• Korean Journal of Pharmacognosy
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• v.44 no.2
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• pp.110-117
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• 2013

Cirsium japonicum (CJ) leaf (L) alcoholic extracts were investigated for analysis their active components (flavonoids and flavanolignans; silymarins) and inhibitory effect on transforming growth factor (TGF)-${\beta}$ induced hepatic stellate cells (HSCs, LX-2 cells) activation. The CJ root (R) extracts were also analyzed and compared with leaf extracts. Total flavonoid and polyphenol contents of the leaf extracts showed higher than those of the root extracts. The content of each flavonoid compound, which was analyzed by HPLC, in CJ-L extracts was also higher than in CJ-R extracts. The results of flavanolignans content in CJ-L and CJ-R extracts were consistent in flavonoid and polyphenol. We studied inhibitory effect of two extracts against TGF-${\beta}1$ induced HSCs activation. The CJ-L extracts significantly suppressed overexpression of profibrogenic factor, ${\alpha}$-smooth muscle actin and collagen-${\alpha}1$(I). The CJ-R extract also showed inhibitory effect on TGF-${\beta}1$ induced HSCs activation, but the efficacy was lower than in CJ-L extract. These results suggest that CJ-L may contribute to the fibrotic liver treatment.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.101.1-101.1
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• 2003

The therapeutic goal in liver fibrosis is to reverse fibrosis and selective clearance of activated hepatic stellate cells (HSCs), which playa central role in liver fibrogenesis, by apoptosis might be essential during resolution of fibrosis. Past several years we screened for natural products which mediate apoptosis in activated HSCs, and among the candidates honokiol, isolated from Magnoliae Cortex, was found to induce apoptotic death in activated rat HSCs in a dose- and time-dependent manner at the concentration between 12.5 microM and 50 microM. (omitted)

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.2
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• pp.605-610
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• 2014

Chronic liver diseases, including cancer, are characterized by inflammation and elevated serum ferritin (SF). However, the causal-relationship remains unclear. This study used primary rat hepatic stellate cells (HSC) as a model to investigate effects of physiological SF concentrations (10, 100 and 1000 pM) because HSCs play a central role in the development and progression of liver fibrosis. Physiological concentrations of SF, either horse SF or human serum, induced pro-inflammatory cytokine $IL1{\beta}$, IL6 and $TNF{\alpha}$ secretion in rat activated HSCs (all p<0.05). By contrast, treatment did not alter activation marker ${\alpha}SMA$ expression. The presence of SF markedly enhanced expression of Grp78 mRNA (p<0.01). Furthermore, transient knock down of Grp78 by endotoxin EGF-SubA abolished SF-induced $IL1{\beta}$ and $TNF{\alpha}$ secretion in activated HSCs (all p<0.05). In conclusion, our results showed that at physiological concentrations SF functions as a pro-inflammatory mediator in primary rat HSCs. We also provide a molecular basis for the action of SF and identified Grp78-associated ER stress pathways as a novel potential therapeutic target for resolution of fibrosis and possible prevention of liver cancer.

• The Journal of Internal Korean Medicine
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• v.31 no.2
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• pp.346-355
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• 2010

Objectives : This study was performed in order to investigate the anti-fibrogenic effect of Acer tegmentosum Maxim. on r at hepatic stellate cell line T6. Materials and Methods : Hepatic stellate Cells (T6) were treated with various concentrations of distilled water Acer teg mentosum Maxim. extract for 24, 48, 72 hours. After the treatment, cell viability, proliferation, procollagen levels, mRNA of AS MA, MMP-2, collagen type 1a2 and IL-6 production were measured using MTT assay, BrdU assay, RT-PCR, procollagen typ e 1 C-peptide EIA kit and murine IL-6 ELISA development kit. Results : Cell viability of HSC-T6 decreased significantly in both 24 hours and 48 hours groups in a dose-dependant man ner. Proliferation of HSC also decreased in the same way. In the RT-PCR, mRNA expression of collagen type 1a2 and ASMA decreased in the groups which were treated with Acer tegmentosum Maxim. for 24 hours. The production of procollagen tended to decrease in a dose-dependant manner in the 24 hours treated group. IL-6 production increased under Acer tegmentosum trea tment in a dose-dependant manner in both 24 and 48 hours groups. Conclusion : These results show the possibility that Acer tegmentosum Maxim. can be an effective remedy for liver fibrosi s and liver cirrhosis.

• Proceedings of the Korean Society of Veterinary Pathology Conference
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• 2003.10a
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• pp.16-16
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• 2003

Hepatic fibrosis is a common response to various chronic hepatic injuries and occurs as a consequence of the transformation of hepatic stellate cells into myofibroblasts (MFBs) producing abnormal extracellular matrix which is mainly induced by transforming growth factor-beta (TGF-${\beta}$), especially TGF-${\beta}$1 [1,2]. As the liver becomes fibrotic, there are both quantitative and qualitative changes in several pathological markers related to the hepatic fibrosis. These fibrotic markers in liver are mainly consisted of several proteins and cytokines, but sometimes included specific type cells. The aim of this study was to detect expression and change of markers (TGF-${\beta}$, mallory body, cytokeratin, ${\alpha}$-SMA, hypoxia, collagen) during hepatic fibrogenesis. (omitted)

• Proceedings of the Korea Environmental Mutagen Society Conference
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• 2004.11a
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• pp.149-149
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• 2004

• Proceedings of the PSK Conference
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• 2001.10a
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• pp.133.1-133.1
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• 2001

• Biomolecules & Therapeutics
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• v.30 no.2
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• pp.162-169
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• 2022

We utilized Fas21, a resveratrol analog, to modulate the function of hepatic stellate cells (HSCs) and liver sinusoidal endothelial cells (LSECs) during the angiogenic phase of murine liver metastasis by B16 melanoma and 51b colorectal carcinoma. Preangiogenic micrometastases were treated with Fas21 (1 mg/kg/day) or vehicle during the development of intra-angiogenic tracts. Mice treated with Fas21 showed reduced liver tumor foci in both liver metastasis models. Micrometastases were classified immunohistochemically, as well as according to their position coordinates and connection to local microvasculature. The volume of liver occupied by sinusoidal-type foci, containing infiltrating angiogenic capillaries, decreased by ~50% in Fas21-treated mice compared to vehicle-treated ones in both tumor metastasis models. The volume of portal foci, containing peripheral neoangiogenesis within a discontinuous layer of myofibroblasts, was similar in all experimental groups in both tumor metastasis models, but displayed enhanced necrotic central areas devoid of angiogenesis following Fas21 treatment. As a result, sinusoidal tumors from mice treated with Fas21 showed a 50% reduction in desmin(+)/asma(+) HSCs and CD31(+) vessel density, and a 45% reduction in intrametastatic VEGF mRNA compared with sinusoidal tumors from vehicle-treated mice. Necrotic portal metastases increased 2-4-fold in treated mice. In vitro, Fas21 reduced VEGF secretion by HSCs and 51b cells dose-dependently. Additionally, HSCs migration in response to tumor soluble factors was dose-dependently diminished by Fas21, as was LSEC migration in response to HSCs and tumor soluble factors. Resveratrol analog Fas21 inhibits the proangiogenic response of HSCs and LSECs during the development of murine liver metastasis.

• IMMUNE NETWORK
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• v.13 no.5
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• pp.168-176
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• 2013

In the last few years major progress has been made in better understanding the role of natural killer (NK) cells in hepatitis C virus (HCV) infection. This includes multiple pathways by which HCV impairs or limits NK cells activation. Based on current genetic and functional data, a picture is emerging where only a rapid and strong NK cell response early on during infection which results in strong T cell responses and possible subsequent clearance, whereas chronic HCV infection is associated with dysfunctional or biased NK cells phenotypes. The hallmark of this NK cell dysfunction is persistent activation promoting ongoing hepatitis and hepatocyte damage, while being unable to clear HCV due to impaired IFN-${\gamma}$ responses. Furthermore, some data suggests certain chronically activated subsets that are $NKp46^{high}$ may be particularly active against hepatic stellate cells, a key player in hepatic fibrogenesis. Finally, the role of NK cells during HCV therapy, HCV recurrence after liver transplant and hepatocellular carcinoma are discussed.

• Biomolecules & Therapeutics
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• v.29 no.3
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• pp.342-351
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• 2021

Liver colonization is initiated through the interplay between tumor cells and adhesion molecules present in liver sinusoidal endothelial cells (LSECs). This crosstalk stimulates tumor COX-2 upregulation and PGE2 secretion. To elucidate the role of the LSEC intercellular adhesion molecule-1 (ICAM-1) in the prometastatic response exerted by tumor and stromal COX-2, we utilized celecoxib (CLX) as a COX-2 inhibitory agent. We analyzed the in vitro proliferative and secretory responses of murine C26 colorectal cancer (CRC) cells to soluble ICAM-1 (sICAM-1), cultured alone or with LSECs, and their effect on LSEC and hepatic stellate cell (HSC) migration and in vivo liver metastasis. CLX reduced sICAM-1-stimulated COX-2 activation and PGE2 secretion in C26 cells cultured alone or cocultured with LSECs. Moreover, CLX abrogated sICAM-1-induced C26 cell proliferation and C26 secretion of promigratory factors for LSECs and HSCs. Interestingly, CLX reduced the protumoral response of HSC, reducing their migratory potential when stimulated with C26 secretomes and impairing their secretion of chemotactic factors for LSECs and C26 cells and proliferative factors for C26 cells. In vivo, CLX abrogated the prometastatic ability of sICAM-1-activated C26 cells while reducing liver metastasis. COX-2 inhibition blocked the creation of a favorable tumor microenvironment (TME) by hindering the intratumoral recruitment of activated HSCs and macrophages in addition to the accumulation of fibrillar collagen. These results point to COX-2 being a key modulator of processes initiated by host ICAM-1 during tumor cell/LSEC/HSC crosstalk, leading to the creation of a prometastatic TME in the liver.