• Archives of Pharmacal Research
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• v.23 no.6
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• pp.613-619
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• 2000

We investigated the expression profiles of rat fibrotic liver induced by bile duct ligation and scission (BDL/S) using the 3'-directed cDNA libraries. The possibility that the 3'-directed cDNA library represents the mRNA population faithfully was examined by northern blots. During the northern analysis based on fibrotic liver expression profile, we found for the first time that purine specific sodium nucleoside cotransporter (SPNT) was upregulated in BDL/S-induced fibrotic liver. To determine whether the accumulation of bile juice could affect the expression of SPNT mRNA or not, we examined the change of SPNT mRNA expression at 3, 14, 28 days after BDL/S operation. No change in SPNT expression was observed in rat liver at 3 days after surgery. In contrast, there were significant increases in SPNT expression at 14 and 28 days after surgery. We also examined whether chronic liver damage affected SPNT mRNA expression. SPNT mRNA level was significantly increased in BDL/S-induced fibrotic rat liver, whereas no significant change was obserbed in fibrotic livers chronically exposed to carbon tetrachloride or dimethylnitrosamine. From the above results, although further study might be needed, it was considered that the increment of SPNT mRNA in BDL/S liver morphological compatibility to human was remarkable.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1994.04a
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• pp.202-202
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• 1994

G009의 hepatic cirrhosis animal model중 bile duct ligation/scission (BDL/S) rat에서의 항섬유화 효과를 조사하였다. BDL/S 수술 후 4주간 투약군에는 G009 saline soln.(5mg/rat/day)을, 대조군에는 saline을 경구투여하였다. fibrosis가 최고에 달하는 4주후 rat를 도살하여, 혈청중 N-terminal procollagen type III peptide(PIIINP) level, 간 조직중 hydroxy proline content, serum biochemical value(ALT, AST, choleterol, total bilirubin, creatinine) 측정 및 간조직검사를 실시하였다. 그 결과 1) 혈청중 PIIINP의 경우, 투약군 BDL/S group(10.3ng/ml$\pm$2.2)이 대조군 (20.5ng/m1$\pm$3.9)에 비해 약 50%정도 유의성 있게 감소하였다(p<0,01). 2) 간 조직중 hydroxy proline치 측정 결과, 투약군 BDL/S group(471$\pm$160$\mu\textrm{g}$/g liver)이 대조군(566$\pm$42.9$\mu\textrm{g}$/g liver)에 비하여 약 13%정도 유의성있게 감소하였다(p<0.05). 3) 간조직검사 결과 투약군의 BDL/S op. group이 대조군보다 necrosis, inflammetion, bile duct proliferation, connective tissue 침착 등이 약화되었다. 위 실험을 종합한 결과 G009는 biliary cirrhosis model에서 antifibrotic effect가 있음이 사료된다.

• Archives of Pharmacal Research
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• v.20 no.4
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• pp.318-323
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• 1997

The experimental hepatic cirrhosis was induced either by bile duct ligation (BDL) or by pretreatment with dimethyinitrosamine (DMNA). The pharmacokinetics of theophylline were studied after a single intravenous or a single oral administration. Using the ultrafiltration method, protein-drug binding experiments were also carried out. The bilirubin level was several-fold increased by BDL, but not by DMNA treatment. The albumin content was decreased in both cirrhotic groups. The total clearance (Clt, ml/kg/hr) of theophylline in both hepatic cirrhosis groups significantly decreased and the terminal half-life $(t_{1/2})$ in the cirrhotic rats was increased about two-fold after intravenous and oral administration. The volume of distribution at steady state (Vdss, ml/kg) was increased slightly in the cirrhotic groups. Protein binding in BDL $(8.67{\pm}4.85%)$ decreased about four-folds, but in DMNA $(73.00{\pm}9.85%)$ similar result war observed as compared with the control. Increased free fraction of theophylline did not increase the volume of distribution in BDL. Therefore decreased total body clearance of theophylline was mainly due to decreased intrinsic clearance of theophylline in the liver. The absolute bioavailability of theophylline in these experiments was between 63.8 and 72.8%(66.1% in BDL, 63.8% in Sham operated and Control, 72.8% in DMNA). These results suggest that in the experimental hepatic cirrhosis model, administration route does not affect the disposition of theophylline.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• v.23 no.4
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• pp.346-355
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• 2020

Purpose: Peroxisome proliferator-activated receptor gamma (PPAR-γ) has a key role in hepatic fibrogenesis by virtue of its effect on the hepatic stellate cells (HSCs). Although many studies have shown that PPAR-γ agonists inhibit liver fibrosis, the mechanism remains largely unclear, especially regarding the cross-talk between PPAR-γ and other potent fibrogenic factors. Methods: This experimental study involved 25 male Wistar rats. Twenty rats were subjected to bile duct ligation (BDL) to induce liver fibrosis, further divided into an untreated group (BDL; n=10) and a group treated with the PPAR-γ agonist thiazolidinedione (TZD), at 14 days post-operation (BDL+TZD; n=10). The remaining 5 rats had a sham operation (sham; n=5). The effect of PPAR-γ agonist on liver fibrosis was evaluated by histopathology, protein immunohistochemistry, and mRNA expression quantitative polymerase chain reaction. Results: Histology and immunostaining showed markedly reduced collagen deposition, bile duct proliferation, and HSCs in the BDL+TZD group compared to those in the BDL group (p<0.001). Similarly, significantly lower mRNA expression of collagen α-1(I), matrix metalloproteinase-2, platelet-derived growth factor (PDGF)-B chain, and connective tissue growth factor (CTGF) were evident in the BDL+TZD group compared to those in the BDL group (p=0.0002, p<0.035, p<0.0001, and p=0.0123 respectively). Moreover, expression of the transforming growth factor beta1 (TGF-β1) was also downregulated in the BDL+TZD group (p=0.0087). Conclusion: The PPAR-γ agonist inhibits HSC activation in vivo and attenuates liver fibrosis through several fibrogenic pathways. Potent fibrogenic factors such as PDGF, CTGF, and TGF-β1 were downregulated by the PPAR-γ agonist. Targeting PPAR-γ activity may be a potential strategy to control liver fibrosis.

• Korean Journal of Clinical Laboratory Science
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• v.36 no.2
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• pp.163-172
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• 2004

Mast cells (MCs) have been implicated in the pathogenesis of tissue fibrosis. However, the role of MC in the development of liver fibrosis has not been fully elucidated. Stem cell factor (SCF) is known to recruit MCs to the liver following injury as it induces mast cell proliferation, survival and differentiation from resident tissue precursors. This study examines the interaction between activated hepatic stellate cells (HSCs) and MCs in rat fibrotic liver, and SCF production by HSCs during culture in vitro. Rats were studied 4, 7, 14 and 21 days after bile duct ligation (BDL). Fibrogenesis was assessed by a measurement of collagen stained with sirius red F3B. Activated HSCs and MCs were identified by ${\alpha}$-smooth muscle actin (${\alpha}-SMA$) immunohistochemical and alcian blue staining and measured by a computerized image analysis system. SCF production was determined in rat HSC cultures using Western blotting. Mild fibrotic changes were noted in BDL rat livers as early as 4 days after induction of cholestasis. Significant expansion and organization of fibrous tissue has occurred in day 14 BDL rats which progressed to bridging fibrosis by day 21. In BDL rats, both a large number of activated HSCs and MCs were detected in portal tracts and fibrous septa. Both area of activated HSCs infiltration and density of MCs were significantly higher in all BDL group compared with Shams. In BDL rats, both areas of activated HSCs infiltration and density of MCs were no significant difference between day 4 and 7 and were significantly higher in day 14. However, the areas of activated HSCs infiltration were significantly lesser in day 21 and the densities of MCs were significantly higher in day 21 compared with day14 BDL. In BDL rats, both areas of activated HSCs infiltration and density of MCs were highly correlated with areas of fibrosis. Western blotting showed that SCF protein was consistently produced in activated HSCs by culture on plastic and freshly isolated HSCs expressed relatively little 30kD SCF compared to late primary culture activated HSCs (day 14) and passaged HSCs. These results suggest that HSCs activated in vitro produce SCF, and may play an important role in recruiting mast cells to the liver during injury and fibrosis.

• YAKHAK HOEJI
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• v.41 no.2
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• pp.220-224
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• 1997

This study was carried out to investigate the dose dependent antifibrotic effects of polysaccharide from mycelium of Ganoderma lucidum. The experimental hepatic cirrhosis was induced by bile duct ligation/scission (BDL/S) in rats. BDL/S rats in each group were dosed 0.5 mg, 2.0 mg, 5.0 mg or 10.O mg/rat/day orally for 4 weeks after the operation. Antifibrotic effects were evaluated by serum biochemical values, hydroxyproline contents, and light microscopical histology. The results obtained were as follows: 1) Hydroxyproline contents in liver of 5.0 and 10.0mg polysaccharide-treated BDL/S rats were significantly reduced 2) In serum test, ALT, AST, ALP values in polysaccharide from Ganoderma lucidum-treated group were lower than BDL/S control group 3) The hepatic damage such as hepatocellular necrosis, inflammation, bile duct proliferation and fibrosis was less severe in the livers of 2.0 mg and 5.0 mg polysaccharide-treated rats. These results suggest that polysaccharide from mycelium of Ganoderma lucidum to be a promising agent for the inhibition of hepatic cirrhosis.

• YAKHAK HOEJI
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• v.41 no.5
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• pp.622-628
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• 1997

Hepatic cirrhosis is a common response to chronic liver injury from many causes and is one of the most common cause of all deaths. This study was carried out to compare experimental hepatic cirrhosis in rats to understand this disease and to apply for the pharmacokinetics in disease state. Following three kinds of experimental models were induced; 1) Bile duct ligation/scission (BDL/S), 2) N, N-dimethylnitrosamine(DMN), 3) Carbon tetrachloride. The hepatic cirrhosis was characterized by examing the liver/body weight ratio, serum biochemical values, hydroxyproline content in liver and histopathological lesions in cirrhotic rat liver. The results are as follows : (1) In BDL/S, the liver was enlarged to 250% of normal liver. In contrast the liver was shrinked to 48% and 78% of the normal liver in DMN and carbon tetrachloride, respectively. (2) In carbon tetrachloride and BDL/S, the serum ALT, AST, ALP and total bilirubin levels were significantly increased to 200~300% of normal level, while ALT and total bilirubin levels were significantly increased in DMN group. (3) Hydroxyproline content in cirrhotic rat liver was significantly 200~500% higher than that of normal liver. (4) Nodular formation with fibrosis was observed in BDL/S, DMN, carbon tetrachloride induced cirrhotic rat liver.

• Natural Product Sciences
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• v.15 no.2
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• pp.101-105
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• 2009

We previously reported that a novel cerebroside, LCC, isolated from the fruits of Lycium chinense (Solanaceae), significantly exerted hepatoprotective activity against both the carbon tetrachloride-induced and galactosamine-induced toxicities in primary cultures of rat hepatocytes. In the present study, we further attempted to determine the effect of LCC on hepatic fibrosis in animal model. Hepatic fibrosis was induced in rats by bile duct ligation/scission (BDL) for a period of 5 weeks. Treatment of BDL rats with LCC significantly reduced collagen deposition and the activities of serum alkaline phosphatase and ${\gamma}$-glutamyl transpeptidase. In addition, the LCC treatment of BDL rats significantly preserved the decreased hepatic glutathione as well as the activities of glutathione reductase and catalase in BDL rats. From the results, it can be speculated that LCC might exert antifibrotic activity in rats with BDL, in part, through the preservation of antioxidant enzymes and hepatic glutathione.

• Journal of Life Science
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• v.31 no.8
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• pp.710-718
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• 2021

Placenta-derived mesenchymal stem cells (PD-MSCs) are promising candidates for cell-based therapy in regenerative medicine. The migration and homing potential of PD-MSCs to injured sites is a critical property of MSC engraftment. MicroRNAs (miRNAs) have recently been shown to regulate the critical functions of MSCs, such as proliferation, survival, and migration. The objective of the present study was to identify the miRNA and target genes involved in PD-MSCs homing in a bile duct ligation (BDL) rat model. We selected candidate miRNAs targeting genes for PD-MSCs homing based on microarray analysis. PD-MSC engraftment in BDL-injured rat liver was identified by immunofluorescence assay and human-specific Alu gene expression by quantitative real-time polymerase chain reaction (qRT-PCR) one week after transplantation. Compared with migrated naïve PD-MSCs under hypoxic and normoxic conditions (Hyp/Nor), the transplanted group with PD-MSCs (Tx) showed distinct differences in miRNA expressions in BDL-injured rat liver. We also validated the miRNAs and their target genes for PD-MSCs homing. The expressions of integrin α4 (ITGA4) and integrin α5 (ITGA5) target genes for miR-199a-5p and miR-148a-3p were significantly upregulated in the Tx group (p<0.05). In addition, integrin β1 (ITGB1) and integrin β8 (ITGB8) were upregulated by suppressing miR-183-5p and miR-145-5p, respectively. These results demonstrated that PD-MSCs regulate miRNA expression related to the integrin family for their homing effects on the BDL-injured rat liver. The findings further suggest that miRNA-mediated regulation of the integrin family contributes to the therapeutic efficacy of PD-MSCs in the rat hepatic fibrosis model by BDL.

• Biomolecules & Therapeutics
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• v.9 no.2
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• pp.112-118
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• 2001

The effects of Malloti Cortex Water Extract (MCWE), bergenin (isolated as an active component from MCWE), and acetylbergenin (synthesized from acetylation of bergenin) on the liver fibrosis induced by bile duct ligation (BDL) in rats. We studied hydroxypro1ine (HYP) as a marker of collagen accumulation in the liver, alanine aminotransferase (s-ALT), aspartate aminotransferase (s-AST), and alkaline phosphatase (s-ALP) as serum markers of liver cell damage induced by BDL, MCWE, bergenin, and acetylbergenin decreased towards normal the accumulated levels of HYP in the liver and the elevated serum levels of s-ALT, s-AST and 5-ALP. The results indicate that MCWE, bergenin, and acetylbergenin ameliorated the liver damage induced by BDL in rats.