Fluorofenidone attenuates hepatic fibrosis by suppressing the proliferation and activation of hepatic stellate cells

Yu, Pei; Yang, Huixiang; Wang, Nasui; Ouyang, Yan; Yi, Yuanjing; Liao, Litao; Shen, Hong; Hu, Gaoyun; Wang, Zhaohe; Tao, Ling

doi:10.1152/ajpgi.00471.2012

Cited by 36 publications

(36 citation statements)

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“…Accordingly, its up-regulation may account for the activated cell death of hepatocytes at 9 weeks and inhibitory proliferation of liver cells at 6 and 9 weeks. Proliferation and activation of HSCs could be suppressed via ERK/MAPK in hepatic fibrosis (Peng et al, 2014), and p38 MAPK was also associated with cell apoptosis in liver fibrosis , so it could be concluded that the above two pathways, which were both enriched in Figure 6, play a vital role in cell growth and apoptosis/death during liver cirrhosis occurrence.…”

Section: Discussionmentioning

confidence: 97%

Relationship analysis between gene expression profiles and rat liver cirrhosis occurrence

Wang¹,

Zhao²,

Chen³

et al. 2017

Afr. J. Biotechnol.

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Liver cirrhosis (LC) is a kind of liver disease which is pathologically characterized by abnormality and necrosis of hepatic cells, proliferation of fibrous tissue, nodular regeneration and pseudolobule formation. To explore the mechanism of LC occurrence at the level of mRNA, Rat Genome 230 2.0 Array was used to detect gene expression profiles of rat fibrotic livers in 3, 6 and 9 weeks after CCl 4 treatment in this study. It was found that a total of 305 genes including 153 up-regulated, 150 down-regulated and 2 up/down-regulated genes, were related to LC occurrence. Then, k-means clustering was employed to classify above 305 genes into 5 clusters based on gene expression similarity, and EASE analysis further indicated that the above genes were mainly associated with metabolic process, stress reaction, cell growth and apoptosis/death. Thereafter, ingenuity pathway analysis (IPA) software was used to analyze potential effects of the above-mentioned 305 genes, and the results suggested that lipid metabolism and cell growth were inhibited while cell apoptosis/death was activated, but immune/inflammatory response was first activated and then inhibited. Furthermore, IPA also predicted that several signal pathways "ERK/MAPK Signaling", "p38 MAPK", "Endothelin-1 Signaling", "Growth Hormone Signaling", "LPS/IL-1-mediated inhibition of RXR function" and "IL-6 Signaling" were involved in regulating the occurrence of liver cirrhosis. It was concluded that 305 genes and 3 kinds of physiological activities were closely related to LC occurrence.

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Section: Discussionmentioning

confidence: 97%

Relationship analysis between gene expression profiles and rat liver cirrhosis occurrence

Wang¹,

Zhao²,

Chen³

et al. 2017

Afr. J. Biotechnol.

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“…16,17 It can reduce fibroblast growth and collagen synthesis of different organs. [18][19][20][21] Furthermore, AKF is able to attenuate bleomycin-induced experimental IPF by reducing inflammation, accelerating the production of caveolin 1, inhibiting the phosphorylated MAPK-signaling pathway, and limiting the fibrosis cytokine TGF-β. 22 However, the curative power of AKF in the lung has been limited by its unsatisfactory pharmacokinetic properties, which include a short half-life (2 hours), as well as rapid absorption and extensive distribution.…”

Section: Introductionmentioning

confidence: 99%

Spermidine-mediated poly(lactic-<em>co</em>-glycolic acid) nanoparticles containing fluorofenidone for the treatment of idiopathic pulmonary fibrosis

Tang¹,

Li²,

Guo³

et al. 2017

IJN

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Idiopathic pulmonary fibrosis is a progressive, fatal lung disease with poor survival. The advances made in deciphering this disease have led to the approval of different antifibrotic molecules, such as pirfenidone and nintedanib. An increasing number of studies with particles (liposomes, nanoparticles [NPs], microspheres, nanopolymersomes, and nanoliposomes) modified with different functional groups have demonstrated improvement in lung-targeted drug delivery. In the present study, we prepared, characterized, and evaluated spermidine (Spd)-modified poly(lactic- co -glycolic acid) (PLGA) NPs as carriers for fluorofenidone (AKF) to improve the antifibrotic efficacy of this drug in the lung. Spd-AKF-PLGA NPs were prepared and functionalized by modified solvent evaporation with Spd and polyethylene glycol (PEG)-PLGA groups. The size of Spd-AKF-PLGA NPs was 172.5±4.3 nm. AKF release from NPs was shown to fit the Higuchi model. A549 cellular uptake of an Spd–coumarin (Cou)-6-PLGA NP group was found to be almost twice as high as that of the Cou-6-PLGA NP group. Free Spd and difluoromethylornithine (DFMO) were preincubated in A549 cells to prove uptake of Spd-Cou-6-PLGA NPs via a polyamine-transport system. As a result, the uptake of Spd-Cou-6-PLGA NPs significantly decreased with increased Spd concentrations in incubation. At higher Spd concentrations of 50 and 500 µM, uptake of Spd-Cou-6-PLGA NPs reduced 0.34- and 0.49-fold from that without Spd pretreatment. After pretreatment with DFMO for 36 hours, cellular uptake of Spd-Cou-6-PLGA NPs reached 1.26-fold compared to the untreated DFMO group. In a biodistribution study, the drug-targeting index of Spd-AKF-PLGA NPs in the lung was 3.62- and 4.66-fold that of AKF-PLGA NPs and AKF solution, respectively. This suggested that Spd-AKF-PLGA NPs accumulated effectively in the lung. Lung-histopathology changes and collagen deposition were observed by H&E staining and Masson staining in an efficacy study. In the Spd-AKF-PLGA NP group, damage was further improved compared to the AKF-PLGA NP group and AKF-solution group. The results indicated that Spd-AKF-PLGA NPs are able to be effective nanocarriers for anti–pulmonary fibrosis therapy.

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“…The human HSC cell line LX-2 was used in this study because of its similarity to primary human stellate cells; LX-2 cells express α-SMA, vimentin, platelet derived growth factor receptor β (PDGF-Rβ), matrix metalloproteinase (MMP)-2, and tissue inhibitor of matrix metalloproteinase (TIMP)-2 [6]. PI3K (phosphoinositide 3-kinase) is composed of an 85-kDa regulatory subunit and a 110-kDa catalytic subunit, which is recruited to and activated by the activated PDGF receptor following HSC activation and growth factor stimulation [7,8,9]. It has been reported that the activation of the PI3K/Akt pathway can facilitate HSC proliferation and α1 collagen expression [7,10,11].…”

Section: Introductionmentioning

confidence: 99%

Depletion of Thymosin �4 Promotes the Proliferation, Migration, and Activation of Human Hepatic Stellate Cells

Xiao¹,

et al. 2014

Cell Physiol Biochem

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Background & Aims: It has recently been reported that thymosin beta-4 (Tβ4) has anti-fibrogenic effects in human hepatic stellate cells (HSCs) in vitro, but the mechanisms underlying these effects remain unclear. The aim of this study was to investigate the roles of Tβ4 in the proliferation, migration, and activation of HSCs. Methods: Enzyme-linked immunosorbent assays (ELISA), immunohistochemistry, and western blot assays were utilized to determine the expression levels of Tβ4 in serum, liver tissues, and LX-2 cells. Tβ4 was depleted in LX-2 cells using small interfering RNAs (siRNAs). Cell proliferation was analyzed using cell counting kit-8 (CCK-8) viability assays, and cell migration was investigated using wound-healing and transwell migration assays. Results: The expression of Tβ4 was significantly reduced during the progression of liver fibrosis. The depletion of Tβ4 significantly promoted the proliferation and migration of LX-2 cells via the activation of the PI3K/Akt signaling pathway. The pro-migratory and pro-proliferative effects of Tβ4 depletion in LX-2 cells can be counteracted by treatment with the Akt inhibitor MK-2206. In addition, Tβ4 depletion was also associated with the activation of HSCs via the enhanced expression of α-smooth muscle actin (α-SMA) and vimentin. Conclusions: Our results suggest that Tβ4 participates in liver fibrosis by inhibiting the migration, proliferation, and activation of HSCs and that Tβ4 may be an effective target in the treatment of liver fibrosis.

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Fluorofenidone attenuates hepatic fibrosis by suppressing the proliferation and activation of hepatic stellate cells

Abstract: Z, Tao L. Fluorofenidone attenuates hepatic fibrosis by suppressing the proliferation and activation of hepatic stellate cells.

Cited by 36 publications

References 50 publications

Relationship analysis between gene expression profiles and rat liver cirrhosis occurrence

Relationship analysis between gene expression profiles and rat liver cirrhosis occurrence

Spermidine-mediated poly(lactic-<em>co</em>-glycolic acid) nanoparticles containing fluorofenidone for the treatment of idiopathic pulmonary fibrosis

Depletion of Thymosin �4 Promotes the Proliferation, Migration, and Activation of Human Hepatic Stellate Cells

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Fluorofenidone attenuates hepatic fibrosis by suppressing the proliferation and activation of hepatic stellate cells

Abstract: Z, Tao L. Fluorofenidone attenuates hepatic fibrosis by suppressing the proliferation and activation of hepatic stellate cells.

Cited by 36 publications

References 50 publications

Relationship analysis between gene expression profiles and rat liver cirrhosis occurrence

Relationship analysis between gene expression profiles and rat liver cirrhosis occurrence

Spermidine-mediated poly(lactic-<em>co</em>-glycolic acid)&nbsp;nanoparticles containing fluorofenidone for the treatment of idiopathic pulmonary fibrosis

Depletion of Thymosin �4 Promotes the Proliferation, Migration, and Activation of Human Hepatic Stellate Cells

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Spermidine-mediated poly(lactic-<em>co</em>-glycolic acid) nanoparticles containing fluorofenidone for the treatment of idiopathic pulmonary fibrosis