• 대한핵의학회지
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• 제37권6호
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• pp.418-427
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• 2003

목적: $^{99m}-lactosylated$ serum albumin ($^{99m}Tc-LSA$)은 간세포에 특이적으로 결합하는 간수용체 영상용 방사성의약품으로 새로이 합성되었다. 간섬유화를 유발하는 dimethylnitrosamine (DMN)을 투여한 간 손상 흰쥐 모델에서 $^{99m}Tc-LSA$의 역동학적인 간섭취를 조사하고 간효소치의 변화와 조직학적 소견을 비교하여, LSA의 간섭취가 간기능의 변화를 반영하는지를 연구하였다. 대상 및 방법: SD계 흰쥐에 DMN를 27 mg/kg으로 복강 내 주사하여 급성 간손상을 유도하고 대조군과 비교하였다. DMN을 주사한 흰쥐를 3일(DMN-3), 8일(DMN-8), 21일(DMN-21)에 $^{99m}Tc-LSA$ (1,665 mg/kg) 29 MBq를 정맥 주사하여, 30분 동안 동적 영상을 획득하고 간과 심장부위에 관심영역을 설정하여 간과 심장부위의 시간방사능 곡선을 얻었다. 간기능 평가를 위해 시간방사능 곡선을 이용하여 간섭취지수와 혈중제거지수를 구하였고 곡선 최적화를 시행하였다. DMN 투여군과 대조군의 간효소치의 변화와 간조직의 광학현미경 소견을 비교하였다. 결과: 대조군에서는 $^{99m}Tc-LSA$가 빠르게 간에 섭취되고 혈중에서 제거되었으나 DMN을 처리한 군에서는 간섭취가 낮았다. 간섭취지수의 비교에서 대조군에 비해 DMN 처리군에서 유의하게 간섭취지수가 낮았다(DMN-3: 0.842, BMN-8: 0.898, DMN-21: 0.91, 대조군: 0.96, p<0.05). 혈중제거지수의 비교에서도 대조군에 비해 DMN 처리군에서 혈중제거지수가 유의하게 높았다(DMN-3: 0.731, DMN-8: 0.654, DMN-21: 0.604, 대조군: 0.473, p<0.05). 비선형 회귀분석에서 $R_2$값은 0.9이상으로 좋은 일치를 보였고, 대조군에서 K값이 DMN처리군에 비해 크고 (DMN-3: 0.28, DMN-8: 0.41, DMN-21: 0.46, 대조군: 0.97, p<0.05), $T_{1/2}$값은 작았다(DMN-3: 2.5, DMN-8: 1.7, DMN-21: 1.5, 대조군: 0.7, p<0.05). 간효소치의 변화는 DMN-3군에서는 대조군에 비해 상승하였으나 DMN-8, DMN-21군에서는 간효소치의 상승이 관찰되지 않았다. 간조직 소견의 경우 DMN-3군에서 중심정맥 주위에 괴사가 관찰되었으나 DMN-8군, DMN-21군에서는 미약한 정도의 염증세포 침윤만이 관찰되었다. 결론: $^{99m}Tc-LSA$ 간신티그래피의 간섭취 정도는 간손상과 반비례하였으며 간섭취의 변화는 조직학적 손상이 심한 정도와 간손상후 회복되는 과정을 반영하여 주었다. $^{99m}Tc-LSA$ 간신티그래피가 간손상을 평가하고 간손상후 회복되는 과정을 추적하는 간수용체 영상용 방사성 의약품으로 사용될 수 있을 것으로 생각된다.

• 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.

• Archives of Pharmacal Research
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• 제25권5호
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• pp.655-663
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• 2002

Liver fibrosis is a prepathological state wherein damaged liver tissues in chronic liver diseases, such as hepatitis, are not repaired to normal tissues, but converted to fibrous tissue. 5-(2-Pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz), a cancer chemopreventive agent, is effective against a wide variety of chemical carcinogens. Recently, we reported that oltipraz inhibits liver fibrogenesis (Kang et al., 2002). In the present study, the effects of oltipraz in combination with dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate (DDb) on dimethylnitrosamine (DMN)-induced liver fibrogenesis were assessed in rats. Oltipraz (30 mg/kg body weight, po, 3 times per week for 4 weeks) was found to inhibit the increases in plasma ALT, AST and bilirubin by DMN, whereas DDB (30 mg/kg body weight, po, 3 times per week for 4 weeks) attenuated the increases in the plasma ALT and bilirubin. The lowered plasma protein and albumin contents in DMN-treated rats were completely restored by oltipraz, but not by DDB. DDB decreases liver cell injury and inflammation through inhibition of nuclear factor-kB. DMN increased the accumulation of liver collagen, as indicated by the increase in the 4-hydroxyproline content in liver homogenates, which was reduced by treatment with oltipraz, but not by DDB. Given the differential effect between oltipraz and DDB, the potential enhancement of antifibrotic efficacy by the drugs was assessed in the animal model. Despite the minimal effect of DDB on DMN-induced fibrogenesis, DDB (5-25 mg/kg), administered together with oltipraz (25-5 mg/kg), showed an additive protective effect against hepatotoxicity and fibrosis induced by DMN, which was shown by the blood chemistry parameters and histopathological analysis. The adequate composition ratio of oltipraz to DDB was 5:1. These results provide information on the pharmaceutical composition, comprising of oltipraz and DDB as the active components, for the treatment and/or prevention of liver fibrosis and cirrhosis.

• Archives of Pharmacal Research
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• 제23권6호
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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.

• Toxicological Research
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• 제17권
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• pp.79-82
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• 2001

The infection of liver flukes, Clonorchis sinensis (CS) and Opisthorchis viverrini (OV), has been known as a risk factor to induce cholangiocellular carcinoma (CCC) in human living in the endemic area, providing promoting effect on the liver initiated by chemical carcinogens. The present study evaluated the relationship between the dosage level of dimethylnitrosamine (DMN) and the infection load of CS in the neoplastic development by histopathological examination of the treated hamsters. To evaluate the effects of DMN, different doses of DMN ranging from 0 to 25 ppm were administered to hamsters with 20 CS metacercariea. For the risk assessment of the infection load, 0, 5, 15, 50 CS metacercariae were respectively infected with 12 ppm DMN. The mortality was closely related to the infection load rather than the concentration of DMN. The infection of CS clearly promoted the induction of CCC even at dose level of 6 ppm DMN. Only five metacercariae were enough to promote CCC induction at the concentration of 12 ppm DMN.

• Journal of Korean Biological Nursing Science
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• 제8권2호
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• pp.41-59
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• 2006

Chronic liver diseases and hepatic cancer have been reported as 10% of cause of death in Koreans. Regardless of various causes, chronic liver disease accompanies commonly hepatic fibrosis. But still the mechanism of hepatic fibrosis remains poorly understood. Using the dimethylnitrosamine(DMN)-induced hepatic fibrosis rat model, We performed to evaluate the possible therapeutic effect of RIP(extracts of Phellodendron amurense and Patrinia scabiosaefolia) and to investigate the changes in referential connective tissue proteins($TGF-{\beta}_1$, ${\alpha}$-smooth muscle actin, and vimentin) as a marker of fibrogenesis. For these purposes, liver tissues were stained with H & E, and Azan staining for estimation of developing fibrosis. In the DMN-treated rat liver tissue, fibrosis were developed forming incomplete septal fibrosis. Whereas, in the RIP-treated rat liver tissues, the fibrosis were decreased recovering to normal morphology. The expressions of $TGF-{\beta}_1$, ${\alpha}$-smooth muscle actin($\alpha-SMA$), and vimetin were increased in the DMN-treated rat liver tissues, but decreased in the various areas of RIP-treated rat liver tissues. According to these results, RIP could be a possible therapeutic agent to reduce hepatic fibrosis, and the $TGF-{\beta}_1$, ${\alpha}$-SMA, and vimentin could be possible indicative markers of hepatic fibrosis development and recovery.

• 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.

• Asian Pacific Journal of Cancer Prevention
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• 제16권15호
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• pp.6279-6284
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• 2015

Opisthorchis viverrini (OV)-induced cholangiocarcinoma (CCA) is an important cancer in the Great Mekong region, particularly in Thailand. Limitations of treatment options and the lack of an effective diagnostic tool for early detection of CCA are major concerns for the control of this type of cancer. The aim of the study was to investigate anti-CCA activity of the ethanolic extract of Atractylodes lancea (Thunb.) DC., and the applicability of positron emission tomography-computed tomography (PET-CT) as a tool for detection and monitoring the progression of CCA in Opisthorchis viverrini (OV)/dimethylnitrosamine (DMN)-induced CCA hamsters. Male Syrian hamsters were used for toxicity tests and anti-CCA activity evaluation. Development of CCA was induced by initial feeding of 50 metacercariae of OV, followed by drinking water containing 12.5 ppm of DMN in hamsters. The ethanolic extract of A. lancea (Thunb.) DC. was administered orally for 30 days. PET-CT was performed every 4 weeks after initiation of CCA using 18F-fluorodeoxyglucose ($^{18}F-FDG$). Results from the present study suggest that the ethanolic extract of A. lancea (Thunb.) DC. rhizome exhibited promising anti-CCA activity and safety profile in the OV/DMN-induced hamster model. To successfully apply PET-CT as a tool for early detection of tumor development and progression, modification of radiolabeling approach is required to improve its specificity for CCA cells.

• 대한수의학회지
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• 제36권1호
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• pp.169-179
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• 1996

This study was carried out to examine the role of small cells and oval cells in cholangiocarcinogenesis in the hamsters infected with Clonorchis(C) sinensis. Forty two female Syrian golden hamsters were divided into two groups. Group I was for the induction of the cholangiocarcinoma, which was infected orally with C sinensis and given dimethylnitrosamine(15ppm) in drinking water for 4 weeks. Group II was served as control. More than 5 heads of hamsters in each group were sacrificed at 4, 7, 11 and 15 weeks after the beginning of the experiment. The livers were examined histopathologically, electron microscopically and immunohistochemically. The results obtained were as follows; 1. Cholangiocarcinomas were occurred in 1 of 6 animals at 11 weeks and in 4 of 6 animals at 15weeks after the beginning of the experiment. 2. Small cells and oval cells were proliferated around the portal triads from 4 weeks and peaked at 11 weeks, and slightly decreased after then. 3. The strong positive reaction to the $\alpha$-fetoprotein was shown in many of small cells and oval cells. But ductlike oval cells, which were arranged rosette form, showed week positive reaction to the $\alpha$-fetoprotein. 4. Most of small cells and oval cells showed negative reaction to the cytokeratin. But weak positive reaction in ductlike oval cells, and moderate positive reaction in cholangiocarcinoma cells were observed. These results suggested that cholangiocarcinoma induced by infection of C sinensis was believed to originate from the proliferated small cells around the portal triads which would be able to differentiate to the oval cells, ductlike oval cells, and cholangiocarcinoma cells gradually.

• 한국수산과학회지
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• 제9권4호
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• pp.223-231
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• 1976

어류가공품중에 분포하는 2급 amino의 생성 원인을 구명하기 위한 연구의 일부로서, 멸치를 $22\%$의 식염을 첨가하여 $17^{\circ}C$와 $27^{\circ}C$의 온도별로 열성시키면서 숙성 일정별로 단백질과 TMAO의 분해생성물을 분석하여 2급 amino의 생성과 관계있는 몇가지 실험결과를 얻었기에 보고한다. 단백질 질소는 $17^{\circ}C$와 $27^{\circ}C$에서 숙성시켰을 때, 전숙성기간을 통하여 일률적으로 감소하는 경향을 보였으나, 아미노태 질소는 단백태 질소의 감소에 반비례하여 증가하였으며, 이때 아미노태 질소의 증가속도는 $27^{\circ}C$에서 숙성한 것이 $17^{\circ}C$에서 숙성한 것에 비하여 훨씬빨랐다. TMA는 TMAO의 감소와 더불어 증가하여 갔으며 숙성 69일까지는 계속 증가하다가 이후 서서히 감소하는 경향을 보였다. 이때 온도에 의한 차이는 보이지 않았다. DMA는 $17^{\circ}C$에서 숙성시켰을 때는 숙성 69일까지 계속 증가하다가 이후 미미한 변화를 보였으며, $27^{\circ}C$에서 열성시킨 것은 숙성 59일까지는 계속 증가하다가 그 이후는 미미한 변화를 보였다. DMA는 TMAO의 양적변화에 비추어, $17^{\circ}C$에서 숙성시켰을 때는 상관계수 r=-0.811, 그리고 $27^{\circ}C$에서 숙성시켰을 때는 상관계수 r=-0.865로서 각각 부의 상관관계를 보였다. 멸치 젓갈 숙성중의 DMA의 생성원인은 그 기여율이 $17^{\circ}C$일 때 $r^2\fallingdotseq0.75$, TMAO의 분해와 밀접한 관련이 있는 것으로 판단되었다.