Crambescin C1 Acts as A Possible Substrate of iNOS and eNOS Increasing Nitric Oxide Production and Inducing In Vivo Hypotensive Effect
| العنوان: | 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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| المؤلفون: | Juan A. Rubiolo, Emilio Lence, Concepción González-Bello, María Roel, José Gil-Longo, Manuel Campos-Toimil, Eva Ternon, Olivier P. Thomas, Antonio González-Cantalapiedra, Henar López-Alonso, Mercedes R. Vieytes, Luis M. Botana |
| المصدر: | Frontiers in Pharmacology Frontiers in Pharmacology, Vol 12 (2021) CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET |
| بيانات النشر: | Frontiers Media S.A., 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, hypotension, CRAMBESCIN, NITRIC OXIDE SYNTHASE, MOLECULAR DYNAMICS SIMULATIONS, Vasodilation, RM1-950, Nitric oxide, purl.org/becyt/ford/1 [https], 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Enos, In vivo, HYPOTENSION, Metallothionein, Pharmacology (medical), DOCKING, purl.org/becyt/ford/1.6 [https], HepG2 cells, Original Research, Pharmacology, biology, METALLOTHIONEIN, nitric oxide synthase, Active site, crambescin, molecular dynamics simulations, HEPG2 CELLS, biology.organism_classification, metallothionein, Molecular biology, In vitro, Nitric oxide synthase, 030104 developmental biology, chemistry, docking, biology.protein, Therapeutics. Pharmacology, 030217 neurology & neurosurgery |
| الوصف: | Crambescins 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. Fil: Rubiolo, Juan Andrés. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina. Ministerio de Ciencia, Tecnologia E Innovacion Productiva (santa Fe). - Gobierno de la Provincia de Santa Fe. Ministerio de Ciencia, Tecnologia E Innovacion Productiva (santa Fe).; Argentina. Universidad de Santiago de Compostela; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina Fil: Lence, Emilio. Universidad de Santiago de Compostela; España Fil: González Bello, Concepción. Universidad de Santiago de Compostela; España Fil: Roel, María. Universidad de Santiago de Compostela; España Fil: Gil Longo, José. Universidad de Santiago de Compostela; España Fil: Campos Toimil, Manuel. Universidad de Santiago de Compostela; España Fil: Ternon, Eva. Université Nice Sophia Antipolis. Laboratoire Jean-alexandre Dieudonné.; Francia Fil: Thomas, Olivier P.. National University of Ireland Galway; Irlanda Fil: González Cantalapiedra, Antonio. Universidad de Santiago de Compostela; España Fil: López Alonso, Henar. Universidad de Santiago de Compostela; España Fil: Vieytes, Mercedes R.. Universidad de Santiago de Compostela; España Fil: Botana, Luis M.. Universidad de Santiago de Compostela; España |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1663-9812 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f5d920472833479228925f6e86e75d91Test http://europepmc.org/articles/PMC8312399Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....f5d920472833479228925f6e86e75d91 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 16639812 |
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