Inhibition of Y1 receptor signaling improves islet transplant outcome

Failure to secrete sufficient quantities of insulin is a pathological feature of type-1 and type-2 diabetes, and also reduces the success of islet cell transplantation. Here we demonstrate that Y1 receptor signaling inhibits insulin release in β-cells, and show that this can be pharmacologically exploited to boost insulin secretion. Transplanting islets with Y1 receptor deficiency accelerates the normalization of hyperglycemia in chemically induced diabetic recipient mice, which can also be achieved by short-term pharmacological blockade of Y1 receptors in transplanted mouse and human islets. Furthermore, treatment of non-obese diabetic mice with a Y1 receptor antagonist delays the onset of diabetes. Mechanistically, Y1 receptor signaling inhibits the production of cAMP in islets, which via CREB mediated pathways results in the down-regulation of several key enzymes in glycolysis and ATP production. Thus, manipulating Y1 receptor signaling in β-cells offers a unique therapeutic opportunity for correcting insulin deficiency as it occurs in the pathological state of type-1 diabetes as well as during islet transplantation.Islet transplantation is considered one of the potential treatments for T1DM but limited islet survival and their impaired function pose limitations to this approach. Here Loh et al. show that the Y1 receptor is expressed in β- cells and inhibition of its signalling, both genetic and pharmacological, improves mouse and human islet function.info:eu-repo/semantics/publishe

Guanosine stimulates neurite outgrowth in PC12 cells via activation of heme oxygenase and cyclic GMP

Undifferentiated rat pheochromocytoma (PC12) cells extend neurites when cultured in the presence of nerve growth factor (NGF). Extracellular guanosine synergistically enhances NGF-dependent neurite outgrowth. We investigated the mechanism by which guanosine enhances NGF-dependent neurite outgrowth. Guanosine administration to PC12 cells significantly increased guanosine 3-5-cyclic monophosphate (cGMP) within the first 24 h whereas addition of soluble guanylate cyclase (sGC) inhibitors abolished guanosine-induced enhancement of NGF-dependent neurite outgrowth. sGC may be activated either by nitric oxide (NO) or by carbon monoxide (CO). \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document} $$N^{\omega }$$ \end{document}-Nitro-l-arginine methyl ester (l-NAME), a non-isozyme selective inhibitor of nitric oxide synthase (NOS), had no effect on neurite outgrowth induced by guanosine. Neither nNOS (the constitutive isoform), nor iNOS (the inducible isoform) were expressed in undifferentiated PC12 cells, or under these treatment conditions. These data imply that NO does not mediate the neuritogenic effect of guanosine. Zinc protoporphyrin-IX, an inhibitor of heme oxygenase (HO), reduced guanosine-dependent neurite outgrowth but did not attenuate the effect of NGF. The addition of guanosine plus NGF significantly increased the expression of HO-1, the inducible isozyme of HO, after 12 h. These data demonstrate that guanosine enhances NGF-dependent neurite outgrowth by first activating the constitutive isozyme HO-2, and then by inducing the expression of HO-1, the enzymes responsible for CO synthesis, thus stimulating sGC and increasing intracellular cGMP

Beta-lactam antibiotics: from antibiosis to resistance and bacteriology

This review focuses on the era of antibiosis that led to a better understanding of bacterial morphology, in particlar the cell wall component peptidoglycan. This is an effort to take readers on a tour de force from the concept of antibiosis, to the serepidity of antibiotics, evolution of betalactam development, and the molecular biology of antibiotic resistance. These areas of research have culminated in a deeper understanding of microbiology, particularly in the area of bacterial cell wall synthesis and recycling. In spite of this knowledge, which has enabled design of new even more effective therapeutics to combat bacterial infection and has provided new research tools, antibiotic resistance remains a worldwide health care problem

Protein kinase C and cardiac dysfunction: a review

Heart failure (HF) is a physiological state in which cardiac output is insufficient to meet the needs of the body. It is a clinical syndrome characterized by impaired ability of the left ventricle to either fill or eject blood efficiently. HF is a disease of multiple aetiologies leading to progressive cardiac dysfunction and it is the leading cause of deaths in both developed and developing countries. HF is responsible for about 73,000 deaths in the UK each year. In the USA, HF affects 5.8 million people and 550,000 new cases are diagnosed annually. Cardiac remodelling (CD), which plays an important role in pathogenesis of HF, is viewed as stress response to an index event such as myocardial ischaemia or imposition of mechanical load leading to a series of structural and functional changes in the viable myocardium. Protein kinase C (PKC) isozymes are a family of serine/threonine kinases. PKC is a central enzyme in the regulation of growth, hypertrophy, and mediators of signal transduction pathways. In response to circulating hormones, activation of PKC triggers a multitude of intracellular events influencing multiple physiological processes in the heart, including heart rate, contraction, and relaxation. Recent research implicates PKC activation in the pathophysiology of a number of cardiovascular disease states. Few reports are available that examine PKC in normal and diseased human hearts. This review describes the structure, functions, and distribution of PKCs in the healthy and diseased heart with emphasis on the human heart and, also importantly, their regulation in heart failure

Increased contractile response to 5-hydroxytryptamine(1)-receptor stimulation in pulmonary arteries from chronic hypoxic rats: role of pharmacological synergy

1. 5-Hydroxytryptamine (5-HT)(1)-receptor-induced contraction is enhanced, or uncovered, by elevated vascular tone in many arteries including pulmonary arteries. In hypoxia-induced pulmonary hypertension, the endogenous tone of pulmonary arteries is elevated and this may contribute to increased 5-HT(1)-receptor-induced contraction. Here we investigate the influence of vascular tone induced by endothelin-1 (ET-1), neuropeptide Y (NPY), KCl, 4-aminopyridine (inactivator of K(v) channels, 4-AP) or the calcium ionophore A23187 on contractile responses to the 5-HT(1)-receptor agonist 5-carboxamidotryptamine (5-CT) in small muscular pulmonary arteries from control rats and rats exposed to chronic hypoxia. The influence of the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME, 100 μM) was also studied. These conditions were chosen to mimic those that influence pulmonary vascular tone in hypoxia-induced pulmonary hypertension. 2. In control rat small pulmonary arteries, only high concentrations of 5-CT (>1 μM) induced vasoconstriction. Tone induced by NPY, 4-AP and A23187 had no effect on responses to 5-CT whilst responses to 5-CT were increased by ET-1- and KCl-induced tone. In the presence of L-NAME these responses to 5-CT were enhanced further. 3. Responses to 5-CT were enhanced 3 – 4 fold in small pulmonary arteries from hypoxia-exposed, pulmonary hypertensive rats and neither L-NAME nor increasing tone with NPY, 4-AP, A23187, ET-1 or KCl had any further effect on responses to 5-CT. 4. The results suggest that inhibition of nitric oxide synthase combined with KCl- or ET-1-induced vascular tone potentiates responses to 5-HT(1)-receptor-induced contraction in pulmonary arteries in a synergistic fashion and this mimics the effects of chronic hypoxic exposure

Limited signal transduction repertoire of human Y_5 neuropeptide Y receptors expressed in HEC-B cells

In HEC-1B cells transfected with human Y5 neuropeptide Y (NPY) receptors (but not in non-transfected cells) NPY inhibited forskolin-stimulated cAMP accumulation in a pertussis toxin-sensitive manner (−log EC50 8.88 ± 0.25). Elevations of intracellular Ca2+ were largely restricted to very high NPY concentrations and similar in transfected and nontransfected cells. NPY did not increase inositol phosphate accumulation and did not activate a variety of isoforms of protein kinase C or mitogen-activated protein kinases. We conclude that at least upon expression in HEC-1B cells the signal transduction of Y5 NPY receptors is limited to inhibition of cAMP accumulation