Cargando…

Bergamot Polyphenols Improve Dyslipidemia and Pathophysiological Features in a Mouse Model of Non-Alcoholic Fatty Liver Disease

There is a need for continued drug development for nonalcoholic steatohepatitis (NASH). Bergamot is a plant whose fruit juice is enriched with flavonoids and phenolic compounds which improves dyslipidemia and markers of systemic inflammation in patients with Metabolic Syndrome. The aim of this study...

Descripción completa

Detalles Bibliográficos
Autores principales: Musolino, Vincenzo, Gliozzi, Micaela, Scarano, Federica, Bosco, Francesca, Scicchitano, Miriam, Nucera, Saverio, Carresi, Cristina, Ruga, Stefano, Zito, Maria Caterina, Maiuolo, Jessica, Macrì, Roberta, Amodio, Nicola, Juli, Giada, Tassone, Pierfrancesco, Mollace, Rocco, Caffrey, Rebecca, Marioneaux, Jonathon, Walker, Ross, Ehrlich, James, Palma, Ernesto, Muscoli, Carolina, Bedossa, Pierre, Salvemini, Daniela, Mollace, Vincenzo, Sanyal, Arun J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018973/
https://www.ncbi.nlm.nih.gov/pubmed/32054943
http://dx.doi.org/10.1038/s41598-020-59485-3
_version_ 1783497425842864128
author Musolino, Vincenzo
Gliozzi, Micaela
Scarano, Federica
Bosco, Francesca
Scicchitano, Miriam
Nucera, Saverio
Carresi, Cristina
Ruga, Stefano
Zito, Maria Caterina
Maiuolo, Jessica
Macrì, Roberta
Amodio, Nicola
Juli, Giada
Tassone, Pierfrancesco
Mollace, Rocco
Caffrey, Rebecca
Marioneaux, Jonathon
Walker, Ross
Ehrlich, James
Palma, Ernesto
Muscoli, Carolina
Bedossa, Pierre
Salvemini, Daniela
Mollace, Vincenzo
Sanyal, Arun J.
author_facet Musolino, Vincenzo
Gliozzi, Micaela
Scarano, Federica
Bosco, Francesca
Scicchitano, Miriam
Nucera, Saverio
Carresi, Cristina
Ruga, Stefano
Zito, Maria Caterina
Maiuolo, Jessica
Macrì, Roberta
Amodio, Nicola
Juli, Giada
Tassone, Pierfrancesco
Mollace, Rocco
Caffrey, Rebecca
Marioneaux, Jonathon
Walker, Ross
Ehrlich, James
Palma, Ernesto
Muscoli, Carolina
Bedossa, Pierre
Salvemini, Daniela
Mollace, Vincenzo
Sanyal, Arun J.
author_sort Musolino, Vincenzo
collection PubMed
description There is a need for continued drug development for nonalcoholic steatohepatitis (NASH). Bergamot is a plant whose fruit juice is enriched with flavonoids and phenolic compounds which improves dyslipidemia and markers of systemic inflammation in patients with Metabolic Syndrome. The aim of this study was to perform a preclinical “proof of concept” study of Bergamot polyphenolic formulation (BPF99) for the treatment of NASH. A disease reversal study was performed in the diet-induced animal model of NAFLD (DIAMOND). Groups of 8 weeks old mice were randomly assigned to receive chow diet, high fat diet with sugar in drinking water (Western diet- WD). Mice on WD were further randomized to continue on WD gavaged with vehicle or continue on WD with additional gavage of BPF99 (50 mg/kg) after 16 weeks of diet. Mice were euthanized after 11 additional weeks. The primary endpoint was resolution of NASH. Secondary endpoints included changes in individual histological features, body weight, liver enzymes, dyslipidemia, markers of oxidative stress and molecular markers of disease activity and fibrosis. The results showed that BPF99 reduced ALT (mean 71.6 vs 44.6 IU/l, p < 0.01), triglycerides (38.8 vs 28.1 mg/dl, p < 0.05), LDL-C (39.2 vs 23.7 mg/dl, p < 0.001). It significantly improved NASH resolution (p < 0.001) and the SAF scores (p < 0.05) while the NAS improvement approached significance. BPF99 reduced markers of oxidative stress, along with reduced JNK and p38 MAP kinase activity. BPF99 did not reduce the number of mice with fibrosis but improved collagen proportional area (p < 0.04) and procollagen I and III expression. Collectively our results showed that BPF99 resolves NASH and ameliorates key histological and pathophysiological features of NASH along with improvement in ALT and dyslipidemia in the DIAMOND mice.
format Online
Article
Text
id pubmed-7018973
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-70189732020-02-21 Bergamot Polyphenols Improve Dyslipidemia and Pathophysiological Features in a Mouse Model of Non-Alcoholic Fatty Liver Disease Musolino, Vincenzo Gliozzi, Micaela Scarano, Federica Bosco, Francesca Scicchitano, Miriam Nucera, Saverio Carresi, Cristina Ruga, Stefano Zito, Maria Caterina Maiuolo, Jessica Macrì, Roberta Amodio, Nicola Juli, Giada Tassone, Pierfrancesco Mollace, Rocco Caffrey, Rebecca Marioneaux, Jonathon Walker, Ross Ehrlich, James Palma, Ernesto Muscoli, Carolina Bedossa, Pierre Salvemini, Daniela Mollace, Vincenzo Sanyal, Arun J. Sci Rep Article There is a need for continued drug development for nonalcoholic steatohepatitis (NASH). Bergamot is a plant whose fruit juice is enriched with flavonoids and phenolic compounds which improves dyslipidemia and markers of systemic inflammation in patients with Metabolic Syndrome. The aim of this study was to perform a preclinical “proof of concept” study of Bergamot polyphenolic formulation (BPF99) for the treatment of NASH. A disease reversal study was performed in the diet-induced animal model of NAFLD (DIAMOND). Groups of 8 weeks old mice were randomly assigned to receive chow diet, high fat diet with sugar in drinking water (Western diet- WD). Mice on WD were further randomized to continue on WD gavaged with vehicle or continue on WD with additional gavage of BPF99 (50 mg/kg) after 16 weeks of diet. Mice were euthanized after 11 additional weeks. The primary endpoint was resolution of NASH. Secondary endpoints included changes in individual histological features, body weight, liver enzymes, dyslipidemia, markers of oxidative stress and molecular markers of disease activity and fibrosis. The results showed that BPF99 reduced ALT (mean 71.6 vs 44.6 IU/l, p < 0.01), triglycerides (38.8 vs 28.1 mg/dl, p < 0.05), LDL-C (39.2 vs 23.7 mg/dl, p < 0.001). It significantly improved NASH resolution (p < 0.001) and the SAF scores (p < 0.05) while the NAS improvement approached significance. BPF99 reduced markers of oxidative stress, along with reduced JNK and p38 MAP kinase activity. BPF99 did not reduce the number of mice with fibrosis but improved collagen proportional area (p < 0.04) and procollagen I and III expression. Collectively our results showed that BPF99 resolves NASH and ameliorates key histological and pathophysiological features of NASH along with improvement in ALT and dyslipidemia in the DIAMOND mice. Nature Publishing Group UK 2020-02-13 /pmc/articles/PMC7018973/ /pubmed/32054943 http://dx.doi.org/10.1038/s41598-020-59485-3 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Musolino, Vincenzo
Gliozzi, Micaela
Scarano, Federica
Bosco, Francesca
Scicchitano, Miriam
Nucera, Saverio
Carresi, Cristina
Ruga, Stefano
Zito, Maria Caterina
Maiuolo, Jessica
Macrì, Roberta
Amodio, Nicola
Juli, Giada
Tassone, Pierfrancesco
Mollace, Rocco
Caffrey, Rebecca
Marioneaux, Jonathon
Walker, Ross
Ehrlich, James
Palma, Ernesto
Muscoli, Carolina
Bedossa, Pierre
Salvemini, Daniela
Mollace, Vincenzo
Sanyal, Arun J.
Bergamot Polyphenols Improve Dyslipidemia and Pathophysiological Features in a Mouse Model of Non-Alcoholic Fatty Liver Disease
title Bergamot Polyphenols Improve Dyslipidemia and Pathophysiological Features in a Mouse Model of Non-Alcoholic Fatty Liver Disease
title_full Bergamot Polyphenols Improve Dyslipidemia and Pathophysiological Features in a Mouse Model of Non-Alcoholic Fatty Liver Disease
title_fullStr Bergamot Polyphenols Improve Dyslipidemia and Pathophysiological Features in a Mouse Model of Non-Alcoholic Fatty Liver Disease
title_full_unstemmed Bergamot Polyphenols Improve Dyslipidemia and Pathophysiological Features in a Mouse Model of Non-Alcoholic Fatty Liver Disease
title_short Bergamot Polyphenols Improve Dyslipidemia and Pathophysiological Features in a Mouse Model of Non-Alcoholic Fatty Liver Disease
title_sort bergamot polyphenols improve dyslipidemia and pathophysiological features in a mouse model of non-alcoholic fatty liver disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018973/
https://www.ncbi.nlm.nih.gov/pubmed/32054943
http://dx.doi.org/10.1038/s41598-020-59485-3
work_keys_str_mv AT musolinovincenzo bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease
AT gliozzimicaela bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease
AT scaranofederica bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease
AT boscofrancesca bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease
AT scicchitanomiriam bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease
AT nucerasaverio bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease
AT carresicristina bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease
AT rugastefano bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease
AT zitomariacaterina bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease
AT maiuolojessica bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease
AT macriroberta bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease
AT amodionicola bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease
AT juligiada bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease
AT tassonepierfrancesco bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease
AT mollacerocco bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease
AT caffreyrebecca bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease
AT marioneauxjonathon bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease
AT walkerross bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease
AT ehrlichjames bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease
AT palmaernesto bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease
AT muscolicarolina bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease
AT bedossapierre bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease
AT salveminidaniela bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease
AT mollacevincenzo bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease
AT sanyalarunj bergamotpolyphenolsimprovedyslipidemiaandpathophysiologicalfeaturesinamousemodelofnonalcoholicfattyliverdisease