• 한국생물공학회:학술대회논문집
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• 2001.11a
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• pp.867-870
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• 2001

All-trans-retinoic acid (RA) plays essential roles in the regulation of differentiation and proliferation. It has been proved that RA is effective in the treatments of epithelial and hematologic malignancies. However, in spite of its pronounced effects, the clinical applications of RA are limited due to the retinoid acute resistance. Although RA induces complete remission in a high proportion of the patients of acute promyelocytic leukemia (APL), the cancer was relapsed in many patients after a brief remission in spite of a continued RA treatment. Patients who relapsed from remission that was initially induced by RA had clinically resistant to further RA treatment. That is, specific cytochrome P450 enzymes in the liver were induced by the continuous oral administration of RA, thereby accelerating the metabolism of RA. To overcome this problem, biodegradable microspheres were proposed by us, previously. And, several microsphere formulations for RA delivery have been prepared and studied on their effectiveness. Recently, poly(D,L-lactide) (PDLLA) microsphere formulation was optimized, And, from the animal studies by using a mouse and a rat, it have appeared to be effective on both the inhibition of tumor growth and chemoprevention of a carcinogenesis. In this study, subacute toxicities of the PDLLA microsphere formulation have been investigated as a preclinical test. For the test, the microspheres was injected subcutaneously into the back site of rats, and body weight change, clinical signs, hematological changes, blood biochemistry were evaluated. As a result, severe toxicities such as mortality were observed at the dose of 100mg RA/kg, and toxicities were not observed at the dose of 50mg RA/kg, which is the effective dose against carcinogenesis. Bone fracture, observed at several rats, might be inhibited by treating them with anti-inflammatory drugs.

• Journal of Pharmacopuncture
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• v.13 no.4
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• pp.5-41
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• 2010

Objectives: This study was performed to analyse four week repeated dose toxicity of Sweet Bee Venom(Sweet BV) extracted from the bee venom in Beagle dogs. Methods: All experiments were conducted under the regulations of Good Laboratory Practice (GLP) at Biotoxtech Company, a non-clinical study authorized institution. Male and female Beagle dogs of 5-6 months old were chosen for the pilot study of four week repeated dose toxicity of Sweet BV which was administered at the level of 0.56mg/kg body weight which is eighty times higher than the clinical application dosage as the high dosage, followed by 0.28 and 0.14mg/kg as midium and low dosage, respectively. Equal amount of excipient(normal saline) to the Sweet BV experiment groups was administered as the control group every day for four weeks. Results: 1. No mortality was witnessed in all of the experiment groups. 2. All experiment groups were appealed pain sense in the treating time compared to the control group, and hyperemia and movement disorder were observed around the area of administration in all experiment groups, and higher occurrence in the higher dosage treatment. 3. For weight measurement, Neither male nor female groups showed significant changes. 4. In the urine analysis, CBC and biochemistry didn't show any significant changes in the experiment groups compared with control group. 5. For weight measurement of organs, experiment groups didn't show any significant changes compared with control group. 6. To verify abnormalities of organs and tissues, thigh muscle which treated with Sweet BV, cerebrum, liver, lung, kidney, and spinal cords were removed and conducted histologocal observation with H-E staining. In the histologocal observation of thigh muscle, cell infiltration, inflammatory, degeneration, necrosis of muscle fiber, and fibrosis were found in both thigh tissue. And the changes were depend on the dose of Sweet BV. But another organs were not detected in any abnormalities. 7. The proper high dosage of Sweet BV for the thirteen week repeated test in Beagle dogs may be 0.28mg/kg in one time. Conclusion: Above findings suggest that Sweet BV is relatively safe treatment medium. Further studies on the subject should be conducted to yield more concrete evidences.

• Herbal Formula Science
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• v.25 no.2
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• pp.193-207
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• 2017

Objectives : This study was designed to investigate anti-obesity effects of DF in a ob/ob mouse model. Methods : Fifteen-week-old ob/ob mice were divided into four groups: a normal lean group given a standard diet, an ob/ob control group given a standard diet, and DF(1) and DF(2) groups given a standard diet with DF(1) (300 mg/kg), and DF(2) (600 mg/kg), respectively. After 10 weeks of treatment, body weight gain, feeding efficiency ratio, blood lipid markers, fat weight and histology were examined. Results : Body weight gain and fat mass were significantly decreased in DF(1) and DF(2) groups compared with control. The extent of decreases was eminent in DF(2) group. Feeding efficiency ratio were significantly decreased in DF(2) group compared with control. Consistent with their effects on body weight gain and fat mass, circulating concentrations of LDL, total cholesterol, free fatty acid, and insulin were decreased in DF(2) group compared with control. The size of adipocytes were significantly decreased by DF(2) compared with control. Consistent with their effects on body weight gain, hepatic lipid accumulation and liver weights were reduced in DF compared with control. Conclusions : In conclusion, these results suggest that DF not only decrease feeding efficiency ratio, and blood anti-obesity biomarkers, but also reduce fat mass, contributing to the improvement of obesity. DF also inhibits hepatic lipid accumulation.

• Nutrition Research and Practice
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• v.9 no.2
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• pp.137-143
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• 2015

BACKGROUND/OBJECTIVES: Mulberry leaves contain quercetin derivatives, which have the effects of reducing obesity and improving lipid and glucose metabolism in mice with obesity. It is not clear whether or not mulberry leaves can directly affect metabolic disorders, in the presence of obesity, because of the interaction between obesity and metabolic disorders. The aim of the current study was to assess the direct action of quercetin derivatives on metabolic disorders in non-obese conditions in short-term high-fat diet fed mice. MATERIALS/METHODS: C57BL/6N mice were fed a high-fat diet, supplemented with either 0% (control), 1%, or 3% mulberry leaf powder (Mul) or 1% catechin powder for five days. Anthropometric parameters and blood biochemistry were determined, and hepatic gene expression associated with lipid and glucose metabolism was analyzed. RESULTS: Body and white fat weights did not differ among the four groups. Plasma triglycerides, total cholesterol, and free fatty acids in the 1%, 3% Mul and catechin groups did not differ significantly from those of the controls, however, plasma glucose and 8-isoprostane levels were significantly reduced. Liver gene expression of gp91phox, a main component of NADPH oxidase, was significantly down-regulated, and PPAR-${\alpha}$, related to ${\beta}$-oxidation, was significantly up-regulated. FAS and GPAT, involved in lipid metabolism, were significantly down-regulated, and Ehhadh was significantly up-regulated. Glucose-metabolism related genes, L-PK and G6Pase, were significantly down-regulated, while GK was significantly up-regulated in the two Mul groups compared to the control group. CONCLUSIONS: Our results suggest that the Mul quercetin derivatives can directly improve lipid and glucose metabolism by reducing oxidative stress and enhancing ${\beta}$-oxidation. The 1% Mul and 1% catechin groups had similar levels of polyphenol compound intake ($0.4{\times}10^{-5}$ vs $0.4{\times}10^{-5}$ mole/5 days) and exhibited similar effects, but neither showed dose-dependent effects on lipid and glucose metabolism or oxidative stress.

• Korean Journal of Veterinary Research
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• v.43 no.1
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• pp.57-66
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• 2003

Single and 28-day repeated dose toxicity studies of botulimnn toxin type A were carried out in ICR mice and Sprague-Dawley rats, respectively. In the single dose toxicity study, botulinwn toxin was injected intraperitoneally to male and female mice at a single dose of 40, 59, 89 133 and 200 ng/10 ml saline/kg. All animals died from 59 ng/kg group. Some clinical signs, such as decrease in locomotor activity, dyspnea, prone position and ptosis, were observed in most of both sexes from 59 ng/kg group, but no signs were seen in all animals at 40 ng/kg group. The results showed that the median lethal dose of botulinum toxin might be in the range of 40-59 ng/kg in both sexes. In the repeated dose toxicity study, the test material was administered intradermally for 28 days at doses of 0 (vehicle-treated control), 1.25, 2.5, 5.0 and $10.0ng/head/50{\mu}{\ell}$ saline in male and female rats. No test material-related changes were noted in survivals, clinical signs, food and water consumptions and gross finding in any group. Botulinum toxin treatment significantly decreased the body weight gain rate in male of 5.0 ng/head group and over and in female of 10.0 ng/head group compared to vehicle-treated control. One or more relative organ weights (i.e., spleen, thymus, liver and kidney) were increased significantly from 5.0 ng/head group compared to vehicle-treated control in both sexes. Serum biochemistry revealed increases in aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine phosphokinase, total protein and albumin in male, and increases in AST and ALT and decreases in $K^+$ and $Cl^-$ in female without dose-pendent manners. In the histopathological study, physical stimulation by needle caused slight inflammations of dennis. In addition, botulinum toxin treatment induced denervation of nerve cell and disuse of muscle, resulting in atrophy of skeletal muscle in both sexes from 2.5 ng/head group. When the antibodies to toxin were determined in all animals, a significant increase in serum antibodies was observed from 5.0 ng/head group. The results showed that the NOAEL of botulinum toxin might be 1.25 ng/head for 28-day repeated dose toxicity in rats.

• Journal of Korean Society of Occupational and Environmental Hygiene
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• v.16 no.3
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• pp.233-244
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• 2006

Of many volatile organic detergents for metals, benzine(CAS No. 8030-30-6), of which the toxicity has not yet been proven, has been used as an alternative of the halide compounds in the consideration of toxic effects, global warming and the destruction of ozone layer. In order to evaluate the effects of the benzine on human body by investigating the subchronic inhalation toxicity, to obtain the basic data for establishing the criteria of exposure in working environments and to classify the hazardousness in compliance with the Industrial Safety and Health Act by evaluating the hazardousness, repeated inhalation exposure test was carried with SD rats. The rats were grouped by 10 females and males each. The repetitive inhalation exposures were carried out at 4 levels of concentration of 0 ppm, 60 ppm, 300 ppm, and 1,500 ppm, for 6 hours a day, 5 days a week, for 13 weeks. The results are described hereunder. 1. No death of the animals of the exposed and controlled groups in the test period. Not any specific clinical symptoms, change in feed intake quantity, abnormality in eye test, or change in activity were observed. 2. In the 300 ppm and 1,500 ppm groups, weight reduction in the female groups and weight increase of liver and kidney in the male groups compared with control group were observed with statistical significance(p<0.05). 3. In the blood test, the HCT increased in the male 300 ppm group and the number of hematocyte increased, MCV and MCH decreased in the male 1,500 ppm group. In the female 1,500 ppm group, the HB decreased and the distribution width of the hematocyte particle size increased. In the blood biochemistry test, the TP in the male 1,500 ppm group and the LDH in the female 1,500 ppm group were increased with statistical significance(p<0.05). 4. Under the test conditions of the present study with SD rats, the NOEL was evaluated to be from 60 ppm to 300 ppm for both male and female groups. By extrapolation, the NOEL for human who work 8 hours a day was evaluated to be from 128 ppm to 640 ppm 5. Since the NOEL evaluated in this study do not exceed 60ppm(0.184 mg/L) the test material does not belong to the classification of the hazardous substance "NOEL${\leq}$0.5mg/L/6hr/90day(rat), for continuous inhalation of 6hours a day for 90 days" nor to the basic hazardous chemical substance class 1(0.2 mg/L/6hr/90day(rat) defined by the GHS which is a criteria of classification and identification of chemical compounds. However, considering the boiling point($30-204^{\circ}C$), flashing point($-40^{\circ}C$), vapor pressure(40 mmHg), and the inflammable range(1.0 - 6.0 %), sufficient care should be taken for handling in the safety aspects including fire or explosion.

• Toxicological Research
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• v.26 no.1
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• pp.75-82
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• 2010

This study was carried out to investigate the short term toxicity of nine phthalate diesters including di-2(ethylhexyl) phthalate (DEHP), di(n-butyl) phthalate (DBP), di-n-octyl phthalate (DnOP), diethyl phthalate (DEP), butylbenzyl phthalate (BBP), dimethyl phthalate (DMP), di-isodecyl phthalate (DIDP), diundecyl phthalate (DUP), and di-isononyl phthalate (DINP) and five phthalate monoesters including mono- (2-ethylhexyl) phthalate (MEHP), monobutyl phthalate (MBuP), monobenzyl phthalate (MBeP), monoethyl phthalate (MEP), monomethyl phthalate (MMP) and phthalic acid (PA) in Sprague-Dawley male rats. Animals were administered 250 mg/kg/day (monoesters and PA) or 500 mg/kg/day (diesters) of phthalate for two weeks. All animals were examined for body and organ weights, blood hematology, serum biochemistry, and urine analysis. The body weight gain was significantly lower in rats treated with BBP, DBP, DINP, MEHP, MBuP, and PA than that of control. Liver weights were significantly increased in the DEHP, DBP, DnOP, DIDP, and MEHP groups as compared to the control group. Testes weights were significantly decreased only in the DEHP-, DnOP-, and DIDP-treated groups as compared to the control. Significant differences in hematological changes were not observed in any treatment groups. Significant increases in blood glucose levels were observed in the DEHP, MEHP, and MBeP groups. Aspartate aminotransferase (AST) levels were significantly increased in the DBP, DUP, DINP, MBuP, and MBeP groups, whereas alanine aminotransferase (ALT) levels were significantly increased only in the DEHP and MEHP groups. Serum ALP levels were significantly higher in phthalate diester (500 mg/kg/day)-treated rats as compared to control. However, the total cholesterol level was significantly reduced in the DEHP- and DIDP-treated groups, whereas serum triglyceride (TG) levels were higher in the DINP-, MEHP-, and MBuP-treated groups. These results suggest that short term toxicity of phthalate monoesters produces adverse effects as similar to phthalate diesters in Sprague-Dawley rats.

• Korean Journal of Clinical Pharmacy
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• v.15 no.2
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• pp.118-126
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• 2005

In our study, osteoporosis was induced by ovariectomized in female Sprague-Daweley (SD) rats, and the prevention and treatment efficacy of the climacteric disease the ostmenopausal type I pattern was examined by using the experimental substance soybeans and arowroot. No clinical signs and mortality after continuous oral administration of experimental substances for 14 weeks were not observed, however, the weight of experimental animals underwent ovariectomized was increased significantly in comparison with control group (p<0.01). The atrophy of the uterus due to T3 group was 23.64% after 7 weeks, 24.44% after 14 weeks (in comparison with N.C. group), and it was statistically significantly increased. In regard to the change of blood cells, it was observed that platelets were statistically significantly reduced in the ovariectomized group, and administered orally experimental substances continuously for 7 weeks, in all groups administered experimental substances, it was found that platelets had the tendency to be increased more than N. C. group. In regard to He change of blood biochemistry, removed the ovary, the concentration of ALP showed the tendency to be increased than control group, and particularly in T3 group, it was increased significantly. In regard to the concentration of cholesterol, in comparison with negative control group, it was reduced 68% at 7 weeks and 35% at 14 weeks. After ovariectomized, the amount of estrogen was found to be reduced by 21.37% in comparison with control group, it showed the tendency to be increased by 4.49% in T1 group and 7.62% in T2 group, the concentration of estrogen in each group showed the tendency to be increased than negative control group, and in T3 group, it was increased to 100.46% and 117.65% in T4 group, and it was increased more than control group. Based on the above experimental results, in the experimental animals female rats, because of the hormonal imbalance induced by ovariectomized, a large mount of fat is accumulated in the body and due to it osteoporosis, obesity, hypertension, hyperlipidemia, fat of the liver, arteriosclerosis, diabetes, and other metabolic diseases were developed. Hence, when the experimental substance Extraction of ferment arrowroot was orally administered continuously for 14 weeks, it was thought that a certain proportion of the hormonal balance was maintained that functioned as a substance interfering the accumulation of fat, and it was considered to be of help in the treatment of not only osteoporosis Type I, but also for the prevention and treatment of various endocrinal diseases.

• BMB Reports
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• v.31 no.6
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• pp.578-584
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• 1998

In a previous paper (Kim et al., 1996a), the immediate 5' -flanking region and coding region of the human UDP-N -acetylglucosamine:-D-mannoside-1,4-Nacetylglucosaminyltransferase III (N-acetylglucosaminyitransferase- III; GnT-III) gene was reported, isolated and analyzed. Herein, we report on amplification of a new 5' -noncoding region of the GnT-III mRNA by single-strand ligation to single-stranded cDNA-PCR (5' -RACE PCR) using poly(A)+ RNA isolated from human fetal liver cells. A cDNA clone was obtained with 5' sequences (96 bp) that diverged seven nucleotides upstream from the ATG (+1) start codon. A concensus splice junction sequence, TCTCCCGCAG, was found immediately 5' to the position where the sequences of the cDNA diverged. The result suggested the presence of an intron in the 5' -noncoding region and that the cDNA was an incompletely reversetranscribed cDNA product derived from an mRNA containing a new noncoding exon. When mRNA expression of GnT-III in various human tissues and cancer cell lines was examined, Northern blot analysis indicated high expression levels of GnT-III in human fetal kidney and brain tissues, as well as for a number of leukemia and lymphoma cancer cell lines. Promoter activities of the 5' -flanking regions of exon 1 and the new noncoding region were measured in a human hepatoma cell line, HepG2, by luciferase assays. The 5'-flanking region of exon 1 was the most active, whilst that of exon 2 was inactive.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.2
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• pp.637-642
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• 2014

The pathogenesis of hepatocellular carcinoma (HCC) related to habitual betel quid (BQ) chewing is unclear. Risk of HCCis increased with adverse hepatic fibrosis. This study aimed to assess the impact of chronic viral hepatitis on adverse hepatic fibrosis in HCC related to BQ chewing. This hospital-based case-control study enrolled 200 pairs of age- and gender-matched patients with HCC and unrelated healthy controls. Serologic hepatitis B surface antigen (HBsAg), antibodies to hepatitis C virus (anti-HCV), ${\alpha}$-fetoprotein (AFP), and surrogate markers for significant hepatic fibrosis were measured. Information on substance-use habits was obtained with a questionnaire. By analysis of surrogate markers for hepatic fibrosis, the prevalence of significant hepatic fibrosis in patients chewing BQ was between 45.8% and 91.7%, whereas that for patients without BQ chewing was between 18.4% and 57.9%. The difference was significant (P <0.05 for each surrogate marker). Multivariate analysis indicated that cirrhosis with Child-Pugh C (odds ratio (OR) = 3.28; 95% confidence interval (CI), 1.29-8.37), thrombocytopenia (OR = 3.92, 95% CI, 1.77-8.68), AFP >400 mg/L (OR = 2.21, 95% CI, 1.05-4.66) and male gender (OR = 4.06, 95% CI, 1.29-12.77) were independent factors associated with habitual BQ chewing. In conclusion, adverse hepatic fibrosis and severe liver damage play important roles in the pathogenesis of BQ-related HCC, which could be aggravated by chronic hepatitis B and hepatitis C. BQ-cessation programs and prevention of chronic HBV/HCV infection are needed to prevent HCC related to BQ chewing.