• Biomolecules & Therapeutics
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• 제29권3호
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• pp.331-341
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• 2021

Liver cancer is a common tumor and currently the second leading cause of cancer-related mortality globally. Liver cancer is highly related to inflammation as more than 90% of liver cancer arises in the context of hepatic inflammation, such as hepatitis B virus and hepatitis C virus infection. Despite significant improvements in the therapeutic modalities for liver cancer, patient prognosis is not satisfactory due to the limited efficacy of current drug therapies in anti-metastatic activity. Therefore, developing new effective anti-cancer agents with anti-metastatic activity is important for the treatment of liver cancer. In this study, SP-8356, a verbenone derivative with anti-inflammatory activity, was investigated for its effect on the growth and migration of liver cancer cells. Our findings demonstrated that SP-8356 inhibits the proliferation of liver cancer cells by inducing apoptosis and suppressing the mobility and invasion ability of liver cancer cells. Functional studies revealed that SP-8356 inhibits the mitogen-activated protein kinase and nuclear factor-kappa B signaling pathways, which are related to cell proliferation and metastasis, resulting in the downregulation of metastasis-related genes. Moreover, using an orthotopic liver cancer model, tumor growth was significantly decreased following treatment with SP-8356. Thus, this study suggests that SP-8356 may be a potential agent for the treatment of liver cancer with multimodal regulation.

• BMB Reports
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• 제40권4호
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• pp.467-474
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• 2007

Autosomal recessive polycystic kidney disease (ARPKD) is one of the important genetic disorders in pediatric practice. Mutation of the polycystic kidney and hepatic disease gene 1 (PKHD1) was identified as the cause of ARPKD. The gene encodes a 67-exon transcript for a large protein of 4074 amino acids termed fibrocystin, but its function remains unknown. The neoplastic-like in cystic epithelial proliferation and the epidermal growth factor/epidermal growth factor receptor (EGF/EGFR) axis overactivity are known as the most important characteristics of ARPKD. Since the misregulation of $Ca^{2+}$ signaling may lead to aberrant structure and function of the collecting ducts in kidney of rat with ARPKD, present study aimed to investigate the further mechanisms of abnormal proliferation of cystic cells by inhibition of PKHD1 expression. For this, a stable PKHD1-silenced HEK-293T cell line was established. Then cell proliferation rates, intracellular $Ca^{2+}$ concentration and extracellular signal-regulated kinase 1/2 (ERK1/2) activity were assessed after treatment with EGF, a calcium channel blocker and agonist, verapamil and Bay K8644. It was found that PKHD1-silenced HEK-293T cell lines were hyperproliferative to EGF stimulation. Also PKHD1-silencing lowered the intracellular $Ca^{2+}$ and caused EGF-induced ERK1/2 overactivation in the cells. An increase of intracellular $Ca^{2+}$ in PKHD1-silenced cells repressed the EGF-dependent ERK1/2 activation and the hyperproliferative response to EGF stimulation. Thus, inhibition of PKHD1 can cause EGF-induced excessive proliferation through decreasing intracellular $Ca^{2+}$ resulting in EGF-induced ERK1/2 activation. Our results suggest that the loss of fibrocystin may lead to abnormal proliferation in kidney epithelial cells and cyst formation in ARPKD by modulation of intracellular $Ca^{2+}$.

• 생명과학회지
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• 제30권7호
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• pp.640-650
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• 2020

간, 췌장 및 지방 조직에서 많은 수준으로 합성되는 섬유 아세포 성장 인자 21(FGF21)은 FGF19과 FGF23와 함께 FGF 패밀리의 비정형 구성원에 속해 있다. FGF21은 발현 조직에 따라 endo/paracrine특징을 보여주며, 포도당 대사 및 에너지 항상성을 포함하는 많은 종류의 대사 경로를 조절하고 있다. 생리학적 조건 하에서 많은 종류의 스트레스가 조직 별 FGF21의 합성을 유도한다고 알려져 있고, 이렇게 증가한 FGF21은 위와 같은 스트레스에 적응하거나 방어하기 위한 세포 내 기전을 활성화 시키게 된다. 이 과정에서 peroxisome proliferator-activated receptor gamma (PPARγ) 및 peroxisome proliferator-activated receptor alpha (PPARα)가 지방 및 간 조직에서 FGF21의 발현을 조절하는 대표적인 전사 조절자로 알려져 있다. 지난 10년간의 연구를 통해 약리학적 FGF21 투여는 체중을 감소시키고 비만 마우스 및 2 형 당뇨병 환자에서 인슐린 감수성 및 지단백질 프로파일을 개선시키는 것으로 보고되었고, 이를 바탕으로 FGF21은 제 2 형 당뇨병, 비만 및 비 알콜 성 지방간 질환(NAFLD)의 치료제로서 큰 주목을 받아 왔다. 그러나 조직 별 상이한 FGF21 발현의 역설적 조건 및 생리 약학적 기능의 차이로 인해 FGF21의 이해는 여전히 부족한 수준에 있다. 따라서 본 총설을 통해 FGF21의 조직 특정 기능 및 해당 동작 메커니즘을 포함한 이전 연구들에서 발생하였던 흥미로운 문제를 논의하고, FGF21 아날로그를 이용한 임상 시험의 현 상황을 요약하고자 한다.

• Animal Bioscience
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• 제34권4호
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• pp.662-669
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• 2021

Objective: Effects of linseed oil (LO) supplementation on the fat content and fatty acid profile of breast meat, and the expression of three genes in the liver, breast muscle and fat tissues of commercial 154-day-old hybrid male turkeys were investigated. Methods: The animals in the control group were fed a commercially available feed and received no LO supplementation (n = 70), whereas animals in the LO group (n = 70) were fed the same basic diet supplemented with LO (day 15 to 21, 0.5%; day 22 to 112, 1%). The effect of dietary LO supplementation on fatty acid composition of breast muscle was examined by gas chromatography, and the expression of fatty acid desaturase 2 (FADS2), peroxisome proliferator activated receptor gamma (PPARγ), and insulin-like growth factor 1 (IGF1) genes was analysed by means of quantitative reverse transcription polymerase chain reaction. Results: The LO supplementation affected the fatty acid composition of breast muscle. Hepatic FADS2 levels were considerably lower (p<0.001), while adipose tissue expression was higher (p<0.05) in the control compared to the LO group. The PPARγ expression was lower (p<0.05), whereas IGF1 was higher (p<0.05) in the fat of control animals. There were no significant (p>0.05) differences in FADS2, PPARγ, and IGF1 gene expressions of breast muscle; however, omega-6/omega-3 ratio of breast muscle substantially decreased (p<0.001) in the LO group compared to control. Conclusion: Fatty acid composition of breast meat was positively influenced by LO supplementation without deterioration of fattening parameters. Remarkably, increased FADS2 expression in the liver of LO supplemented animals was associated with a significantly decreased omega-6/omega-3 ratio, providing a potentially healthier meat product for human consumption. Increased PPARγ expression in fat tissue of the LO group was not associated with fat content of muscle, whereas a decreased IGF1 expression in fat tissue was associated with a trend of decreasing fat content in muscle of the experimental LO group.

• 한국수산과학회지
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• 제51권6호
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• pp.714-719
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• 2018

We investigated the effects of water temperature on physiological parameters in the chicken grunt Parapristipoma trilineatum. At high temperature, the aspartate aminotransferase (AST) and the alanine aminotransferase (ALT) levels were increased, suggesting that high temperature induced hepatic damage. In addition, total protein (TP) was high at high water temperatures, which were considered stressful in the breeding environment. At high water temperatures, triglycerides (TG) were low due to increased metabolic activity, which decreased the blood TG levels as TG were used as an energy source. There was no significant difference in the plasma osmolality or the blood ion concentrations with water temperature. In generally, lysozyme, a factor in innate immunity, increased with water temperature. However, lysozyme activity tended to decrease with increasing water temperature, but the difference was not significant. These results suggested that the decrease of biophylaxis at high temperature was affect the growth or survival of the population.

• 대한임상검사과학회지
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• 제43권4호
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• pp.194-204
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• 2011

This study was carried out to compare the histopathological differences of liver lesions in carbon tetrachloride ($CCI_4$), dimethylnitrosamine (DMN), thioacetamide (TAA) and bile duct ligation (BDL)-induced rats. $CCl_4$, DMN and TAA were administered intraperitoneally and conducted bile duct ligation for 4 weeks to induce hepatic fibrosis. Indices of liver cell injury (steatosis, hydropic degeneration, bile duct hyperplasia, hemorrhage & hemosiderin deposition), the extent of liver fibrosis (fibrotic area) and the rate of regeneration (number of PCNA-positive cells) were investigated in each group. Liver tissues were stained with hematoxylin-eosin (HE), sirius red, prussian blue and immunostained with ${\alpha}$-smooth muscle actin (${\alpha}$-SMA), transforming growth factor-${\beta}1$ (TGF-${\beta}1$), proliferative cell nuclear antigen (PCNA), and quantified using a computerized image analysis system. Liver cell steatosis was significantly increased in $CCl_4$ and TAA groups, and hydropic degeneration and bile duct hyperplasia were significantly increased in TAA and BDL groups when compared with that in normal control, respectively. Fibrosis area was significantly increased in all four groups, especially in $CCl_4$ group. Correlation between ${\alpha}$-SMA and TGF-${\beta}1$ expressions in four groups was good. Hemorrhage area in liver parenchyma was significantly increased in DMN group only when compared with that in normal control, while hemosiderin deposition area was significantly increased in TAA and BDL groups as well as DMN group. The Number of PCNA-positive cells was significantly increased in all four groups, especially in TAA group. These results indicate that the duration and methods of hepatotoxic drug treatment are very important factors to make plans for animal experimentation on the induction of hepatic fibrogenesis in rats.

• 한국발생생물학회지:발생과생식
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• 제10권1호
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• pp.63-73
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• 2006

간질환 환자의 대부분은 간 조직 손상으로 인해 간세포의 재생 능력이 감소한다. 간세포 이식은 이러한 간질환을 치료하는데 있어 혁신적인 방법으로 대두되고 있으나, 여전히 많은 의문과 문제점이 제기되고 있다. 사람의 양막으로부터 얻은 줄기 세포를 이용하여 간세포 분화를 위한 최적의 조건을 알아 보고자 하였다. 세포내 알부민에 대한 면역 화학적 방법, 세포내 글리코겐의 특이 염색법, 세포의 형태적 변화 연구 방법 등을 이용하여 여러가지 배양 조건을 조사한 결과, 배양 접시를 fibronectin으로 coating하고 배양액내에 insulin/transferrin/selenium(ITS)을 첨가하는 것이 양막 줄기세포의 간세포로의 분화에 효과적이었다. 또한 배양액내에 fibroblast growth factor(FGF)-1과 FGF-2를 함께 첨가하는 것이 둘 중 하나만 첨가하거나 첨가하지 않는 것보다 효과적이었다. 한편 분화 배양은 한가지 배양액을 사용한 지속적인 배양법(continuous culture method)보다 배양 조건을 달리하여 두 단계로 배양하는 2단계 배양법(two-step culture method)가 훨씬 효과적이었다. 마지막으로, 기본 배양액에 FGF-2와 FGF-4를 첨가한 조건과 FGF-4와 $TGF-{\alpha}$를 첨가한 조건이 다른 조건 보다 알부민 분비를 많이 하는 것으로 보아 FGF-4가 간세포 분화 과정에 중요한 역할을 하는 것으로 여겨지며 FGF-2 및 $TGF-{\alpha}$ 첨가는 더욱 효과적인 배양 조건으로 관찰되었다. 따라서, 양막에서 유래한 성체 줄기 세포는 적절한 배양 조건이 주어질 때, 간세포로 분화가 가능하며, 분화 과정에서 FGF-4가 주도적인 역할을 하며 FGF-2와 $TGF-{\alpha}$는 상승 효과를 갖는 것으로 사료된다.

• Nuclear Medicine and Molecular Imaging
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• 제42권sup1호
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• pp.66-70
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• 2008

Reports about FDG PET in biliary tumor are limited and there are almost no reports regarding its efficacy. Biliary tumor is divided to intrahepatic and extrahepatic bile duct cancer, and intrahepatic bile duct cancer can be further divided to peripheral type which occurs at lobular duct and hilar type which occurs at hepatic hilum. Surgical resection is the only curative method for bile duct tumor, and accurate staging plays an important role in deciding treatment modality. Among intrahepatic bile duct tumors, peripheral type and hilar type have the same histological characteristics, but different clinical manifestations and tumor growth pattern. On PET image, FDG uptake is also different between peripheral type and hilar type. Most of the former shows high FDG uptake at primary and metastasis site so it is very useful for determining stage and changing treatment plans. However, the later is diversified among low uptake and very high uptake. The FDG uptake pattern of hilar type is similar to that of extrahepatic bile duct cancer, and mucinous component is an important factor, which affects FOG uptake. When tumor cells are scattered in desmoplatsic stroma, then FDG uptake is low as well. In contrast, when FDG uptake is high, it is likely to be tubular type which has high tumor density. Tumor growth pattern also affects FDG uptake. Nodular type mostly takes higher FDG compared to infiltrative type. There are many cases where benign inflammatory diseases take high FDG that PET alone can not distinguish malignant lesion from benign lesion. In conclusion, studies about PET using FDG are still limited. Thus, it is hard to make accurate conclusion about the roles of PET or PET/CT in biliary cancers, but peripheral type intrahepatic bile duct cancers and mass forming hilar and extrahepatic bile duct cancers appear to be good indications performing FDG PET or PET/CT.

• 생명과학회지
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• 제34권4호
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• pp.227-235
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• 2024

약물이나 허브 제품으로 인한 간세포 손상은 이러한 화합물을 만성적으로 투여할 때 일어날 수 있는 중요한 문제 중 하나이다. 따라서 여러 가지의 치료 과정 중 간세포 생존율을 향상시키는 것은, 약물 적용에 있어 광범위한 기회를 제공할 수 있다. Valproic acid (VPA)는 자연적으로 발생하는 발레르산에서 파생된 분지형 단사슬 지방산으로 뇌전증과 발작을 치료하는 데 일반적으로 사용된다. 뿐만 아니라 VPA는 암, HIV 치료, 신경 퇴행성 질환에 수많은 효과를 발휘하지만, 간에 대한 VPA의 잠재적인 영향과 그 작용 메커니즘은 완전히 설명되지 않았다. 여기서, 우리는 VPA의 처리가 쥐 간세포(Hepa1c1c7)에서 PPAR 알파(PPAR-α)와 섬유아세포 성장 인자 21(FGF21)의 전사 수준을 증가시킨다는 것을 입증했다. VPA에 의해 유도된 FGF21 발현은 PPAR-α 결손 조건에서 상당히 억제되었다. 후속 실험에서 FGF21 신호 경로가 FGF 수용체 억제제에 의해 차단되었을 때, 간세포 생존력이 크게 억제되었음을 보여주었다. 마지막으로, 우리는 AMPK 인산화가 VPA에 의해 유도된 PPAR-α 증가에 작용하지 않는다는 것을 추가로 확인했다. 이러한 결과는 FGF21 발현의 증가가 VPA에 의해 유도된 간 독성을 완화시킬 수 있다는 것을 제시하며, 이와 같은 결과는 FGF21의 증감 여부가 VPA 치료 중 나타날 수 있는 간 손상을 예측하는 잠재적인 바이오마커로 사용될 수 있음을 제시한다.

• Asian-Australasian Journal of Animal Sciences
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• 제20권9호
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• pp.1334-1341
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• 2007

This study identified hepatic differentially expressed genes (DEGs) affecting the marbling of muscle. Most dietary nutrients bypass the liver and produce plasma lipoproteins. These plasma lipoproteins transport free fatty acids to the target tissue, adipose tissue and muscle. We examined hepatic genes differentially expressed in a differential-display reverse transcription-polymerase chain reaction (ddRT-PCR) analysis comparing high- and low-marbled Hanwoo steers. Using 60 arbitrary primers, we found 13 candidate genes that were upregulated and five candidate genes that were downregulated in the livers of high-marbled Hanwoo steers compared to low-marbled individuals. A BLAST search for the 18 DEGs revealed that 14 were well characterized, while four were not annotated. We examined four DEGs: ATP synthase F0, complement component CD, insulin-like growth factor binding protein-3 (IGFBP3) and phosphatidylethanolamine binding protein (PEBP). Of these, only two genes (complement component CD and IGFBP3) were differentially expressed at p<0.05 between the livers of high- and low-marbled individuals. The mean mRNA levels of the PEBP and ATP synthase F0 genes did not differ significantly between the livers of high- and low-marbled individuals. Moreover, these DEGs showed very high inter-individual variation in expression. These informative DEGs were assigned to the bovine chromosome in a BLAST search of MS marker subsets and the bovine genome sequence. Genes related to energy metabolism (ATP synthase F0, ketohexokinase, electron-transfer flavoprotein-ubiquinone oxidoreductase and NADH hydrogenase) were assigned to BTA 1, 11, 17, and 22, respectively. Syntaxin, IGFBP3, decorin, the bax inhibitor gene and the PEBP gene were assigned to BTA 3, 4, 5, 5, and 17, respectively. In this study, the in silico physical maps provided information on the specific location of candidate genes associated with economic traits in cattle.