• Journal of Veterinary Science
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• v.21 no.2
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• pp.26.1-26.14
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• 2020

Pancreatic ductal adenocarcinoma is a lethal cancer type that is associated with multiple gene mutations in somatic cells. Genetically engineered mouse is hardly applicable for developing a pancreatic cancer model, and the xenograft model poses a limitation in the reflection of early stage pancreatic cancer. Thus, in vivo somatic cell gene engineering with clustered regularly interspaced short palindromic repeats is drawing increasing attention for generating an animal model of pancreatic cancer. In this study, we selected Kras, Trp53, Ink4a, Smad4, and Brca2 as target genes, and applied Campylobacter jejuni Cas9 (CjCas9) and Streptococcus pyogens Cas9 (SpCas9) for developing pancreatic cancer using adeno associated virus (AAV) transduction. After confirming multifocal and diffuse transduction of AAV2, we generated SpCas9 overexpression mice, which exhibited high double-strand DNA breakage (DSB) in target genes and pancreatic intraepithelial neoplasia (PanIN) lesions with two AAV transductions; however, wild-type (WT) mice with three AAV transductions did not develop PanIN. Furthermore, small-sized Cjcas9 was applied to WT mice with two AAV system, which, in addition, developed high extensive DSB and PanIN lesions. Histological changes and expression of cancer markers such as Ki67, cytokeratin, Mucin5a, alpha smooth muscle actin in duct and islet cells were observed. In addition, the study revealed several findings such as 1) multiple DSB potential of AAV-CjCas9, 2) peri-ductal lymphocyte infiltration, 3) multi-focal cancer marker expression, and 4) requirement of > 12 months for initiation of PanIN in AAV mediated targeting. In this study, we present a useful tool for in vivo cancer modeling that would be applicable for other disease models as well.

• Journal of Nutrition and Health
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• v.47 no.6
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• pp.394-402
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• 2014

Purpose: Dendropanax morifera Leveille (DML) exhibits diverse biological and pharmacological activities, including anti-oxidative effect, anti-cancer activity, hepatoprotection, immunological stimulation, and bone regeneration. As part of the identification for novel functions of DML, we investigated the therapeutic effects of DML on diabetes induced by streptozotocine (STZ) treatment. Methods: First, the four extracts including the water extract of leaf (DLW), the ethanol extract of leaf (DLE), the water extract of stem (DSW), and the ethanol extract of stem (DSE) were collected from the leaf and stem of DML using a hot water and ethanol solvent. Alterations in body weight, glucose concentration, insulin level, and pancreatic islet structure were investigated in diabetic mice after treatment with extracts of DML for 2 weeks. Results: Among four extracts, the highest level of total polyphenols and total flavonoids was detected in DLW, while the lowest level of these was measured in DSE. The radical scavenging activity was also higher in DLW than in the other three extracts at the concentration of $25-100{\mu}g/mL$, although this activity was maintained at a constant level in all groups at the concentration of $500{\mu}g/mL$. Based on the results of anti-oxidant activity, DLW and DLE were selected for examination of anti-diabetic effects in a diabetes model. Body weight was gradually decreased in all STZ treated groups compared with the No treated group. However, four STZ/DML treated groups maintained a high level of body weight during 7-14 days, while the STZ/vehicle treated group showed a gradual decrease of body weight during the same period. Also, a significant decrease or increase in the concentration of glucose and insulin in the blood of the diabetes model was detected in a subset of groups, although the highest increase was detected in the STZ/DLE-200 treated group. In addition, the histological structure of pancreatic islet was significantly recovered after treatment with DLW and DLE. Conclusion: These results suggest that DLW and DLE may contribute to attenuation of clinical symptoms of diabetes as well as prevent the destruction of pancreatic ${\beta}$-cells in STZ-induced diabetes mice.

• Korean Journal of Pharmacognosy
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• v.41 no.4
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• pp.282-288
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• 2010

We evaluated the anti-diabetic effects of Triticum aestivum sprout water extract (TA) in diabetes mellitus type 2. For the experiments, the diabetic animal model db/db mice were divided to 3 groups: diabetic control (db/db) and two experimental groups orally treated with 25 and 100 mg/kg single dose of TA (TA-25 and TA-100, respectively). The lean mice were used as the non-diabetic normal control. All mice have free access to water and AIN-93 diet. TA was administrated to diabetic mice for 5 weeks and the diabetic clinical markers, including blood glucose level, body weight, food intake and insulin level, were measured at a time. After administration for 5 weeks, the blood glucose level was decreased 1.10 and 1.98 folds in TA-25 and TA-100 groups, respectively, compared with db/db group. The body weight and diet consumption were significantly reduced by TA treatment in dose-dependent manner. The treatments of TA-100 also significantly decreased remarkedly liver weight and slightly serum insulin levels when compared with them of the diabetic control group. However the immunohistochemical staining for insulin clearly showed high expression of insulin in the pancreatic islet cells derived from all db/db mice, even if TA was administrated. Moreover, TA-100 treatment significantly improved impaired glucose tolerance in diabetic db/db mice. The results suggest that TA has anti-hyperglycemic effect attenuating blood glucose in the animal model of type 2 diabetes and might be useful as a functional diet for human diabetic diseases.

• Journal of Life Science
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• v.16 no.5
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• pp.767-772
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• 2006

This study was to investigate the effect of betaine on the hypoglycemia and hepatoprotection of streptozotocin(STZ)-induced diabetic rats. Male Sprague-Dawley rats weighing around 280 g were randomly assigned to the three experimental groups: a healthy normal group and two groups with STZ-induced diabetes and fed either control diet or betaine diet. Betaine given to the STZ-diabetic rats had significant effect in lowering the serum glucose concentrations compared to the STZ-diabetic rats. The alanine aminotransferase (AST) and aspartate aminotransferase (ALT) activities and triglyceride contents in serum were dramatically higher in the STZ-diabetic rats, but these increases in relation to diabetes also decreased in the STZ-diabetic rats fed betaine. However, the total-cholesterol concentration in the STZ-diabetic rats was even increased by betaine. The morphology of the pancreatic islets in the normal rats showed a typical round form, but most of the islets in the STZ-diabetic rats showed severe morphological alterations by being markedly destroyed. However, the islet morphology of STZ-diabetic rats given betaine mostly maintained a normal rounded appearance. The present study strongly suggests that the administration of betaine showed a moderate hypoglycemic effect by protecting the pancreatic beta-cells by morphological examination from STZ-induced destruction.

• Journal of Ginseng Research
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• v.27 no.2
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• pp.56-61
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• 2003

This study was designed to compare the antidiabetic activities between Ginseng Radix Alba (GRA), Ginseng Radix Rubra (GRR) and Panax Quinquefoli Radix (PQR) in multiple low dose (MLD) streptozotocin (STZ) (20 mg/kg i.p injection far 5 days) induced diabetic rats. In the glucose tolerance test, 500 mg/kg of each ginseng ethanol extract was administered intraperitoneally 30 min before glucose challenge. While GRA failed to lower blood glucose level, GRR and PQR both significantly prevented the hyperglycemia when compared with the control group. In the MLD STZ-induced diabetic rats, 300 mg/kg of each ginseng ethanol extract was administered intraperitoneally for 2 weeks. Plasma glucose and insulin levels were markedly improved in all treatment groups. While GRR showed the highest antidiabetic activity, and GRA and PQR revealed somewhat equipotent antidiabetic activities, but less than that in GRR-treated group as far as blood parameters and diabetic symptoms such as polyphagia and polydipsia are concerned. Blood glucose levels were closely associated with plasma insulin levels, and this result may suggest that ginseng ethanol extracts showed the activity to enhance insulin secretion as well as preventing destruction of pancreatic islet cells. To elucidate the relationship between antidiabetic activity and ginsenoside profiles, seven major ginsenosides were quantified by HPLC. We figured out the fact that protopanaxatriol (PPT): proptopanaxadiol (PPD) ratio might play an important role in its hypoglycemia effects.

• Journal of Physiology & Pathology in Korean Medicine
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• v.20 no.6
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• pp.1497-1501
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• 2006

The therapeutic anti-diabetic effect of Nelumbo Folium and a poly herbal formula (NOC) was evaluated in the streptozotocin (STZ 60 mg/kg, I.p.) induced diabetic rats. For this study, test articles were orally administrated once a day from 7 d after STZ-injection for 3 weeks. The fasting blood glucose, body weight, pancreas weight changes, oral glucose tolerance test, hemoglobin Alc (Hb A1c) level changes and the histopathological changes were observed. WNL-treated rat had lower fasting blood glucose levels compared to control group and NOC-treated rat had significantly lower fasting blood glucose levels, compared to control group (p < 0.05). After 21 days of extract treatment, body weight in control was reduced (p < 0.001). WNL and NOC groups were also reduced compared to control group but insignificantly. Pancreas weight of control group was reduced (p < 0.001), but the weight of NOC group were increased (P< 0.05). During the 2 h oral glucose tolerance test (OGTT), WNL group were improved compared to control group (P < 0.05). NOC group were improved compared to control group but insignificantly. WNL and NOC groups had lower Hb Alc level compared to control group. In addition, atrophy of islet and decrease of insulin-producing cells were detected in STZ induced diabetes rats. However, these diabetic changes were decreased in WNL and NOC groups. These results suggest that N. Folium and NOC have favorable effects to inhibit the changes on the fasting blood glucose levels, pancreas weight, glucose tolerance, hemoglobin Alc and the histopathological changes of pancreas in STZ-induced diabetes.

• Journal of Life Science
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• v.17 no.12
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• pp.1627-1633
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• 2007

c-Jun N-terminal kinase (JNK)-interacting protein 1 (JIP1), also known as Islet-brain 1 (IB1), is a scaffold protein that is highly expressed in neurons and pancreatic ${\beta}-cells$. In this study subcellular localization of JIP was investigated in cultured rat hippocampal neurons using an antibody that recognize all variants of JIP1, JIP-2 and JIP-3. The overall expression profile of JIP is punctate throughout soma and dendrites. Statistic analysis showed that $54.8{\pm}4.0%\;and\;94.1{\pm}4.5%$ of total JIP immunopuncta overlapped with those of excitatory postsynaptic markers SD-95 and ${\alpha}Camik$, respectively. In contrast, only $8.6{\pm}0.5%\;and\;7.3{\pm}0.5%$ of JIP clusters overlapped with those of inhibitory postsynaptic markers glycine receptor (GlyR) and gephyrin, respectively. JIP clusters overlapped or juxtaposed with SV2 but not GAD, markers for general and inhibitory nerve terminals, respectively. A substantial fraction $(29.3{\pm}1.0%)$ of flotillin immunopuncta, a marker for lipid rafts, clusters overlapped with those of JIP. In addition, JIP was highly expressed in some select ends of dendrites but minimal in axons. These data suggest important roles of JIP in excitatory postsynaptic sites, lipid rafts and dendritic ends.

• Journal of the Korean Society of Food Science and Nutrition
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• v.40 no.3
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• pp.401-408
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• 2011

Type 2 diabetes mellitus (NIDDM) is a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. In order to control the type 2 diabetes mellitus, anti-hyperglycemic effect of Triticum aestivum L. water extracts (TAWE) was investigated in 7 week old male diabetic C57BL6/J-ob/ob mice. For the experiments, the diabetic animal model ob/ob mice and non-diabetic animal model lean mice were divided into 3 groups: non-treatment control group (Control), and two experimental groups orally treated with 25 or 100 mg/kg/day dose of TAWE (TAWE-25 and TAWE-100, respectively). The lean mice were used as the non-diabetic normal control. TAWE was orally administrated for 6 weeks and the diabetic clinical markers, including blood glucose level, body weight, organs weight and insulin level were determined. The oral administration of TAWE-100 in ob/ob diabetic mice significantly decreased blood glucose level (78.4%) and body weight (11.9%) compared with diabetic control group. The weights of organs, including spleen, liver, kidneys, heart and lung were not different among groups, while the treatments of TAWE-100 in ob/ob diabetic mice significantly reduced blood total cholesterol (24.35%) and triglyceride (23.97%) levels compared with the diabetic control group. The levels of serum insulin and glucose tolerance were improved after TAWE-100 treatment in ob/ob diabetic mice. Moreover, the immunohistochemical staining for insulin detection in pancreatic islet $\beta$-cells expressed high level of insulin in TAWE-100 treated ob/ob mice. From the above results, the intake of TAWE may be effective in anti-hyperglycemia by the attenuation of glucose and lipid levels. TAWE-containing diets or drugs may be beneficial for controlling diabetes mellitus type 2 in human.

• Journal of Ginseng Research
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• v.26 no.4
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• pp.191-195
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• 2002

In this study, we like to examine whether Panax ginseng water extract (PGWE) exerts antidiabetic activities in prevention and treatment modes in multiple low dose (MLD) streptozotocin (STZ) (20 mg/kg i.p injection for 5 days) induced diabetic SD rats. In the prevention mode,150 mg/kg of GRWE was administered intraperitoneally with STG for 3 weeks, and this group is called CO 150. In the treatment mode, we started to administer the same dose of PGWE on day 8 and for 3 weeks, and this group is called POST150. PGWE exerted significant hypoglycemic activities in both prevention (normal control, 97 ${\pm}$ 6 mg/dl; diabetic control, 331${\pm}$23; CO150, 211${\pm}$37) and treatment groups (normal control, 128${\pm}$4 mg/dl; diabetic control, 392${\pm}$33: POST150, 263${\pm}$44). Of great importance is the fact that plasma insulin levels in both groups were markedly increased as compared to the diabetic control (normal control,428.7${\pm}$62.1 pg/dl; diabetic control, 167.0${\pm}$91.7; CO150, 377.6${\pm}$68.7 in prevention mode, and in treatment mode normal control 417.9${\pm}$84.6 pg/dl; diabetic control, 166.1${\pm}$104.7; POST150, 315.2${\pm}$47.4). Blood glucose levels were closely associated with plasma insulin levels, and this result may suggest that PGWE showed the activity to enhance insulin secretion as well as preventing destruction of pancreatic islet cells. Food and water intakes were also determined at the last week of treatment i n both groups. Characteristic symptoms of diabetes were significantly improved in both groups. In the prevention mode, water intake (ml/rat/day) in normal control was increased from 30.6${\pm}$1.5 to 122.2${\pm}$3.4 in diabetic control rats. In the CO150-treated group, water intake was dramatically reduced to 68.3${\pm}$4.4 (p<0.001 vs. diabetic control). In the treatment mode, POST-treated group also reduced the water intake from 128.9${\pm}$2.2 to 113.3${\pm}$1.7. Taken together, our data suggest that PGWE showed comparable antidiabetic activities in prevention and treatment modes. Therefore, PGWE may have a potential as a prophylactic as well as therapeutic agent fur type 2 diabetes mellitus (T2DM).