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Porto Salvo, Portugal

Fagone P.,University of Catania | Mangano K.,University of Catania | Coco M.,University of Catania | Perciavalle V.,University of Catania | And 3 more authors.
Clinical and Experimental Immunology | Year: 2012

Carbon monoxide (CO) is produced during the catabolism of free haem, catalyzed by haem oxygenase (HO) enzymes, and its physiological roles include vasodilation, neurotransmission, inhibition of platelet aggregation and anti-proliferative effects on smooth muscle. In vivo preclinical studies have shown that exogenously administered quantities of CO may represent an effective treatment for conditions characterized by a dysregulated immune response. The carbon monoxide-releasing molecules (CORMs) represent a group of compounds capable of carrying and liberating controlled quantities of CO in the cellular systems. This review covers the physiological and anti-inflammatory properties of the HO/CO pathway in the central nervous system. It also discusses the effects of CORMs in preclinical models of inflammation. The accumulating data discussed herein support the possibility that CORMs may represent a novel class of drugs with disease-modifying properties in multiple sclerosis. © 2012 The Authors. Clinical and Experimental Immunology © 2012 British Society for Immunology. Source

Marazioti A.,University of Patras | Bucci M.,University of Naples Federico II | Coletta C.,University of Texas Medical Branch | Vellecco V.,University of Naples Federico II | And 11 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2011

Objective-: Carbon monoxide (CO) is a weak soluble guanylyl cyclase stimulator, leading to transient increases in cGMP and vasodilation. The aim of the present work was to measure the effect of CO-releasing molecules (CORMs) on the cGMP/nitric oxide (NO) pathway and to evaluate how selected CORMs affect NO-induced vasorelaxation. Methods and Results-: Incubation of smooth muscle cells with some but not all of the CORMs caused a minor increase in cGMP levels. Concentration-response curves were bell-shaped, with higher CORMs concentrations producing lower increases in cGMP levels. Although exposure of cells to CORM-2 enhanced cGMP formation, we observed that the compound inhibited NO-stimulated cGMP accumulation in cells and NO-stimulated soluble guanylyl cyclase activity that could be reversed by superoxide anion scavengers. Reactive oxygen species generation from CORMs was confirmed using luminol-induced chemiluminescence and electron spin resonance. Furthermore, we observed that NO is scavenged by CORM-2. When used alone CORM-2 relaxed vessels through a cGMP-mediated pathway but attenuated NO donor-stimulated vasorelaxation. Conclusion-: We conclude that the CORMs examined have context-dependent effects on vessel tone, as they can directly dilate blood vessels, but also block NO-induced vasorelaxation. © 2011 American Heart Association. All rights reserved. Source

Rodrigues C.A.B.,Alfama Lda | De Matos M.N.,Alfama Lda | Guerreiro B.M.H.,Alfama Lda | Goncalves A.M.L.,Alfama Lda | And 3 more authors.
Tetrahedron Letters | Year: 2011

Decarbonylation of the tertiary aldehydes 4-ethyl-4-formyl-hexanenitrile (2) and 2-methyl-2-phenylpropanal (4) promoted by dioxygen occurs at room temperature only if suspended in water probably via the sequential acyl radical-CO liberation-tertiary radical that is promoted by an 'on water' process originating preferentially from the corresponding tertiary hydroperoxide. © 2011 Elsevier Ltd. All rights reserved. Source

Pena A.C.,University of Lisbon | Penacho N.,Alfama Lda | Mancio-Silva L.,University of Lisbon | Neres R.,University of Lisbon | And 9 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2012

Severe forms of malaria infection, such as cerebral malaria (CM) and acute lung injury (ALI), are mainly caused by the apicomplexan parasite Plasmodium falciparum. Primary therapy with quinine or artemisinin derivatives is generally effective in controlling P. falciparum parasitemia, but mortality from CM and other forms of severe malaria remains unacceptably high. Herein, we report the design and synthesis of a novel carbon monoxide-releasing molecule (CO-RM; ALF492) that fully protects mice against experimental CM (ECM) and ALI. ALF492 enables controlled CO delivery in vivo without affecting oxygen transport by hemoglobin, the major limitation in CO inhalation therapy. The protective effect is CO dependent and induces the expression of heme oxygenase-1, which contributes to the observed protection. Importantly, when used in combination with the antimalarial drug artesunate, ALF492 is an effective adjunctive and adjuvant treatment for ECM, conferring protection after the onset of severe disease. This study paves the way for the potential use of CO-RMs, such as ALF492, as adjunctive/adjuvant treatment in severe forms of malaria infection. Copyright © 2012, American Society for Microbiology. All Rights Reserved. Source

Santos-Silva T.,New University of Lisbon | Mukhopadhyay A.,New University of Lisbon | Seixas J.D.,New University of Lisbon | Seixas J.D.,Alfama Lda | And 5 more authors.
Current Medicinal Chemistry | Year: 2011

The biological role of carbon monoxide (CO) has completely changed in the last decade. Beyond its widely feared toxicity, CO has revealed a very important biological activity as a signaling molecule with marked protective actions namely against inflammation, apoptosis and endothelial oxidative damage. Its direct use as a therapeutic gas showed significant and consistent positive results but also intrinsic severe limitations. The possibility of replacing the gas by pro-drugs acting as CO-Releasing Molecules (CO-RMs) has clearly been demonstrated with several experimental compounds. Transition metal carbonyls complexes have proven to be the most versatile experimental CO-RMs so far. Presently, the challenge is to equip them with drug-like properties to turn them into useful pharmaceuticals. This requires studying their interactions with biological molecules namely those that control their pharmacokinetic and ADME profiles like the plasma proteins. In this account we analyze these questions and review the existing interactions between Metal Carbonyls and proteins. The recently explored case of CORM-3 is revisited to exemplify the methodologies involved and the importance of the results for the understanding of the mode of action of such pro-drugs. © 2011 Bentham Science Publishers Ltd. Source

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