Crambescin C1 acts as a possible substrate of iNOS and eNOS increasing nitric oxide production and inducing in vivo hypotensive effect

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dc.citation.titleFrontiers in Pharmacology
dc.citation.volume1-15
dc.citation.volume12
dc.creatorRubiolo, Juan Andrés
dc.creatorLence, Emilio
dc.creatorGonzález Bello, Concepción
dc.creatorRoel, María
dc.creatorGil Longo, José
dc.creatorCampos Toimil, Manuel
dc.creatorTernon, Eva
dc.creatorThomas, Olivier P.
dc.creatorGonzález Cantalapiedra, Antonio
dc.creatorLópez Alonso, Henar
dc.creatorVieytes, Mercedes R.
dc.creatorBotana, Luis M.
dc.date.accessioned2024-04-26T14:06:46Z
dc.date.available2024-04-26T14:06:46Z
dc.date.issued2021-07-07
dc.description.abstractCrambescins are guanidine alkaloids from the sponge Crambe crambe. Crambescin C1 (CC) induces metallothionein genes and nitric oxide (NO) is one of the triggers. We studied and compared the in vitro, in vivo, and in silico effects of some crambescine A and C analogs. HepG2 gene expression was analyzed using microarrays. Vasodilation was studied in rat aortic rings. In vivo hypotensive effect was directly measured in anesthetized rats. The targets of crambescines were studied in silico. CC and homo-crambescine C1 (HCC), but not crambescine A1 (CA), induced metallothioneins transcripts. CC increased NO production in HepG2 cells. In isolated rat aortic rings, CC and HCC induced an endothelium-dependent relaxation related to eNOS activation and an endothelium-independent relaxation related to iNOS activation, hence both compounds increase NO and reduce vascular tone. In silico analysis also points to eNOS and iNOS as targets of Crambescin C1 and source of NO increment. CC effect is mediated through crambescin binding to the active site of eNOS and iNOS. CC docking studies in iNOS and eNOS active site revealed hydrogen bonding of the hydroxylated chain with residues Glu377 and Glu361, involved in the substrate recognition, and explains its higher binding affinity than CA. The later interaction and the extra polar contacts with its pyrimidine moiety, absent in the endogenous substrate, explain its role as exogenous substrate of NOSs and NO production. Our results suggest that CC serve as a basis to develop new useful drugs when bioavailability of NO is perturbed.
dc.description.filFil: Rubiolo, Juan Andrés. Universidad de Santiago de Compostela. Departamento de Zoología, Genética y Antropología Física; Spain.
dc.description.filFil: Rubiolo, Juan Andrés. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Ministerio de Ciencia. Centro Científico y Tecnológico Acuario del Río Paraná, Tecnología e Innovación Productiva de Santa Fe; Argentina.
dc.description.filFil: Lence, Emilio. Universidade de Santiago de Compostela. Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS). Departamento de Química Orgánica; Spain.
dc.description.filFil: González Bello, Concepción. Universidade de Santiago de Compostela. Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS). Departamento de Química Orgánica; Spain.
dc.description.filFil: Roel, María. Universidad de Santiago de Compostela. Facultad de Veterinaria. Departamento de Farmacología; Spain.
dc.description.filFil: Gil Longo, José. Universidad de Santiago de Compostela. Facultad de Farmacia, Farmacia y Tecnología Farmacéutica. Departamento de Farmacología; Spain.
dc.description.filFil: Campos Toimil, Manuel. Universidad de Santiago de Compostela. Facultad de Farmacia, Farmacia y Tecnología Farmacéutica. Departamento de Farmacología; Spain.
dc.description.filFil: Campos Toimil, Manuel. Universidad de Santiago de Compostela. Center for Research in Molecular Medicine and Chronic Diseases (CIMUS). Fisiología y Farmacología de las Enfermedades Crónicas (FIFAEC); Spain.
dc.description.filFil: Ternon, Eva. Université Côte d’Azur. Centre national de la recherche scientifique (CNRS). Observatoire de la Côte d'Azur (OCA). Institut de recherche pour le développement; France.
dc.description.filFil: Thomas, Olivier P. National University of Ireland Galway. Marine Biodiscovery. School of Chemistry and Ryan Institute; Ireland.
dc.description.filFil: González Cantalapiedra, Antonio. Universidad de Santiago de Compostel. Facultad de Veterinaria. Hospital Veterinario Universitario Rof Codina. Departamento de Anatomía, Producción Animal y Ciencias Clínicas Veterinarias; Spain.
dc.description.filFil: López Alonso, Henar. Universidad de Santiago de Compostel. Facultad de Veterinaria. Hospital Veterinario Universitario Rof Codina. Departamento de Anatomía, Producción Animal y Ciencias Clínicas Veterinarias; Spain.
dc.description.filFil: Vieytes, Mercedes R. Universidad de Santiago de Compostela. Facultad de Veterinaria. Departamento de Fisiología; Spain.
dc.description.filFil: Botana, Luis M. Universidad de Santiago de Compostela. Facultad de Veterinaria. Departamento de Farmacología; Spain.
dc.description.sponsorshipConselleria de Cultura, Educacion e Ordenación Universitaria, Xunta de Galicia: ED431C 2021/01
dc.description.sponsorshipCentro singular de investigación de Galicia accreditation: ED431G 2019/03
dc.description.sponsorshipMinisterio de Ciencia e Innovación: IISCIII/PI19/001248, PID2019-105512RB-I00
dc.description.sponsorshipEuropean Union Interreg AlertoxNet: EAPA-317–2016, Interreg Agritox EAPA-998–2018, H2020 778069-EMERTOX
dc.identifier.issn1663-9812
dc.identifier.urihttps://hdl.handle.net/2133/26948
dc.language.isoen
dc.publisherFrontiers Media
dc.relation.publisherversionhttps://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.694639/full
dc.relation.publisherversionhttps://doi.org/10.3389/fphar.2021.694639
dc.rightsopenAccess
dc.rights.holderRubiolo, Juan Andrés
dc.rights.holderLence, Emilio
dc.rights.holderGonzález Bello, Concepción
dc.rights.holderRoel, María
dc.rights.holderGil Longo, José
dc.rights.holderCampos Toimil, Manuel
dc.rights.holderTernon, Eva
dc.rights.holderThomas, Olivier P.
dc.rights.holderGonzález Cantalapiedra, Antonio
dc.rights.holderLópez Alonso, Henar
dc.rights.holderVieytes, Mercedes R.
dc.rights.holderBotana, Luis M.
dc.rights.holderUniversidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas
dc.rights.textAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectCrambescin
dc.subjectNitric oxide synthase
dc.subjectDocking
dc.subjectMolecular dynamics simulations
dc.subjectHypotension
dc.subjectMetallothionein
dc.subjectHepG2 cells
dc.titleCrambescin C1 acts as a possible substrate of iNOS and eNOS increasing nitric oxide production and inducing in vivo hypotensive effect
dc.typearticulo
dc.type.collectionarticulo
dc.type.versionpublishedVersion

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