• 센서학회지
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• 제20권2호
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• pp.71-76
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• 2011

To characterize the relationship between the stage of hepatic fibrosis and bioimpedance, several electric parameters were estimated in rats with $CCl_4$-induced liver fibrosis. Thirty three Sprague-Dawley rats were intraperitoneally injected with a $CCl_4$-mineral oil mixture (1:1, 0.2 mL/100 g) twice a week for 8 weeks. The resistance(R), reactance(X), impedance(Z), and dissipation factor(D) between 1 kHz and 100 kHz were then evaluated in the livers of the rats under pentobarbital anesthesia using an HP4294A Impedance Analyzer. The rats were killed 2, 4, 6, and 8 weeks later, and their livers were classified in accordance with Ishak's scoring system. R, X, and Z changed in accordance with the progression of hepatic fibrosis and the changes were greater at lower frequencies than at higher frequencies. In comparison, the D spectrum was biphasic; D increased initially then decreased with increasing frequency. All of the parameters(R, X, Z, and D) changed in accordance with the stage of fibrosis in the livers, but D changed specifically with the progression of fibrosis. These results indicate that hepatic fibrosis may be evaluated by determining the changes in D.

• 한국방사선학회논문지
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• 제17권7호
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• pp.1057-1065
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• 2023

비침습적 간섬유화 진단은 만성 간질환 환자들에게 매우 중요한 사항이다. 많은 환자들에게 간조직검사를 시행할 수가 없기 때문에 의미 있는 간섬유화 정도를 조기에 예측함으로써 만성 간질환의 치료와 간세포암 및 간경변증으로 인한 합병증을 감소시킬 수 있다. 본 연구는 비침습적인 간섬유화 검사 방법 중 간초음파 소견과 함께 전단파 탄성 초음파를 이용하여 간섬유화의 정량적 측정과 간탄성도 수치와 연관성을 갖는 혈청학적 인자도 비교 분석하였다(p<0.05). 그 결과 정상 집단의 횡파탄성측정값은 4.55 ± 0.69 kPa였으며, 에코 패턴의 비정상 대조군은 8.27 ± 1.83 kPa로 B형 간염 보균 집단에서 전단파 탄성 초음파 측정값이 높게 나타났으며, 혈청학적 인자들 중 AST, ALT, GGT, PT가 SWE 범주에 따른 섬유화의 정도에 따라 통계학적으로 유의한 양의 연관성을 보였으나(p<0.05) ALP와 TB는 통계적으로 유의미한 차이를 나타내지 않았다(p=0.163, p=0.567). 반면에 Albumin과 PLT는 유의한 음의 연관성을 보였다(p<0.05). 임상적으로 간경변 증후가 없는 만성 B형 간염 환자들의 간섬유화 추적 관찰 및 반복 검사 시 간초음파와 전단파 탄성 초음파 검사를 통한 탄성도 값을 추가로 활용한다면 검사자 간 객관적 진단에 있어 도움이될 것이며, 일차적인 진료에 유용할 것으로 사료된다.

• BMB Reports
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• 제50권2호
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• pp.58-59
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• 2017

The beneficial paracrine roles of mesenchymal stem cells (MSCs) in tissue repair have potential in therapeutic strategies against various diseases. However, the key therapeutic factors secreted from MSCs and their exact molecular mechanisms of action remain unclear. In this study, the cell-free secretome of umbilical cord-derived MSCs showed significant anti-fibrotic activity in the mouse models of liver fibrosis. The involved action mechanism was the regulation of hepatic stellate cell activation by direct inhibition of the $TGF{\beta}$/Smad-signaling. Antagonizing the milk fat globule-EGF factor 8 (MFGE8) activity blocked the anti-fibrotic effects of the MSC secretome in vitro and in vivo. Moreover, MFGE8 was secreted by MSCs from the umbilical cord as well as other tissues, including teeth and bone marrow. Administration of recombinant MFGE8 protein alone had a significant anti-fibrotic effect in two different models of liver fibrosis. Additionally, MFGE8 downregulated $TGF{\beta}$ type I receptor expression by binding to ${\alpha}v{\beta}3$ integrin on HSCs. These findings revealed the potential role of MFGE8 in modulating $TGF{\beta}$-signaling. Thus, MFGE8 could serve as a novel therapeutic agent for liver fibrosis.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• 제24권3호
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• pp.295-305
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• 2021

Purpose: Hepcidin levels have previously been reported to be correlated with liver damage. However, the association between hepcidin levels and liver fibrosis in children with fatty liver disease remains unclear. This study therefore aimed to investigate the pathophysiology of fibrosis in children with fatty liver disease and its association with hepcidin levels. Methods: This retrospective case series included 12 boys aged 6-17 years who were diagnosed with nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH) at the Tokyo Medical University Hospital. Sixteen liver biopsy samples from 12 subjects were analyzed. Serum hepcidin levels were assayed using enzyme-linked immunosorbent assay. Immunostaining for hepcidin was performed, and the samples were stratified by staining intensity. Results: Serum hepcidin levels were higher in pediatric NAFLD/NASH patients than in controls. Conversely, a significant inverse correlation was observed between hepcidin immunostaining and Brunt grade scores and between hepcidin scores and gamma-glutamyltranspeptidase, hyaluronic acid, and leukocyte levels. We observed inverse correlations with a high correlation coefficient of >0.4 between hepcidin immunostaining and aspartate aminotransferase, alanine aminotransferase, total bile acid, and platelet count. Conclusion: There was a significant inverse correlation between hepcidin immunoreactivity and fibrosis in pediatric NAFLD patients; however, serum hepcidin levels were significantly higher, suggesting that these patients experienced a reduction in the hepcidin-producing ability of the liver in response to iron levels, leading to subsequent fibrosis. Therefore, hepcidin levels can be used as markers to identify the progression of fibrosis in patients with NAFLD.

• Biomolecules & Therapeutics
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• 제28권6호
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• pp.527-536
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• 2020

Liver fibrosis constitutes a significant health problem worldwide due to its rapidly increasing prevalence and the absence of specific and effective treatments. Growing evidence suggests that apoptosis-signal regulating kinase 1 (ASK1) is activated in oxidative stress, which causes hepatic inflammation and apoptosis, leading to liver fibrogenesis through a mitogen-activated protein kinase (MAPK) downstream signals. In this study, we investigated whether selonsertib, a selective inhibitor of ASK1, shows therapeutic efficacy for liver fibrosis, and elucidated its mechanism of action in vivo and in vitro. As a result, selonsertib strongly suppressed the growth and proliferation of hepatic stellate cells (HSCs) and induced apoptosis by increasing Annexin V and TUNEL-positive cells. We also observed that selonsertib inhibited the ASK1/MAPK pathway, including p38 and c-Jun N-terminal kinase (JNK) in HSCs. Interestingly, dimethylnitrosamine (DMN)-induced liver fibrosis was significantly alleviated by selonsertib treatment in rats. Furthermore, selonsertib reduced collagen deposition and the expression of extracellular components such as α-smooth muscle actin (α-SMA), fibronectin, and collagen type I in vitro and in vivo. Taken together, selonsertib suppressed fibrotic response such as HSC proliferation and extracellular matrix components by blocking the ASK1/MAPK pathway. Therefore, we suggest that selonsertib may be an effective therapeutic drug for ameliorating liver fibrosis.

• Biomolecules & Therapeutics
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• 제9권2호
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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.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• 제22권6호
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• pp.501-510
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• 2019

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children. The global prevalence of pediatric NAFLD from general populations is 7.6%. In obese children, the prevalence is higher in Asia. NAFLD has a strong heritable component based on ethnic difference in the prevalence and clustering within families. Genetic polymorphisms of patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily member 2, and glucokinase regulatory protein (GCKR) are associated with the risk of NAFLD in children. Variants of PNPLA3 and GCKR are more common in Asians. Alterations of the gut microbiome might contribute to the pathogenesis of NAFLD. High fructose intake increases the risk of NAFLD. Liver fibrosis is a poor prognostic factor for disease progression to cirrhosis. Magnetic resonance spectroscopy and magnetic resonance proton density fat fraction are more accurate for steatosis quantification than ultrasound. Noninvasive imaging methods to assess liver fibrosis, such as transient elastography, shear-wave elastography, and magnetic resonance elastography are useful in predicting advanced fibrosis, but they need further validation. Longitudinal follow-up studies into adulthood are needed to better understand the natural history of pediatric NAFLD.

• Journal of Ginseng Research
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• 제37권1호
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• pp.45-53
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• 2013

Korean red ginseng, the processed root of Panax ginseng Meyer, has been frequently used for various therapeutic purposes in oriental medicine. The present study investigated the possible effect of Korean red ginseng extract (RGE) for the treatment of liver fibrosis in mice injected with carbon tetrachloride ($CCl_4$) for 4 wk. Liver injuries were assessed by blood biochemistry and histopathology in mice treated with $CCl_4$ alone or $CCl_4$+ RGE (30, 100, and 300 mg/kg). Concomitant treatment with RGE and $CCl_4$ (three times/wk for 4 wk) effectively inhibited liver fibrosis as evidenced by decreases in plasma alanine and aspartate aminotransferases, as well as by the percentages of degenerative regions, numbers of degenerative hepatocytes, and collagen accumulation in hepatic parenchyma. Treatment with $CCl_4$ for 4 wk increased mRNA levels of transforming growth factor ${\beta}1$ and plasminogen activator inhibitor 1 in fibrogenic liver, whereas RGE (30, 100, and 300 mg/kg) significantly blocked the induction of fibrogenic genes by $CCl_4$. Similarly, RGE also prevented transforming growth factor ${\beta}1$-mediated induction of fibrogenic genes in human hepatic stellate cell lines. More importantly, RGE markedly reduced the number of ${\alpha}$-smooth muscle actin-positive cells in liver tissue. This study implies that RGE efficaciously protects against the liver fibrosis induced by chronic $CCl_4$ treatment, and may therefore have potential to treat liver disease.

• 약학회지
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• 제46권2호
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• pp.129-136
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• 2002

The pathogenesis of cholestatic liver injury as well as the modulation of hepatic fibrogenesis is causally associated with involvement of reactive oxygen species (ROS) and free radical reactions. In this study, we investigated whether dried extracts of oriental medicine (LH) have antioxidant and antifibrotic effect under the biliary liver fibrosis (cirrhosis) c ondition. The female Sprague-Dawley rats were divided in six groups (Normal, N-LH, op-2, op-4, opLH-2, opLH-4) and were observed in 2 weeks or 4 weeks. For this purpose the rats were operated by bile duct ligation/scission (BDL/S), which induced to liver fibrosis and cirrhosis. After surgery, the prepared LH was administered p.o. 2 mι/day/rat in 2 weeks or 4 weeks for opLH groups. During the observation period, jaundices appeared in eyes, ears and tail of all BDL/S operated rats. And at the time of sacrifice, cholestasis was observed in proximal bile duct, especially the color of bile juice and urine in opLH-4 group showed more clear than op-2, op-4 and opLH-2 group. The value of clinical parameters and product of lipid peroxidation (MDA) in sera and the hydroxyproline (hyp) content in liver tissue were significantly increased in all liver fibrosis (cirrhosis) developed rats (p＜0.001~0.05). Among the clinical parameters of sera, value of BUN, ALP in opLH-4 group showed significantly lower than in op-4 group (p＜0.05, p＜0.001). The content of hyp in opLH-2, opLH-4 group (478.0 $\pm$ 134.3 $\mu\textrm{g}$/g 897.5 $\pm$ 118.2 $\mu\textrm{g}$/g) showed lower than in op-2, op-4 group (528.9 $\pm$ 220.7 $\mu\textrm{g}$/g, 1023.8 $\pm$ 277.1 $\mu\textrm{g}$/g) and then the value of MDA in opLH-4 was also significantly reduced to 59.4% of that in op-4 group (p＜0.001). The histological change (bile duct proliferation, fibrosis, collagen bundle) was similarly observed in op-2 group and in opLH-2 group, but the weak fibrosis and bile duct proliferation were observed in opLH-4 group compared with in op-4 group. Our data indicate that the 4 weeks treatment with LH extract suppressed lipid peroxidation and inhibited fibrotic (cirrhosis) process, and experimental cholestatic liver disease is associated with increased lipid peroxidation in BDL/S operated rats. Hence we concluded that the measurement of MDA and hyp can be useful monitor for the screening of antioxidant and antifibrotic effect in experimental liver fibrosis (cirrhosis), and LH has been shown to have hepatoprotective effect, antifibrotic effect and antioxidant effect.

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2-2
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• pp.86.2-87
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• 2003

Introduction: Liver fibrosis is defined unbalance of collagen metabolism, especially a stimulation of collagen synthesis and inhibition of collagen degradation, and antifibrotic effect is delaying or inhibition of new collagen synthesis and deposition in liver tissue. In this study, we investigated the antifibrotic and antioxidative effect of Solanum lycopersicum (SL) in liver fibrosis induced rats. Methods: : Rats were randomly divided in three groups (normal, CCl$_4$ and CCl$_4$-SL group) and were received 0.6 ml mixture of CCl$_4$ and olived oil (1:1 v/v) 3 times/week for 4 weeks except of the normal group. (omitted)