmitic acid in (Pro(3))GIP does not improve its biological effectiveness as a GIP receptor antagonist.

Degradation, receptor binding, insulin secreting and antihyperglycaemic actions of palmitate-derivatised native and Ala(8)-substituted GLP-1 analogues

The hormone glucagonlike peptide-1(736)amide (GLP-1) is released in response to ingested nutrients and acts to promote glucosedependent insulin secretion ensuring efficient postprandial glucose homeostasis. Unfortunately, the beneficial actions of GLP-1 which give this hormone many of the desirable properties of an antidiabetic drug are short lived due to degradation by dipeptidylpeptidase IV (DPP IV) and rapid clearance by renal filtration. In this study we have attempted to extend GLP-1 action through the attachment of palmitoyl moieties to the epsilon-amino group in the side chain of the Lys(26) residue and to combine this modification with substitutions of the Ala(8) residue, namely Val or aminobutyric acid (Abu). In contrast to native GLP-1, which was rapidly degraded, [Lys(pal)(26)]GLP-1, [Abu(8),Lys(pal)(26)]GLP-1 and [Val(8),Lys(pal)(26)]GLP-1 all exhibited profound stability during 12 h incubations with DPP IV and human plasma. Receptor binding affinity and the ability to increase cyclic AMP in the clonal beta-cell line BRIN-BD11 were decreased by 86- to 167-fold and 15- to 62-fold, respectively compared with native GLP-1. However, insulin secretory potency tested using BRIN-BD11 cells was similar, or in the case of [Val(8),Lys(pal)(26)]GLP-1 enhanced. Furthermore, when administered in vivo together with glucose to diabetic (ob/ob) mice, [Lys(pal)(26)]GLP-1, [Abu(8),Lys(pal)(26)]GLP-1 and [Val8,Lys(pal)26]GLP-1 did not demonstrate acute glucoselowering or insulinotropic activity as observed with native GLP-1. These studies support the potential usefulness of fatty acid linked analogues of GLP-1 but indicate the importance of chain length for peptide kinetics and bioavailability.

Recognising Ecological Contexts of Diverse Ethnic Groups: Experiences of British-Indian Adult Children of Divorce

The process of divorce as a family change process including outcomes and consequences has received considerable research attention in the western context. However, the experience of divorce for children within specific ethnic contexts has been rather limited leading to poor planning and practice provision with diverse families. By drawing upon an empirical qualitative study of British Indian adult children, this paper will make a case for recognising diverse needs within specific historical, socio-cultural and developmental contexts. There is a need to acknowledge these contexts in policy design to establish practice that is flexible, accessible and relevant to the needs of different and diverse communities. Results indicate that areas of impact may be similar to those identified by other studies within the literature review. However, the experiences, expressions, implications and larger consequences of impact are located within specific socio-cultural contexts. In support of this, major findings of the study (outlined below) will be discussed - Context: patriarchy, stigma, immigration; Impact: economic, social, emotional, career/education, physical; Coping: psychological strategies, physical strategies, social strategies, sources of support.

Interaction of water, hydrogen and their mixtures with SnO2 based materials: the role of surface hydroxyl groups in detection mechanisms

DRIFTS, TGA and resistance measurements have been used to study the mechanism of water and hydrogen interaction accompanied by a resistance change (sensor signal) of blank and Pd doped SnO2. It was found that a highly hydroxylated surface of blank SnO2 reacts with gases through bridging hydroxyl groups, whereas the Pd doped materials interact with hydrogen and water through bridging oxygen. In the case of blank SnO2 the sensor signal maximum towards H-2 in dry air (R-0/R-g) is observed at similar to 345 degrees C, and towards water, at similar to 180 degrees C, which results in high selectivity to hydrogen in the presence of water vapors (minor humidity effect). In contrast, on doping with Pd the response to hydrogen in dry air and to water occurred in the same temperature region (ca. 140 degrees C) leading to low selectivity with a high effect of humidity. An increase in water concentration in the gas phase changes the hydrogen interaction mechanism of Pd doped materials, while that of blank SnO2 is unchanged. The interaction of hydrogen with the catalyst doped SnO2 occurs predominantly through hydroxyl groups when the volumetric concentration of water in the gas phase is higher than that of H-2 by a factor of 1000.

Emerging cardiovascular actions of the incretin hormone glucagon-like peptide-1: potential therapeutic benefits beyond glycaemic control?

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by the small intestine in response to nutrient ingestion. It has wide-ranging effects on glucose metabolism, including stimulation of insulin release, inhibition of glucagon secretion, reduction of gastric emptying and augmentation of satiety. Importantly, the insulinotropic actions of GLP-1 are uniquely dependent on ambient glucose concentrations, and it is this particular characteristic which has led to its recent emergence as a treatment for type 2 diabetes. Although the major physiological function of GLP-1 appears to be in relation to glycaemic control, there is growing evidence to suggest that it may also play an important role in the cardiovascular system. GLP-1 receptors (GLP-1Rs) are expressed in the heart and vasculature of both rodents and humans, and recent studies have demonstrated that GLP-1R agonists have wide-ranging cardiovascular actions, such as modulation of heart rate, blood pressure, vascular tone and myocardial contractility. Importantly, it appears that these agents may also have beneficial effects in the setting of cardiovascular disease (CVD). For example, GLP-1 has been found to exert cardioprotective actions in experimental models of dilated cardiomyopathy, hypertensive heart failure and myocardial infarction (MI). Preliminary clinical studies also indicate that GLP-1 infusion may improve cardiac contractile function in chronic heart failure patients with and without diabetes, and in MI patients after successful angioplasty. This review will discuss the current understanding of GLP-1 biology, examine its emerging cardiovascular actions in both health and disease and explore the potential use of GLP-1 as a novel treatment for CVD.

Insulinotropic actions of nateglinide in type 2 diabetic patients and effects on dipeptidyl peptidase-IV activity and glucose-dependent insulinotropic polypeptide degradation

Background: Nateglinide restores early-phase insulin secretion to feeding and reduces postprandial hyperglycaemia in type 2 diabetes. This study evaluated the effects of nateglinide on dipeptidyl peptidase-IV (DPP-IV) activity and glucose-dependent insulinotropic polypeptide (GIP) degradation

Mechanisms underlying the metabolic actions of galegine that contribute to weight loss in mice

Background and purpose: Galegine and guanidine, originally isolated from Galega officinalis, led to the development of the biguanides. The weight-reducing effects of galegine have not previously been studied and the present investigation was undertaken to determine its mechanism(s) of action.

Experimental approach: Body weight and food intake were examined in mice. Glucose uptake and acetyl-CoA carboxylase activity were studied in 3T3-L1 adipocytes and L6 myotubes and AMP activated protein kinase (AMPK) activity was examined in cell lines. The gene expression of some enzymes involved in fat metabolism was examined in 3T3-L1 adipocytes.

Key results: Galegine administered in the diet reduced body weight in mice. Pair-feeding indicated that at least part of this effect was independent of reduced food intake. In 3T3-L1 adipocytes and L6 myotubes, galegine (50 µm-3 mm) stimulated glucose uptake. Galegine (1–300 µm) also reduced isoprenaline-mediated lipolysis in 3T3-L1 adipocytes and inhibited acetyl-CoA carboxylase activity in 3T3-L1 adipocytes and L6 myotubes. Galegine (500 µm) down-regulated genes concerned with fatty acid synthesis, including fatty acid synthase and its upstream regulator SREBP. Galegine (10 µm and above) produced a concentration-dependent activation of AMP activated protein kinase (AMPK) in H4IIE rat hepatoma, HEK293 human kidney cells, 3T3-L1 adipocytes and L6 myotubes.

Conclusions and implications: Activation of AMPK can explain many of the effects of galegine, including enhanced glucose uptake and inhibition of acetyl-CoA carboxylase. Inhibition of acetyl-CoA carboxylase both inhibits fatty acid synthesis and stimulates fatty acid oxidation, and this may to contribute to the in vivo effect of galegine on body weight.

Cardiovascular actions of trout urotensin II in the conscious trout, Oncorhynchus mykiss

The central and peripheral cardiovascular effects of synthetic trout urotensin II (UII) were investigated in the conscious rainbow trout. Intracerebroventricular injection of 50 pmol UII produced a slight (3%) but significant (P < 0.05) increase in heart rate but had no effect on mean arterial blood pressure. Injection of 500 pmol UII icy produced a significant (P < 0.05) rise (8%) in blood pressure with no change in heart rate. In contrast to the weak presser effect of centrally administered UII, intra-arterial injection of UII produced a dose-dependent increase in arterial blood pressure and decrease in heart rate with significant (P < 0.05) effects on both parameters observed at a dose of 25 pmol. Higher doses of the peptide produced a sustained decrease in cardiac output that accompanied the bradycardia and rise in arterial blood pressure. The UII-induced bradycardia, but not the increase in pressure, was abolished by pretreatment with phentolamine. Trout UII produced a sustained and dose-dependent contraction of isolated vascular rings prepared from trout efferent branchial [-log 50% of the concentration producing maximal contraction (pD(2)) = 8.30] and celiacomesenteric (pD(2) = 8.22) arteries but was without effects on vascular rings from the anterior cardinal vein. The data indicate that the presser effect of UII in trout is mediated predominantly, if not exclusively, by an increase in systemic vascular resistance. The UII-induced hypertensive response does not seem to involve release of catecholamines, but the bradycardia may arise from adrenergic-mediated activation of cardioinhibitory baroreflexes.

The structure of compact disjointness preserving operators on continuous functions

Let T be a compact disjointness preserving linear operator from C0(X) into C0(Y), where X and Y are locally compact Hausdorff spaces. We show that T can be represented as a norm convergent countable sum of disjoint rank one operators. More precisely, T = Snd ?hn for a (possibly finite) sequence {xn }n of distinct points in X and a norm null sequence {hn }n of mutually disjoint functions in C0(Y). Moreover, we develop a graph theoretic method to describe the spectrum of such an operator

Time-Resolved DRIFTS, MS, and Resistance Study of SnO2 Materials: The Role of Surface Hydroxyl Groups in Formation of Donor States

Time-resolved DRIFTS, MS, and resistance measurements were used to study the interaction of undoped and Pd-doped SnO2 with H-2 in air and argon at 300 degrees C. Using first-order kinetics, we compare the time constants for the resistance drop and its partial recovery with those of the surface hydroxyl evolution and water formation in the gas phase upon exposure to hydrogen. In the case of the undoped oxide, resistance and bridging hydroxyls (BOHs) evolve similarly, manifesting a fast main drop followed by recovery at a similar rate. The rate of water formation for this material was found to be much slower than that of the main drop in both the resistance and BOHs. In contrast, the resistance change for SnO2-Pd appeared to be similar to that of water formation, and no correlation was found between the evolution of resistance and surface OHs. Isotopic exchange on both materials revealed that water formation occurs via fast and slow hydrogen transfer to surface oxygen species. While the former originates from just-adsorbed hydrogen, the latter appears to proceed from the preadsorbed OHs. Both surfaces exhibit close interaction between chemisorbed oxygen and existing bridging OH groups, indicating that the latter is an intermediate in the hydrogen oxidation and generation of donor states on the surface.

A class of almost C_0(K)-C*-algebras

We consider in this paper the family of exponential Lie groups Gn,µ, whose Lie algebra is an extension of the Heisenberg Lie algebra by the reals and whose quotient group by the centre of the Heisenberg group is an ax + b-like group. The C*-algebras of the groups Gn,µ give new examples of almost C0(K)-C*-algebras.