dc.contributor.author | Caballero Camino, Francisco Javier | |
dc.contributor.author | Rivilla de la Cruz, Iván | |
dc.contributor.author | Herráez Aguilar, Elisa | |
dc.contributor.author | Briz Sánchez, Oscar | |
dc.contributor.author | Santos Laso, Álvaro | |
dc.contributor.author | Izquierdo Sánchez, Laura | |
dc.contributor.author | Lee-Law, Pui Y. | |
dc.contributor.author | Rodrigues, Pedro M. | |
dc.contributor.author | Muñoz Garrido, Patricia | |
dc.contributor.author | Jin, Sujeong | |
dc.contributor.author | Peixoto, Estanislao | |
dc.contributor.author | Richard, Seth | |
dc.contributor.author | Gradilone, Sergio A. | |
dc.contributor.author | Perugorria Montiel, María Jesús | |
dc.contributor.author | Esteller, Manel | |
dc.contributor.author | Bujanda Fernández de Pierola, Luis | |
dc.contributor.author | Marin, José J. G. | |
dc.contributor.author | Bañales Asurmendi, Jesús María | |
dc.contributor.author | Cossío Mora, Fernando Pedro | |
dc.date.accessioned | 2021-02-23T09:39:10Z | |
dc.date.available | 2021-02-23T09:39:10Z | |
dc.date.issued | 2020-09-22 | |
dc.identifier.citation | Hepatology 73(1) : 186-203 (2021) | es_ES |
dc.identifier.issn | 0270-9139 | |
dc.identifier.issn | 1527-3350 | |
dc.identifier.uri | http://hdl.handle.net/10810/50279 | |
dc.description.abstract | Background and Aims Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of symptomatic biliary cysts. Current surgical and pharmacological approaches are ineffective, and liver transplantation represents the only curative option. Ursodeoxycholic acid (UDCA) and histone deacetylase 6 inhibitors (HDAC6is) have arisen as promising therapeutic strategies, but with partial benefits. Approach and Results Here, we tested an approach based on the design, synthesis, and validation of a family of UDCA synthetic conjugates with selective HDAC6i capacity (UDCA-HDAC6i). Four UDCA-HDAC6i conjugates presented selective HDAC6i activity, UDCA-HDAC6i #1 being the most promising candidate. UDCA orientation within the UDCA-HDAC6i structure was determinant for HDAC6i activity and selectivity. Treatment of polycystic rats with UDCA-HDAC6i #1 reduced their hepatomegaly and cystogenesis, increased UDCA concentration, and inhibited HDAC6 activity in liver. In cystic cholangiocytes UDCA-HDAC6i #1 restored primary cilium length and exhibited potent antiproliferative activity. UDCA-HDAC6i #1 was actively transported into cells through BA and organic cation transporters. Conclusions These UDCA-HDAC6i conjugates open a therapeutic avenue for PLDs. | es_ES |
dc.description.sponsorship | Supported by the Spanish Carlos III Health Institute (ISCIII; J.M. Banales: FIS PI15/01132, PI18/01075 and Miguel Servet Program CON14/00129; M.J. Perugorria: PI14/00399, PI17/00022; J.J.G. Marin: FIS PI16/00598) cofinanced by "Fondo Europeo de Desarrollo Regional" (FEDER); CIBERehd (ISCIII): J.M. Banales, M.J. Perugorria, L. Bujanda, and J.J.G. Marin; Spanish Ministry of Economy and Competitiveness (M. J. Perugorria: Ramon y Cajal Program RYC-2015-17755); IKERBASQUE, Basque foundation for Science (M.J. Perugorria and J.M. Banales), Spain; "Junta de Castilla y Leon" (J.J.G. Marin: SA06P17); " Diputacion Foral Gipuzkoa" (J.M. Banales: DFG15/010, DFG16/004; M.J. Perugorria: DFG18/114, DFG19/081), BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD to J.M. Banales), Department of Health of the Basque Country (J.M. Banales: 2017111010; M.J. Perugorria: 2019111024), and Euskadi RIS3 (J.M. Banales: 2016222001, 2017222014, and 2018222029; 2019222054); La Caixa Scientific Foundation (J.M. Banales: HR17-00601); "Fundacion Cientifica de la Asociacion Espanola Contra el Cancer" (AECC Scientific Foundation, to J.M. Banales and J.J.G. Marin); and "Centro Internacional sobre el Envejecimiento", Spain (J.J.G. Marin: OLD-HEPAMARKER, 0348-CIE-6-E). F.J. Caballero-Camino was funded by the Spanish Ministry of Science and Innovation (BES-2014-069148), A. Santos-Laso by the Basque Government (PRE_2018_2_0195), and Pui Y. Lee-Law by the European Association for the Study of the Liver (EASL; Sheila Sherlock Award). The Spanish Ministry of Science and Innovation supported F. P. Cossio: (CTQ2016-80375-P and CTQ2014-51912-REDC) as well as the Basque Government (F.P. Cossio: IT-324-07). I. Rivilla had a postdoctoral contract from the Donostia International Physics Center. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Wiley | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/FIS PI15/01132 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICIU/PI18/01075 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/PI14/00399 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICINN/PI17/00022 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/FIS PI16/00598 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/RYC-2015-17755 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/BES-2014-069148 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICINN/CTQ2016-80375-P | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICINN/CTQ2014-51912-REDC | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc/3.0/es/ | * |
dc.subject | histone deacetylase 6 | es_ES |
dc.subject | bile-acids | es_ES |
dc.subject | cystic cholangiocytes | es_ES |
dc.subject | hepatic cystogenesis | es_ES |
dc.subject | HDAC6 inhibitor | es_ES |
dc.subject | primary cilium | es_ES |
dc.subject | PCK rat | es_ES |
dc.subject | chemistry | es_ES |
dc.subject | ACY-1215 | es_ES |
dc.subject | insights | es_ES |
dc.title | Synthetic Conjugates of Ursodeoxycholic Acid Inhibit Cystogenesis in Experimental Models of Polycystic Liver Disease | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | This is an open access article under the terms of the Creative Commons Attribution NonCommercial License (CC BY-NC 4.0) | es_ES |
dc.rights.holder | Atribución-NoComercial 3.0 España | * |
dc.relation.publisherversion | https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.31216 | es_ES |
dc.identifier.doi | 10.1002/hep.31216 | |
dc.departamentoes | Medicina | es_ES |
dc.departamentoes | Química orgánica I | es_ES |
dc.departamentoeu | Kimika organikoa I | es_ES |
dc.departamentoeu | Medikuntza | es_ES |