Anti-inflammatory and anti-fibrotic effects of modafinil in nonalcoholic liver disease

Small- and intermediate-conductance Ca2+-activated K+ channels, KCa2.3 and KCa3.1, are involved in cellular signaling processes associated with inflammation and fibrosis. KCa2.3 and KCa3.1 are upregulated by proinflammatory cytokines and profibrotic growth factors. Cyclic AMP, which downregulates KC...

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Autores principales:	Shinkyu Choi, Ji Aee Kim, Haiyan Li, Seong-Eun Jo, Huisu Lee, Tae Hun Kim, Minje Kim, Seong-Jin Kim, Suk Hyo Suh
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Modafinil Liver disease Inflammation Fibrosis KCa2.3 and KCa3.1 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/248c5d63c5e548cd81023d099535ae43
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spelling	oai:doaj.org-article:248c5d63c5e548cd81023d099535ae432021-11-14T04:30:24ZAnti-inflammatory and anti-fibrotic effects of modafinil in nonalcoholic liver disease0753-332210.1016/j.biopha.2021.112372https://doaj.org/article/248c5d63c5e548cd81023d099535ae432021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0753332221011562https://doaj.org/toc/0753-3322Small- and intermediate-conductance Ca2+-activated K+ channels, KCa2.3 and KCa3.1, are involved in cellular signaling processes associated with inflammation and fibrosis. KCa2.3 and KCa3.1 are upregulated by proinflammatory cytokines and profibrotic growth factors. Cyclic AMP, which downregulates KCa2.3 and KCa3.1, is elevated by modafinil in cells; accordingly, we investigated whether modafinil exerts anti-inflammatory and anti-fibrotic responses via KCa2.3- and KCa3.1-mediated pathways in high-fat diet (HFD)- or thioacetamide-induced liver disease models in mice. Modafinil was administered orally in the form of a racemate, (R)-isomer, or (S)-isomer. We also determined whether the treatment targeted the profibrotic activity of hepatic stellate cells using immortalized human hepatic stellate cells (LX-2 cells). Modafinil improved HFD- or thioacetamide-induced changes compared to the control, leading to a reduced inflammatory response, collagen deposition, and α-smooth muscle actin expression both in vivo and in vitro. However, modafinil did not relieve HFD-induced steatosis. There were no significant differences in the effects of the (R)- and (S)-isomers of modafinil. KCa2.3 and KCa3.1 were upregulated and catalase was downregulated in liver tissues from thioacetamide- or HFD-induced liver disease models or in TGF-β-treated LX-2 cells. TGF-β-induced upregulation of KCa2.3, KCa3.1, collagen, and α-smooth muscle actin and downregulation of catalase were reversed by modafinil, polyethylene glycol catalase, N-acetylcysteine, siRNA against KCa2.3 or KCa3.1, and Epac inhibitors. Our investigation revealed that modafinil attenuated inflammatory and fibrotic progression via KCa2.3- and KCa3.1-mediated pathways in nonalcoholic hepatitis, suggesting that inhibiting KCa2.3- and KCa3.1-mediated signaling may serve as a novel therapeutic approach for inflammatory and fibrotic liver diseases.Shinkyu ChoiJi Aee KimHaiyan LiSeong-Eun JoHuisu LeeTae Hun KimMinje KimSeong-Jin KimSuk Hyo SuhElsevierarticleModafinilLiver diseaseInflammationFibrosisKCa2.3 and KCa3.1Therapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 144, Iss , Pp 112372- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Modafinil Liver disease Inflammation Fibrosis KCa2.3 and KCa3.1 Therapeutics. Pharmacology RM1-950
spellingShingle	Modafinil Liver disease Inflammation Fibrosis KCa2.3 and KCa3.1 Therapeutics. Pharmacology RM1-950 Shinkyu Choi Ji Aee Kim Haiyan Li Seong-Eun Jo Huisu Lee Tae Hun Kim Minje Kim Seong-Jin Kim Suk Hyo Suh Anti-inflammatory and anti-fibrotic effects of modafinil in nonalcoholic liver disease
description	Small- and intermediate-conductance Ca2+-activated K+ channels, KCa2.3 and KCa3.1, are involved in cellular signaling processes associated with inflammation and fibrosis. KCa2.3 and KCa3.1 are upregulated by proinflammatory cytokines and profibrotic growth factors. Cyclic AMP, which downregulates KCa2.3 and KCa3.1, is elevated by modafinil in cells; accordingly, we investigated whether modafinil exerts anti-inflammatory and anti-fibrotic responses via KCa2.3- and KCa3.1-mediated pathways in high-fat diet (HFD)- or thioacetamide-induced liver disease models in mice. Modafinil was administered orally in the form of a racemate, (R)-isomer, or (S)-isomer. We also determined whether the treatment targeted the profibrotic activity of hepatic stellate cells using immortalized human hepatic stellate cells (LX-2 cells). Modafinil improved HFD- or thioacetamide-induced changes compared to the control, leading to a reduced inflammatory response, collagen deposition, and α-smooth muscle actin expression both in vivo and in vitro. However, modafinil did not relieve HFD-induced steatosis. There were no significant differences in the effects of the (R)- and (S)-isomers of modafinil. KCa2.3 and KCa3.1 were upregulated and catalase was downregulated in liver tissues from thioacetamide- or HFD-induced liver disease models or in TGF-β-treated LX-2 cells. TGF-β-induced upregulation of KCa2.3, KCa3.1, collagen, and α-smooth muscle actin and downregulation of catalase were reversed by modafinil, polyethylene glycol catalase, N-acetylcysteine, siRNA against KCa2.3 or KCa3.1, and Epac inhibitors. Our investigation revealed that modafinil attenuated inflammatory and fibrotic progression via KCa2.3- and KCa3.1-mediated pathways in nonalcoholic hepatitis, suggesting that inhibiting KCa2.3- and KCa3.1-mediated signaling may serve as a novel therapeutic approach for inflammatory and fibrotic liver diseases.
format	article
author	Shinkyu Choi Ji Aee Kim Haiyan Li Seong-Eun Jo Huisu Lee Tae Hun Kim Minje Kim Seong-Jin Kim Suk Hyo Suh
author_facet	Shinkyu Choi Ji Aee Kim Haiyan Li Seong-Eun Jo Huisu Lee Tae Hun Kim Minje Kim Seong-Jin Kim Suk Hyo Suh
author_sort	Shinkyu Choi
title	Anti-inflammatory and anti-fibrotic effects of modafinil in nonalcoholic liver disease
title_short	Anti-inflammatory and anti-fibrotic effects of modafinil in nonalcoholic liver disease
title_full	Anti-inflammatory and anti-fibrotic effects of modafinil in nonalcoholic liver disease
title_fullStr	Anti-inflammatory and anti-fibrotic effects of modafinil in nonalcoholic liver disease
title_full_unstemmed	Anti-inflammatory and anti-fibrotic effects of modafinil in nonalcoholic liver disease
title_sort	anti-inflammatory and anti-fibrotic effects of modafinil in nonalcoholic liver disease
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/248c5d63c5e548cd81023d099535ae43
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Anti-inflammatory and anti-fibrotic effects of modafinil in nonalcoholic liver disease

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