• 한국임상수의학회지
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• 제16권1호
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• pp.100-107
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• 1999

Apoptosis is now widely recognized as a common form of cell death and represents mechanism of cell clearance in many physiological situations where deletion of cells is required. In vivo administration of bacterial lipopolysaccharide (LPS) to Balb/c mice induced DNA fragmentation in the thymus. DNA fragmentation in the thymus was roughly dependent on the dose of LPS injected and reached the peak 18 hours after injection. This apoptosis in the thymus might be mediated due to LPS stimulant. DEN (diethylnitrosamine) has been shown to cause liver cancer in experimental animals and humans. The hepatic tumorigenesis was induced by ad libitum feeding of DEN only. It was suggested that DEN induced hepatic tumorgenesis in rat is a good reproducible model for studying biochemical and pathophysiological changes associated with the development of hepatic tumorigenesis and apoptosis.

• 한국임상수의학회지
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• 제16권1호
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• pp.108-117
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• 1999

Hepatic tumorigenesis was induced by ad libitum feeding of diethylnitrosamine (DEN) only. We could also observe hepatic tumor induction in 100% of DEN treated rats without any other cocarcinogen. The liver specific enzyme activities (AST, ALT, ALP, ${\gamma}$-GTP) were significantly increased (P<0.05) in all treated groups compared to control and induced apoptosis groups. In histopathological analysis, the altered foci, hyperplastic nodules, neoplastic nodules, adenomas and carcinomas were observed in liver tumors induced by administration of DEN in rats. Lipopolysaccharide-induced apoptosis in D-galactosamine sensitized mice was investigated in hepatocytes in vivo. Typical morphological changes of apoptosis were detectable in liver 12 hr and 24 hr after the injection of Lipopolysaccharide (5 $\mu\textrm{g}$) and D-galactosamine (20 mg) to mice. It was suggested that organ specific enzyme activities and morphological findings might be very useful for understanding the role of hepatic tumorigenesis including the apoptotic cell death.

• BMB Reports
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• 제50권12호
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• pp.599-600
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• 2017

Many studies have focused on the tumor suppressive role of $TGF-{\beta}$ signaling during the early stages of tumorigenesis by activating the target genes involved in cytostasis and apoptosis. We investigated the effects of $TGF-{\beta}$ inhibition on early tumorigenesis in the liver, by employing diverse inhibitory methods. Strikingly, $TGF-{\beta}$ inhibition consistently suppressed hepatic tumorigenesis that was induced either by activated RAS plus p53 downregulation or by the co-activation of RAS and TAZ signaling; this demonstrates the requirements for canonical $TGF-{\beta}$ signaling in tumorigenesis. Moreover, we found that Snail is the target gene of the $TGF-{\beta}$ signaling pathway that promotes hepatic carcinogenesis. The knockdown of Snail suppressed the early tumorigenesis in the liver, as did the $TGF-{\beta}$ inhibition, while the ectopic expression of Snail restored tumorigenesis that was suppressed by the $TGF-{\beta}$ inhibition. Our findings establish the oncogenic $TGF-{\beta}$-Smad-Snail signaling axis during the early tumorigenesis in the liver.

• 대한수의학회지
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• 제41권4호
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• pp.583-589
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• 2001

To estalish bio-indices for detection of the development of multistep hepatotumorigenesis, rats were fed water containing 0.01% diethylnitrosamine (DEN) ad libitum for 13-14 weeks. Hepatocellular carcinoma was developed by treatment with DEN, DEN only was able to induce hepatic tumors in rats without any other cocarcinogen. Compared to control group, liver cytosol protein concentration in all treated grous was significantly decreased (p<0.05). From week to week, $20{\alpha}$-hydroxysteroid dehydrogenase ($20{\alpha}$-HSD) activity was increased and the highest activity was observed on the 12th week (p<0.05). In addition, the urine biopterin concentration was also significantly increased compared to control groups (p<0.05) in a time course manner. These results indicated that $20{\alpha}$-HSD activity, urine biopterin and liver cytosol protein concentration might be very useful maker to hepatic tumorigenesis.

• 대한한방내과학회지
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• 제29권3호
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• pp.595-607
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• 2008

Objectives: The aim of this study was to determine the effects of Salvia miltiorrhiza (SM) extract in urethane-induced lung tumorigenesis in A/J mice. Methods : We examined change of body weight, histological, apoptosis, immunohistochemical and gene expression of cyclooxygenase (COX-2) in lung tumors. Mice were divided into 3 groups: normal, saline, and experimental group administered SM extract after injection with urethane. Results : Histological observation showed shrunken alveoli in the control group, but recovered from damage in the SM extract administered group. The COX-2 positive materials were observed in the smooth muscle of terminal bronchiole and alveoli from the control group, but these positive materials decreased in the SM extract treatment group. The results of electron microscopical observation, dilated capillary and degenerated endothelia were observed in the control group. The apoptotic nuclei increased more in the control group compared with the normal and SM extract administered groups. Serial sections of the whole lung showed solid and papillary tumors. The size and number of tumors decreased in the SM groups compared with the control groups. Conclusions : These results suggest the possibility that SM may exert an anti-tumor effect on urethane-induced lung tumorigenesis.

• 대한한방내과학회지
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• 제29권3호
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• pp.582-594
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• 2008

Objective : The purpose of our study was to investigate the effect of JinlnWhaChul-tang-ga-wasong (JIN) on NDEA-induced liver tumorigenesis. Materials and Methods : We investigated the possible protective effects of Jininwhachul-tang-ga-wasong (JIN) as an anticancer against NDEA-induced liver injury in mice. Experimental mice were classified into 3 groups; normal, saline administered group (control group), and JIN extract (0.15g/kg/every other day) administered group (JIN group) after being injected with NDEA over 12 weeks. We examined the state of differentiation of these tumors and the effects of JIN after 6 weeks. To confirm the induction of apoptosis, the cells were analyzed by terminal deorynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, acridine orange staining and flow cytometric analysis. To investigate inhibitory effect on the expression of COX-2 by JIN, we performed COX-2 immunohistochemistry and reverse transcription polymerase chain reaction analysis. Results : Body weights significantly decreased in the control and JIN groups compared with the normal group. The levels of cholesterol, hemoglobin and testosterone decreased in the control compared with the normal group. The level of estradiol significantly increased in the control compared with the normal group. The control group reacted with TUNEL assay more than the normal and JIN groups. Upon naked eye, light and electron microscopic examination, JIN improved the morphological and histopathological changes of the liver caused by NDEA-induced hepatic neoplasm. COX-2 immunoreactivity decreased in the JIN group compared with the control group, mRNA expression of the control group was greater than the normal and JIN groups. Conclusion : these results suggest the possibility that JIN may exert an anti-tumor effect on NDEA-induced liver tumorigenesis.

• Asian Pacific Journal of Cancer Prevention
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• 제14권1호
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• pp.261-265
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• 2013

Scutellaria barbata D. Don (S. barbata), a traditional Chinese medicine, is used to treat cancers, inflammation, and urinary diseases. This study aimed to determine any protective effects of S. barbata crude extract (CE-SB) against rat liver tumorigenesis induced by diethylnitrosamine (DENA). Liver malfunction indices in serum were measured by biochemical examination. Hematoxylin and eosin staining was performed to examine liver pathology. Contents of malondialdehyde (MDA) and superoxide dismutase (SOD) were measured in liver homogenates to evaluate oxidative stress. The levels of liver malfunction indices in the CE-SB groups, especially in the CE-SB high dose group, were lower than that of the model group (P<0.05). The results from histological examination indicated that the number of liver nodules in the CE-SB groups decreased compared with the model group (P<0.05). Content of MDA determined in liver was significantly decreased, and level of SOD elevated by CE-SB. CE-SB can inhibit experimental liver tumorigenesis and relieve hepatic injury in rats.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1994년도 춘계학술대회 and 제3회 신약개발 연구발표회
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• pp.339-339
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• 1994

It has been reported that Indole-3-carbinol (I3C), a naturally occurring compound In cruclferous vegetables, exerts anticarcinogenic activity In several organs In rodents. The modifying effects of I3C were therefore assessed uging a rat multi-organ carcinogenesis model. A total of 100 male Sprague-Dawley rats were divided Into 3 groups. Animals of groups 1 and 2 were sequentially treated with diethylnitrosamine (DEN; 100 mg/kg b.w., i.p.), N-methylnitrosourea (NNU; 20 mg/kg b.w., 4 times for 2 weeks, i.p), and dihydroxy-di-N-propylnitrosauine (DHPN; 0.1% In d.w. for 2 weeks) for 4 weeks (DMD treatment). Animals of groups 1 and 3 were given the diet of 0.25% I3C for 20 weeks after DMD initiation and then were given basal diet for 28 weeks. All animals were sacrificed at week 24 and 52, respectively. I3C has been clearly demonstrated promoting effects on the development of glutathione S-transferase placental form (GST-P) positive hepatic foci at 24 weeks of the experiment. And I3C also exerted promoting potential In the hepatocellular adenoma (4/14; 29%) and the adenoma (7/14; 50%) of the thyroid gland at 52 weeks of the experiment. Therefore, I3C may promote hepatocarcinogenesis and thyroid tumorigenesis in the rat multi-organ carcinogenesis model.

• BMB Reports
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• 제51권5호
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• pp.209-210
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• 2018

NAFLD induces the development of advanced liver diseases such as NASH and liver cancer. Therefore, understanding the mechanism of NAFLD development is critical for its prevention and treatment. Ablation of PTEN or Hippo pathway components induces liver cancer in a murine model by hyperactive AKT or YAP/TAZ, respectively. Although the regulation of these two pathways occurs in the same hepatocyte, the details of crosstalk between Hippo-YAP/TAZ and PTEN-AKT pathways in liver homeostasis and tumorigenesis still remain unclear. Here, we found that depletion of both PTEN and SAV1 in liver promotes spontaneous NAFLD and liver cancer through hyperactive AKT via YAP/TAZ-mediated up-regulation of IRS2 transcription. Conversely, NAFLD is rescued by both ablation of YAP/TAZ and activation of the Hippo pathway. Furthermore, human HCC patients with NAFLD showed strong correlation between YAP/TAZ and IRS2 or phospho-AKT expression. Finally, the inhibition of AKT by MK-2206 treatment attenuates NAFLD development and tumorigenesis. Our findings indicate that Hippo pathway interacts with AKT signaling during the intervention with IRS2 to prevent NAFLD and liver cancer.

• 대한수의학회지
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• 제39권6호
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• pp.1057-1065
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• 1999

The study was designated to investigate the electron microscopic findings following diethylnitrosamine (DEN) treatment in rats. Forty four male (Srague Dawley) rats were continuously given water containing 0.01% DEN for 13 weeks and livers of five rats with more tumor lesions at 16 and 17 weeks after initial treatment were used as EM materials. In transmission electron microscopic findings, most small-sized hepatocytes were active cells containing large mount of organelles, but light (pale staining) hepatocytes among small-sized hepatocytes were injured cells containg disorganized organelles. Tumor cells among small-sized hepatocytes were irregularly arranged and have pleomorphic nuclei containing electron dense chromatin but the organelles in cytoplasm were swelled. Large-sized hepatocytes were active cells with condensed chromatin but the cytoplasm of these cells were pale due to be injured and dilated organelles. Dark hepatocytes were apoptotic cells with homogenous pyknotic nuclei and cytoplasm, and the cytoplasm of these cells contained dilated smooth endoplasmic reticulum (sER) but these sER were non-vesiculated. Cholangiocarninoma cells were crowded and were pale by far less number of organelles in cytoplasm and nuclei. In scanning electron microscopic findings, the lumens of portal veins, bile canaliculi, bile ductules, bile ducts and sinusoids were dilated and have irregular folded inner surface by protruded parenchyma.