• Journal of Applied Biological Chemistry
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• 제66권
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• pp.138-143
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• 2023

Liver fibrosis is caused by metabolic problems such as cholestasis, genetic problems, or viral infections. Inhibiting hepatic stellate cell (HSC) activation or inducing selective apoptosis of activated HSCs is used as a treatment strategy for liver fibrosis. It has been reported that when HSCs are activated, their apoptosis sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is enhanced because the expression of death receptor 5 is elevated. Finding a natural compound that can enhance the apoptotic effect of TRAIL on HSCs is a necessary strategy for liver fibrosis treatment. It was confirmed here that mangosteen-derived gartanin increased the effect of TRAIL-induced apoptosis by increasing the expression of DR5 in a p38-dependent manner in the hepatic stellate cell line LX-2. Combined treatment with gartanin and TRAIL accelerated DNA cleavage through caspase-3 activation and enhanced antifibrotic effects in LX-2 cells.

• Archives of Pharmacal Research
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• 제27권12호
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• pp.1238-1244
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• 2004

The suppressive effects of Platycodi Radix (Changkil: CK), the root of Platycodon grandiflorum A. DC (Campanulaceae), on the progress of acute carbon tetrachloride $(CCl_4)$-induced hepatic fibrosis were investigated in the rat. CK significantly suppressed $(CCl_4)$-induced hepatic necrosis and inflammation, as determined by the serum enzymatic activities of alanine and aspartate aminotransferase and serum tumor necrosis factor-${\alpha}$ levels, in dose-dependent manners. In addition, the increased hepatic fibrosis after acute $(CCl_4)$ treatment was suppressed by the administration of CK. CK also significantly prevented the elevation of hepatic ${\alpha}$ 1(I) procollagen (type I collagen) mRNA and ${\alpha}$ -smooth muscle actin (${\alpha}$ -SMA) expressions in the liver of $(CCl_4)$-intoxicated rats and also suppressed the induction of ${\alpha}$ -SMA and type I collagen in cultured hepatic stellate cells, in dose-dependent manners. These results suggest that the suppressive effects of CK against the progress of acute $(CCl_4)$-induced hepatic fibrosis possibly involve mechanisms related to its ability to block both hepatic inflammation and the activation of hepatic stellate cells.

• 한국독성학회:학술대회논문집
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• 한국독성학회 2003년도 추계학술대회
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• pp.120-120
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• 2003

Synthesis and distribution of extracellular matrix (ECM) components are dynamically altered in response to the pathophysiological processes including infection, inflammation and apoptosis. In particular, the levels of hyaluronan (HA) change with concomitant increases in the levels of collagen (e.g. type I collagen) and fibronectin in chronic liver diseases.(omitted)

• 한국환경성돌연변이발암원학회:학술대회논문집
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• 한국환경성돌연변이발암원학회 2003년도 추계학술대회
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• pp.167-167
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• 2003

• Archives of Pharmacal Research
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• 제29권9호
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• pp.762-767
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• 2006

Danshen is an herbal medication frequently used in oriental medicine to treat liver or kidney malfunction. In the course of our studies, we observed that compounds purified from Danshen exhibit an inhibitory activity against Discoidin Domain Receptor 2 (DDR2) tyrosine kinase. Through this inhibition, these compounds also inhibited the growth of HSC T6 cells and suppressed the expression of alpha-smooth muscle actin and MMP2, as well as collagen synthesis, all of which are increased in activated liver stellate cells. Given that activation of liver stellate cells is the hallmark of liver fibrosis and that DDR2 plays a critical role in this activation, these results suggest that one of the pharmacological activities of Danshen extract that protects the liver is the inhibition of key cell-signaling kinases, such as DDR2, in liver stellate cells.

• Preventive Nutrition and Food Science
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• 제18권2호
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• pp.124-132
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• 2013

In this study, novel peptides (NIPP-1, NIPP-2) derived from Navicula incerta (microalgae) protein hydrolysate were explored for their inhibitory effects on collagen release in hepatic fibrosis with the investigation of its underlying mechanism of action. TGF-${\beta}1$ activated fibrosis in LX-2 cells was examined in the presence or absence of purified peptides NIPP-1 and NIPP-2. Besides the mechanisms of liver cell injury, protective effects of NIPP-1 and NIPP-2 were studied to show the protective mechanism against TGF-${\beta}1$ stimulated fibrogenesis. Our results showed that the core protein of NIPP-1 peptide prevented fibril formation of type I collagen, elevated the MMP level and inhibited TIMP production in a dose-dependent manner. The treatment of NIPP-1 and NIPP-2 on TGF-${\beta}1$ induced LX-2 cells alleviated hepatic fibrosis. Moreover, ${\alpha}$-SMA, TIMPs, collagen and PDGF in the NIPP-1 treated groups were significantly decreased. Therefore, it could be suggested that NIPP-1 has potential to be used in anti-fibrosis treatment.

• International Journal of Molecular Medicine
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• 제44권2호
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• pp.491-502
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• 2019

Although the migration of hepatic stellate cells (HSCs) is important for hepatic fibrosis, the regulation of this migration is poorly understood. Notably, transforming growth factor (TGF)-β1 induces monocyte migration to sites of injury or inflammation during the early phase, but inhibits cell migration during the late phase. In the present study, the role of transforming protein RhoA signaling in TGF-β1-induced HSC migration was investigated. TGF-β1 was found to increase the protein and mRNA levels of smooth muscle actin and collagen type I in HSC-T6 cells. The level of RhoA-GTP in TGF-β1-stimulated cells was significantly higher than that in control cells. Furthermore, the phosphorylation of cofilin and formation of filamentous actin (F-actin) were more marked in TGF-β1-stimulated cells than in control cells. Additionally, TGF-β1 induced the activation of nuclear factor-κB, and the expression of extracellular matrix proteins and several cytokines in HSC-T6 cells. The active form of Rap1 (Rap1 V12) suppressed RhoA-GTP levels, whereas the dominant-negative form of Rap1 (Rap1 N17) augmented RhoA-GTP levels. Therefore, the data confirmed that Rap1 regulated the activation of RhoA in TGF-β1-stimulated HSC-T6 cells. These findings suggest that TGF-β1 regulates Rap1, resulting in the suppression of RhoA, activation of and formation of F-actin during the migration of HSCs.

• Natural Product Sciences
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• 제19권3호
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• pp.231-235
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• 2013

Activity-guided isolation to search for antifibrotic compounds from natural products using HSC-T6 cells afforded nine flavonoids or phenolics, luteolin (1), 3'-O-methylorobol (2), acactin 7-rutinoside (3), sedelolactone (4), 4-methoxyphenol (5), 4-hydroxyaldehyde (6), 4-hydoxyaldehyde (7), 4-hydroxy-3-methoxybenzoic acid (8), and ferulic acid (9) from the methanolic extract of aerial parts of Eclipta prostrata L.. Among the isolated compounds, luteolin (1) significantly inhibited the proliferation of HSCs in dose- and time-dependent manners. Antifibrotic activity of E. prostrata and its phenolic compounds might provide potential therapeutical choice in the treatment of hepatic fibrosis.

• 대한한방내과학회지
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• 제31권3호
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• pp.415-424
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• 2010

Objectives : This study was performed to investigate the anti-fibrogenic effect of Angelica Gigantis Radix on cultured rat hepatic stellate cells. Materials and Methods : Hepatic stellate cells(HSC-T6) were treated with various concentrations of Angelica Gigantis Radix extract for both 24 and 48 hours. The extraction was done either with distilled water or 80% EtOH. After the treatment, cell viability, cell proliferation, procollagen production and the mRNA expression of the ASMA, TIMP1, TIMP2, procollagen Type 1a2, and Cytokine IL-6 production were measured by using MTT assay, BrdU assay, RT-PCR, procollagen Type I C-peptide EIA and IL-6 ELISA assay. Results : The cell viability treated with water extraction was significantly increased, but there were no significant changes treated with 80% EtOH extraction. The cell proliferation treated with water extraction decreased only in the 24 hours group, while there were significant decreases either in the 24 and 48 hours groups treated with 80% EtOH extraction. The mRNA expressions of the ASMA, TIMP2 and procollagen 1a2 decreased in a concentration-dependent manner in the 48 hours group. Procollagen production decreased in a concentration-dependent manner in both the 24 and 48 hours groups. Cytokine IL-6 production increased in a concentration-dependent manner in both the 24 and 48 hours groups. Conclusion : These results suggest that Angelica Gigantis Radix is beneficial in the treatment of cirrhotic patients as well as for patients with chronic hepatitis.

• Natural Product Sciences
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• 제14권2호
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• pp.118-121
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• 2008

Manassantin B, a dilignan isolated from Saururus chinensis, significantly inhibited proliferation in HSC-T6 cells in concentration- and time-dependent manners. In addition, treatment of HSC-T6 cells with manassantin B changed cell morphology from flattened myofibroblastic membranous morphology, representing activation state, to slender shape, representing quiescent state. Furthermore, manassantin B effectively reduced collagen content in HSC-T6 cells. These results suggested that manassantin B exerted antifibrotic activity in HSCT6 cells, in part, via inhibition of cell proliferation and decrease of collagen production.