Philip K. Moore

Bio: Philip K. Moore is an academic researcher from National University of Singapore. The author has contributed to research in topics: Nitric oxide & Nitric oxide synthase. The author has an hindex of 74, co-authored 169 publications receiving 19111 citations. Previous affiliations of Philip K. Moore include Barts Health NHS Trust & Yale-NUS College.

Hydrogen Sulfide and Cell Signaling

Abstract: Hydrogen sulfide (H₂S) is a gaseous mediator synthesized from cysteine by cystathionine γ lyase (CSE) and other naturally occurring enzymes. Pharmacological experiments using H₂S donors and genetic experiments using CSE knockout mice suggest important roles for this vasodilator gas in the regulation of blood vessel caliber, cardiac response to ischemia/reperfusion injury, and inflammation. That H₂S inhibits cytochrome c oxidase and reduces cell energy production has been known for many decades, but more recently, a number of additional pharmacological targets for this gas have been identified. H₂S activates K(ATP) and transient receptor potential (TRP) channels but usually inhibits big conductance Ca²(+)-sensitive K(+) (BK(Ca)) channels, T-type calcium channels, and M-type calcium channels. H₂S may inhibit or activate NF-κB nuclear translocation while affecting the activity of numerous kinases including p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), and Akt. These disparate effects may be secondary to the well-known reducing activity of H₂S and/or its ability to promote sulfhydration of protein cysteine moieties within the cell.

L-NG-nitro arginine (L-NOARG), a novel, L-arginine-reversible inhibitor of endothelium-dependent vasodilatation in vitro.

Abstract: 1. The effect of L-NG-nitro arginine (L-NOARG) was compared with that of L-NG-monomethyl arginine (L-NMMA) on vasodilatation of the isolated aorta of the rabbit and perfused mesentery of the rat in response to acetylcholine (ACh) and sodium nitroprusside (NP). 2. L-NOARG (1.5-100 microM) and L-NMMA (3-100 microM) produced concentration-related contraction of the rabbit aorta precontracted with phenylephrine (700-900 nM). Similarly, L-NOARG (10-200 microM) and L-NMMA (30-100 microM) elevated perfusion pressure of the noradrenaline (NA, 0.6-2.5 mM)-preconstricted rat mesentery preparation. 3. L-NOARG (1.5-100 microM) and L-NMMA (3-100 microM) caused concentration-related inhibition of the vasodilator effect of ACh (0.01-1.0 microM) on the rabbit aorta without influencing responses to NP (0.03-0.5 microM). L-NOARG methyl ester (30 microM) also inhibited ACh-induced vasorelaxation with similar potency to NOARG. L-arginine (30-150 microM) but not D-arginine (100 microM) caused graded reversal of the inhibitory effect of both L-NOARG (15 microM) and L-NMMA (30 microM). Complete reversal of the effect of both inhibitors was achieved with 150 microM L-arginine. L-Alanine (50 microM), L-arginosuccinic acid (5 microM), L-citrulline (50 microM), L-methionine (50 microM) and L-ornithine (50 microM) failed to reverse the inhibitory effect of L-NOARG (15 microM). 4. L-NOARG (10-200 microM) and L-NMMA (30-100 microM) inhibited the vasodilator effect of ACh (0.006-18.0 nmol) in the rat mesentery without affecting vasodilatation due to NP (1.1-11.1 nmol). L-Arginine (100 microM) but not D-arginine (100 microM) produced partial reversal of the effect of L-NOARG (30 microM) and L-NMMA (30 microM). 5. L- and D-N'-butyloxycarbonyl No-nitro arginine (100 microM) produced modest (approximately 20%) inhibition of the effect of ACh on the rabbit aorta; this effect was not reversible with L-arginine (100 microM). L-Namonocarbobenzoxy arginine (L-NMCA, 5O microM), L-N-NG-dicarbobenzoxy arginine (L-NDCA, 5 microM) and L-NG-tosyl arginine (50 microM) were inactive. 6. These results identify L-NOARG as a potent, L-arginine reversible inhibitor of endothelium-dependent vasodilatation. The available data suggests that L-NOARG, like L-NMMA, inhibits endothelial nitric oxide (NO) biosynthesis.

Hydrogen sulfide is a novel mediator of lipopolysaccharide-induced inflammation in the mouse

Abstract: Hydrogen sulfide (H2S) is synthesized in the body from L-cysteine by several enzymes including cystathionine-gamma-lyase (CSE). To date, there is little information about the potential role of H2S in inflammation. We have now investigated the part played by H2S in endotoxin-induced inflammation in the mouse. E. coli lipopolysaccharide (LPS) administration produced a dose (10 and 20 mg/kg ip)- and time (6 and 24 h)-dependent increase in plasma H2S concentration. LPS (10 mg/kg ip, 6 h) increased plasma H2S concentration from 34.1 +/- 0.7 microM to 40.9 +/- 0.6 microM (n=6, P<0.05) while H2S formation from added L-cysteine was increased in both liver and kidney. CSE gene expression was also increased in both liver (94.2+/-2.7%, n=6, P<0.05) and kidney (77.5+/-3.2%, n=6, P<0.05). LPS injection also elevated lung (148.2+/-2.6%, n=6, P<0.05) and kidney (78.8+/-8.2%, n=6, P<0.05) myeloperoxidase (MPO, a marker of tissue neutrophil infiltration) activity alongside histological evidence of lung, liver, and kidney tissue inflammatory damage. Plasma nitrate/nitrite (NOx) concentration was additionally elevated in a time- and dose-dependent manner in LPS-injected animals. To examine directly the possible proinflammatory effect of H2S, mice were administered sodium hydrosulfide (H2S donor drug, 14 micromol/kg ip) that resulted in marked histological signs of lung inflammation, increased lung and liver MPO activity, and raised plasma TNF-alpha concentration (4.6+/-1.4 ng/ml, n=6). In contrast, DL-propargylglycine (CSE inhibitor, 50 mg/kg ip), exhibited marked anti-inflammatory activity as evidenced by reduced lung and liver MPO activity, and ameliorated lung and liver tissue damage. In separate experiments, we also detected significantly higher (150.5+/-43.7 microM c.f. 43.8+/-5.1 microM, n=5, P<0.05) plasma H2S levels in humans with septic shock. These findings suggest that H2S exhibits proinflammatory activity in endotoxic shock and suggest a new approach to the development of novel drugs for this condition.

Characterization of a Novel, Water-Soluble Hydrogen Sulfide–Releasing Molecule (GYY4137): New Insights Into the Biology of Hydrogen Sulfide

Abstract: Background— The potential biological significance of hydrogen sulfide (H2S) has attracted growing interest in recent years The aim of this study was to characterize a novel, water-soluble, slow-releasing H2S compound [morpholin-4-ium 4 methoxyphenyl(morpholino) phosphinodithioate (GYY4137)] and evaluate its use as a tool to investigate the cardiovascular biology of this gas Methods and Results— The acute vasorelaxant effect of drugs was assessed in rat aortic rings and perfused rat kidney in vitro and in the anesthetized rat in vivo The chronic effect of GYY4137 on blood pressure in normotensive and spontaneously hypertensive rats was determined by tail-cuff plethysmography GYY4137 released H2S slowly both in aqueous solution in vitro and after intravenous or intraperitoneal administration in anesthetized rats in vivo GYY4137 caused a slow relaxation of rat aortic rings and dilated the perfused rat renal vasculature by opening vascular smooth muscle KATP channels GYY4137 did not affect rat heart rat

The novel neuromodulator hydrogen sulfide: an endogenous peroxynitrite ‘scavenger’?

Abstract: Hydrogen sulfide (H2S) is a well-known cytotoxic gas. Recently it has been shown to stimulate N-methyl-d-aspartate (NMDA) receptors to enhance long-term potentiation suggesting a novel neuromodulatory role in vivo. Endogenous levels of H2S in the brain are reported to range between 10 and 160 µm. Considerably lower H2S levels are reported in the brains of Alzheimer's disease (AD) patients, where levels of brain protein nitration (probably mediated by peroxynitrite) are markedly increased. Activation of NMDA receptors leads to intracellular tyrosine nitration by peroxynitrite. Because H2S and peroxynitrite are important mediators in brain function and disease, we investigated the effects of the H2S ‘donor’, sodium hydrogen sulfide (NaSH) on peroxynitrite-mediated damage to biomolecules and to cultured human SH-SY5Y cells. H2S significantly inhibited peroxynitrite-mediated tyrosine nitration and inactivation of α1-antiproteinase to a similar extent to reduced glutathione at each concentration tested (30–250 µm). H2S also inhibited peroxynitrite-induced cytotoxicity, intracellular protein nitration and protein oxidation in human neuroblastoma SH-SY5Y cells. These data suggest that H2S has the potential to act as an inhibitor of peroxynitrite-mediated processes in vivo and that the potential antioxidant action of H2S deserves further study, given that extracellular GSH levels in the brain are very low.

The L-Arginine-Nitric Oxide Pathway

Abstract: The discovery that mammalian cells generate nitric oxide, a gas previously considered to be merely an atmospheric pollutant, is providing important information about many biologic processes. Nitric oxide is synthesized from the amino acid L-arginine by a family of enzymes, the nitric oxide synthases, through a hitherto unrecognized metabolic route -- namely, the L-arginine-nitric oxide pathway1–8. The synthesis of nitric oxide by vascular endothelium is responsible for the vasodilator tone that is essential for the regulation of blood pressure. In the central nervous system nitric oxide is a neurotransmitter that underpins several functions, including the formation of memory. . . .

Aggregation-Induced Emission: Together We Shine, United We Soar!

Abstract: Ju Mei,†,‡,∥ Nelson L. C. Leung,†,‡,∥ Ryan T. K. Kwok,†,‡ Jacky W. Y. Lam,†,‡ and Ben Zhong Tang*,†,‡,§ †HKUST-Shenzhen Research Institute, Hi-Tech Park, Nanshan, Shenzhen 518057, China ‡Department of Chemistry, HKUST Jockey Club Institute for Advanced Study, Institute of Molecular Functional Materials, Division of Biomedical Engineering, State Key Laboratory of Molecular Neuroscience, Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China Guangdong Innovative Research Team, SCUT-HKUST Joint Research Laboratory, State Key Laboratory of Luminescent Materials and Devices, South China University of Technology, Guangzhou 510640, China

Nitric oxide synthases: structure, function and inhibition

Abstract: This review concentrates on advances in nitric oxide synthase (NOS) structure, function and inhibition made in the last seven years, during which time substantial advances have been made in our understanding of this enzyme family. There is now information on the enzyme structure at all levels from primary (amino acid sequence) to quaternary (dimerization, association with other proteins) structure. The crystal structures of the oxygenase domains of inducible NOS (iNOS) and vascular endothelial NOS (eNOS) allow us to interpret other information in the context of this important part of the enzyme, with its binding sites for iron protoporphyrin IX (haem), biopterin, L-arginine, and the many inhibitors which interact with them. The exact nature of the NOS reaction, its mechanism and its products continue to be sources of controversy. The role of the biopterin cofactor is now becoming clearer, with emerging data implicating one-electron redox cycling as well as the multiple allosteric effects on enzyme activity. Regulation of the NOSs has been described at all levels from gene transcription to covalent modification and allosteric regulation of the enzyme itself. A wide range of NOS inhibitors have been discussed, interacting with the enzyme in diverse ways in terms of site and mechanism of inhibition, time-dependence and selectivity for individual isoforms, although there are many pitfalls and misunderstandings of these aspects. Highly selective inhibitors of iNOS versus eNOS and neuronal NOS have been identified and some of these have potential in the treatment of a range of inflammatory and other conditions in which iNOS has been implicated.

Metal-organic frameworks in biomedicine.

Abstract: Metal Organic Frameworks in Biomedicine Patricia Horcajada,* Ruxandra Gref, Tarek Baati, Phoebe K. Allan, Guillaume Maurin, Patrick Couvreur, G erard F erey, Russell E. Morris, and Christian Serre* Institut Lavoisier, UMR CNRS 8180, Universit e de Versailles St-Quentin en Yvelines, 45 Avenue des Etats-Unis, 78035 Versailles Cedex, France Facult e de Pharmacie, UMR CNRS 8612, Universit e Paris-Sud, 92296 Châtenay-Malabry Cedex, France Institut Charles Gerhardt Montpellier, UMR CNRS 5253, Universit e Montpellier 2, 34095 Montpellier cedex 05, France EaStChem School of Chemistry, University of St. Andrews Purdie Building, St Andrews, KY16 9ST U.K.

Localization of nitric oxide synthase indicating a neural role for nitric oxide

Abstract: Nitric oxide (NO), apparently identical to endothelium-derived relaxing factor in blood vessels, is also formed by cytotoxic macrophages, in adrenal gland and in brain tissue, where it mediates the stimulation by glutamate of cyclic GMP formation in the cerebellum Stimulation of intestinal or anococcygeal nerves liberates NO, and the resultant muscle relaxation is blocked by arginine derivatives that inhibit NO synthesis It is, however, unclear whether in brain or intestine, NO released following nerve stimulation is formed in neurons, glia, fibroblasts, muscle or blood cells, all of which occur in proximity to neurons and so could account for effects of nerve stimulation on cGMP and muscle tone We have now localized NO synthase protein immunohistochemically in the rat using antisera to the purified enzyme We demonstrate NO synthase in the brain to be exclusively associated with discrete neuronal populations NO synthase is also concentrated in the neural innervation of the posterior pituitary, in autonomic nerve fibres in the retina, in cell bodies and nerve fibres in the myenteric plexus of the intestine, in adrenal medulla, and in vascular endothelial cells These prominent neural localizations provide the first conclusive evidence for a strong association of NO with neurons