Full metadata record
DC FieldValueLanguage
dc.creatorWahyu-Kurniawan, D. (Dhadhang)-
dc.creatorJajoriya, A.K. (Arun Kumar)-
dc.creatorDhawan, G. (Garima)-
dc.creatorMishra, D. (Divya)-
dc.creatorArgemí, J. (Josepmaria)-
dc.creatorBataller, R. (Ramón)-
dc.creatorStorm, G. (Gert)-
dc.creatorPrasad-Mishra, D. (Durga)-
dc.creatorPrakash, J. (Jai)-
dc.creatorBansal, R. (Ruchi)-
dc.identifier.citationWahyu-Kurniawan, D. (Dhadhang); Jajoriya, A.K. (Arun Kumar); Dhawan, G. (Garima); et al. "Therapeutic inhibition of spleen tyrosine kinase in inflammatory macrophages using PLGA nanoparticles for the treatment of non-alcoholic steatohepatitis.". Journal of controlled release : official journal of the controlled release society. 288, 2018, 227 - 238es_ES
dc.description.abstractNon-alcoholic steatohepatitis (NASH) is the leading cause of cirrhosis worldwide and the most rapidly growing indication for liver transplantation. Macrophages are the important cellular component in the inflammatory milieu in NASH. Inflammatory and pro-fibrotic mediators produced by macrophages causes significant tissue injury in many inflammatory diseases. Therefore, inhibition of the inflammatory macrophages would be a promising approach to attenuate NASH. In this study, we studied the implication of SYK pathway in NASH, and investigated PLGA nanoparticles-based delivery of SYK pathway inhibitor as an effective and promising therapeutic approach for the treatment of NASH. We found positive correlation between SYK expression with the pathogenesis of NASH and alcoholic hepatitis in patients. Importantly, SYK expression was significantly induced in M1-differentiated inflammatory macrophages. To inhibit SYK pathway specifically, we used a small-molecule inhibitor R406 that blocks Fc-receptor signaling pathway and reduces immune complex-mediated inflammation. R406 dose-dependently inhibited nitric-oxide release and M1-specific markers in M1-differentiated macrophages. Thereafter, we synthesized PLGA nanoparticles to deliver R406 to increase the drug pharmacokinetics for the efficient treatment of NASH. We investigated the therapeutic efficacy of R406-PLGA in-vitro in differentiated macrophages, and in-vivo in Methionine-Choline-deficient (MCD)-diet induced NASH mouse model. R406-PLGA inhibited M1-specific differentiation markers in RAW and bone-marrow-derived macrophages. Invivo, R406 and more strongly R406-PLGA ameliorated fibrosis, inflammation and steatosis in mice. R406 and more significantly R406-PLGA reduced ALT, AST, cholesterol and triglyceride plasma levels. These results suggest that delivery of SYK inhibitor using PLGA nanoparticles can be a potential therapeutic approach for the treatment of Non-alcoholic steatohepatitis.es_ES
dc.description.sponsorshipThis study was funded by Endowment Fund for the Education Republic of Indonesia (Lembaga Pengelola Dana Pendidikan/LPDP RI). This project was partially supported by the Netherlands Organization for Health Research and Development (ZonMW, NWO)-funded VENI innovation grant 916.151.94 (to R.B.). Authors thank Hetty ten Hoopen for her technical assistance.es_ES
dc.subjectSpleen tyrosine kinases SYKes_ES
dc.subjectInflammatory macrophageses_ES
dc.subjectNon-alcoholic steatohepatitises_ES
dc.subjectPLGA nanoparticleses_ES
dc.subjectTargeted therapyes_ES
dc.titleTherapeutic inhibition of spleen tyrosine kinase in inflammatory macrophages using PLGA nanoparticles for the treatment of non-alcoholic steatohepatitis.es_ES
dc.description.noteThis is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/).es_ES
dadun.citation.publicationNameJournal of controlled release : official journal of the controlled release societyes_ES

Files in This Item:
1-s2.0-S0168365918305248-main (2).pdf
4.89 MB
Adobe PDF

Statistics and impact
0 citas en
0 citas en

Items in Dadun are protected by copyright, with all rights reserved, unless otherwise indicated.