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314 results on '"Distrutti, E."'

1. Combinatorial therapy with BAR502 and UDCA resets FXR and GPBAR1 signaling and reverses liver histopathology in a model of NASH

Author

Marchiano, S., Biagioli, M., Morretta, E., Di Giorgio, C., Roselli, R., Bordoni, M., Bellini, R., Urbani, G., Massa, C., Monti, M. C., Zampella, A., Distrutti, E., and Fiorucci, S.

Subjects
Multidisciplinary
Abstract

Non-alcoholic steatosis (NAFLD) and steatohepatitis (NASH) are two highly prevalent human disorders for which therapy remains suboptimal. Bile acids are signaling molecules acting on two main receptors the Farnesoid-x-receptor (FXR) and G protein coupled receptor GPB AR1. Clinical trials have shown that FXR agonism might result in side effects along with lack of efficacy in restoring liver histopathology. For these reasons a multi-targets therapy combined FXR agonists with agent targeting additional molecular mechanisms might have improved efficacy over selective FXR agonists. In the present study we have compared the effects of BAR502, a dual FXR/GPBAR1 ligand) alone or in combination with ursodeoxycholic acid (UDCA) in a model of NAFLD/NASH induced by feeding mice with a Western diet for 10 weeks. The results demonstrated that while BAR502 and UDCA partially protected against liver damage caused by Western diet, the combination of the two, reversed the pro-atherogenic lipid profile and completely reversed the histopathology damage, attenuating liver steatosis, ballooning, inflammation and fibrosis. Additionally, while both agents increased insulin sensitivity and bile acid signaling, the combination of the two, modulated up top 85 genes in comparison of mice feed a Western diet, strongly reducing expression of inflammatory markers such as chemokines and cytokines. Additionally, the combination of the two agents redirected the bile acid metabolism toward bile acid species that are GPBAR1 agonist while reduced liver bile acid content and increased fecal excretion. Together, these data, highlight the potential role for a combinatorial therapy based on BAR502 and UDCA in treating of NAFLD.

Published
2023
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8. Investigation on bile acid receptor regulators. Discovery of cholanoic acid derivatives with dual G-protein coupled bile acid receptor 1 (GPBAR1) antagonistic and farnesoid X receptor (FXR) modulatory activity

Author

Sepe, V, Renga, B, Festa, C, Finamore, C, Masullo, D, Carino, A, Cipriani, S, Distrutti, E, Fiorucci, Stefano, Zampella, A., Carino, Adriana, Sepe, Valentina, Renga, Barbara, Festa, Carmen, Finamore, Claudia, Masullo, Dario, Carino, Adriana, Cipriani, Sabrina, Distrutti, Eleonora, Fiorucci, Stefano, and Zampella, Angela

Subjects
0301 basic medicine, Transcriptional Activation, medicine.drug_class, GPBAR1 antagonists, Clinical Biochemistry, Receptors, Cytoplasmic and Nuclear, Bile acid, GPBAR1 antagonist, Biochemistry, Calcitriol receptor, Receptors, G-Protein-Coupled, Bile Acids and Salts, G protein-coupled bile acid receptor, 03 medical and health sciences, chemistry.chemical_compound, Endocrinology, Farnesoid X receptor, medicine, Humans, Receptor, Molecular Biology, Pharmacology, Pregnane X receptor, Chemistry, Organic Chemistry, Cholic acid, FXR modulator, Cholic Acids, Bile acids, FXR modulators, Hep G2 Cells, 030104 developmental biology, HEK293 Cells, Nuclear receptor
Abstract

Bile acids, the end products of cholesterol metabolism, activate multiple mechanisms through the interaction with membrane G-protein coupled receptors including the bile acid receptor GPBAR1 and nuclear receptors such as the bile acid sensor, farnesoid X receptor (FXR). Even if dual FXR/GPBAR1 agonists are largely considered a novel opportunity in the treatment of several liver and metabolic diseases, selective targeting of one of these receptors represents an attractive therapeutic approach for a wide range of disorders in which dual modulation is associated to severe side effects. In the present study we have investigated around the structure of LCA generating a small library of cholane derivatives, endowed with dual FXR agonism/GPBAR1 antagonism. To the best of our knowledge, this is the first report of bile acid derivatives able to antagonize GPBAR1.

Published
2015

9. Enhanced activity of a hydrogen sulphide-releasing derivative of mesalamine (ATB-429) in a mouse model of colitis

Author

FIORUCCI S, ORLANDI S, MENCARELLI A, DISTRUTTI E, SANTUCCI L, WALLACE J. L., CALIENDO, GIUSEPPE, SANTAGADA, VINCENZO, CIRINO, GIUSEPPE, Fiorucci, S, Orlandi, S, Mencarelli, A, Caliendo, Giuseppe, Santagada, Vincenzo, Distrutti, E, Santucci, L, Cirino, Giuseppe, and Wallace, J. L.

Subjects
Mice, Inbred BALB C, Time Factors, Dose-Response Relationship, Drug, Colon, Anti-Inflammatory Agents, Gene Expression, Colitis, Research Papers, Severity of Illness Index, Disease Models, Animal, Mice, coliti, Gastrointestinal Agents, Trinitrobenzenesulfonic Acid, inflammatory bowel disease, Animals, Cytokines, Female, Disulfides, Hydrogen Sulfide, RNA, Messenger, Chemokines, hydrogen sulphide, Mesalamine, Granulocytes
Abstract

Mesalamine is the first-line therapy for colitis, but it lacks potency and is only effective for mild-to-moderate forms of this disease. Hydrogen sulphide has been shown to be a potent, endogenous anti-inflammatory substance, modulating leukocyte-endothelial adhesion and leukocyte migration. The purpose of this study was to determine if an H(2)S-releasing derivative of mesalamine (ATB-429) would exhibit increased potency and effectiveness in a mouse model of colitis.Colitis was induced in mice with trinitrobenzene sulphonic acid and the effects of ATB-429 and mesalamine were compared in several treatment regimens. The severity of colitis was determined using several indices, including a disease activity score (comprised of scores for diarrhea, weight loss and fecal blood), colonic myeloperoxidase activity and macroscopic/microscopic scoring of tissue injury.Irrespective of the treatment regiment, ATB-429 was more effective than mesalamine in reducing the severity of colitis. ATB-429 was particularly effective in reducing granulocyte infiltration into the colonic tissue (by approximately 70%), as well as reducing the expression of mRNA for several key proinflammatory cytokines/chemokines (e.g., TNFalpha, IFNgamma). Treatment with ADT-OH, the H(2)S-releasing moiety of ATB-429, did not affect severity of colitis.ATB-429 exhibits a marked increase in anti-inflammatory activity and potency in a murine model of colitis, as compared to mesalamine. These results are consistent with recently described anti-inflammatory effects of H(2)S. ATB-429 may represent an attractive alternative to mesalamine for the treatment of inflammatory bowel disease.

Published
2007

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