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21 results on '"Cagna, Marta"'

4. FXR agonists INT‐787 and OCA increase RECK and inhibit liver steatosis and inflammation in diet‐induced ob/ob mouse model of NASH.

Author

Di Pasqua, Laura G., Cagna, Marta, Palladini, Giuseppina, Croce, Anna C., Cadamuro, Massimiliano, Fabris, Luca, Perlini, Stefano, Adorini, Luciano, Ferrigno, Andrea, and Vairetti, Mariapia

Subjects
*FARNESOID X receptor, *LABORATORY mice, *ANIMAL disease models, *LIVER cells, *HIGH-fat diet
Abstract

Background and Aims: We have previously shown in a model of hepatic ischaemia/reperfusion injury that the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) restores reversion‐inducing‐cysteine‐rich protein with Kazal motifs (RECK), an inverse modulator of metalloproteases (MMPs) and inhibitor of the sheddases ADAM10 and ADAM17 involved in inflammation and fibrogenesis. Here, the effects of FXR agonists OCA and INT‐787 on hepatic levels of RECK, MMPs, ADAM10 and ADAM17 were compared in a diet‐induced ob/ob mouse model of non‐alcoholic steatohepatitis (NASH). Methods: Lep ob/ob NASH mice fed a high‐fat diet (HFD) or control diet (CD) for 9 weeks (wks) were treated with OCA or INT‐787 0.05% dosed via HFD admixture (30 mg/kg/day) or HFD for further 12 wks. Serum alanine transaminase (ALT) and inflammatory cytokines, liver RECK, MMP‐2 and MMP‐9 activity as well as ADAM10, ADAM17, collagen deposition (Sirius red), hepatic stellate cell activation (α‐SMA) and pCK+ reactive biliary cells were quantified. Results: Only INT‐787 significantly reduced serum ALT, IL‐1β and TGF‐β. A downregulation of RECK expression and protein levels observed in HFD groups (at 9 and 21 wks) was counteracted by both OCA and INT‐787. HFD induced a significant increase in liver MMP‐2 and MMP‐9; OCA administration reduced both MMP‐2 and MMP‐9 while INT‐787 markedly reduced MMP‐2 expression. OCA and INT‐787 reduced both ADAM10 and ADAM17 expression and number of pCK+ cells. INT‐787 was superior to OCA in decreasing collagen deposition and α‐SMA levels. Conclusion: INT‐787 is superior to OCA in controlling specific cell types and clinically relevant anti‐inflammatory and antifibrotic molecular mechanisms in NASH. [ABSTRACT FROM AUTHOR]

Published
2024
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21. The selective blockade of metabotropic glutamate receptor-5 attenuates fat accumulation in an <em>in vitro</em> model of benign steatosis.

Author

Ferrigno A, Berardo C, Di Pasqua LG, Cagna M, Siciliano V, Richelmi P, and Vairetti M

Subjects
Glycine analogs & derivatives, Glycine pharmacology, Hep G2 Cells, Humans, PPAR alpha metabolism, Receptor, Metabotropic Glutamate 5 agonists, Resorcinols pharmacology, Sterol Regulatory Element Binding Protein 1 metabolism, Fatty Liver drug therapy, Pyridines pharmacology, Receptor, Metabotropic Glutamate 5 antagonists & inhibitors, Triglycerides metabolism
Abstract

It has been previously found that the blockade of metabotropic glutamate receptor type 5 (mGluR5) protects against hepatic ischemia/reperfusion injury and acetaminophen toxicity. The role of mGluR5 in NAFLD has not yet been elucidated. Here, we evaluated the effects of mGluR5 blockade in an in vitro model of steatosis. HepG2 cells were pre-incubated for 12 h with an mGluR5 agonist, a negative allosteric modulator (DHPG and MPEP, respectively) or vehicle, then treated with 1.5 mM oleate/palmitate (O/P) for another 12 h. Cell viability was evaluated with the MTT assay; fat accumulation was measured using the fluorescent dye nile red; SREBP-1, PPAR-α, iNOS and Caspase-3 protein expression were evaluated by Western blot; NFkB activity was evaluated as pNFkB/NFkB ratio. mGluR5 modulation did not alter cell viability in O/P-incubated cells; MPEP prevented intracellular lipid accumulation in O/P treated cells; MPEP administration was also associated with a reversion of O/P-induced changes in SREBP-1 and PPAR-α expression, involved in free fatty acid (FFA) metabolism and uptake. No changes were observed in iNOS and Caspase-3 expression, or in NFkB activity. In conclusion, mGluR5 pharmacological blockade reduced fat accumulation in HepG2 cells incubated with O/P, probably by modulating the expression of SREBP-1 and PPAR-α.

Published
2020
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