• Journal of Chest Surgery
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• v.37 no.8
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• pp.691-701
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• 2004

Background: Tissue hypoxia is a characteristic of many human malignant neoplasms, and hypoxia inducible factor-1 (HIF-1) plays a pivotal role in essential adaptive response to hypoxia, and activates a signal pathway for the expression of the hypoxia-regulated genes, resulting in increased oxygen delivery or facilitating metabolic adaptation to hypoxia. Increased level of HIF-1 a has been reported in many human malignancies, but in esophageal squamous cell carcinoma, the influence of HIF-1 a on tumor biology, including neovascularization, is not still defined. Material and Method: The influence of HIF-1 a expression on angiogenic factors, correlation between the tumor proliferation and HIF-1 a expression, interaction of HIF-1 a expression and p53, and correlation between HIF-1 a expression and clinicopathological prognostic parameters were investigated, using immunohistochemical stains for HIF-1 a, VEGF, CD34, p53, and Ki-67 on 77 cases of resected esophageal squamous cell carcinoma. Result: HIF-1 a expression in cancer cells was found in 33 of 77 esophageal squamous cell carcinoma cases. The 33 cases (42.9%) showed positive stain for HIF-1 a. High HIF-1 a expression was significantly associated with several pathological parameters, such as histologic grade (p=0.032), pathological TMN stage (p=0.002), the depth of tumor invasion (p=0.022), regional lymph node metastasis (p=0.002), distant metastasis (p=0.049), and lymphatic invasion (p=0.004). High HIF-1 a expression had significant VEGF immunoreactivity (p=0.008) and Ki-67 labeling index (p<0.001), but was not correlated with microvascular density within tumors (p=0.088). The high HIF-1 a expression was correlated with aberrant p53 accumulation with a marginal significance (p=0.056). The overall 5-year survival rate was 34.9%. The survival rate of patients with a high HIF-1 a expression was worse than that of patients with low-expression tumors (log-rank test, p=0.0001). High HIF-1 a expression was independent unfavorable factors although statistical significance is marginal in multivariate analysis. Conclusion: It is suggested that (1) high HIF-1 a expression in esophageal squamous cell carcinoma is associated with tumor hypoxia, or with genetic alteration in early carcinogenesis and progressive stages, (2) high HIF-1 a expression may be associated with intratumoral neovascularization through HIF-VEGF pathway, and (3) high HIF-1 a expression is associated with poor prognosis in patients with esophageal squamous cell carcinoma and may playa role as biomarker for regional lymph node metastasis.

• Journal of Chest Surgery
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• v.39 no.11 s.268
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• pp.828-837
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• 2006

Background: Tissue hypoxia is characteristic of many human malignant neoplasm, and hypoxia inducible factor-1(HIF-1) plays a pivotal role in essential adaptive response to hypoxia, and activates a signal pathway for the expression of the hypoxia-regulated genes, resulting in increasing $O_2$ delivery or facilitating metabolic adaptation to hypoxia. Increased level of HIF-$1{\alpha}$ has been reported in many human malignancies, but in non-small cell lung carcinoma the influence of HIF-$1{\alpha}$ on tumor biology, including neovascularization, is not still defined. In present study the relationship of HIF-$1{\alpha}$ expression on angiogenetic factors, relationship between the tumor proliferation and HIF-$1{\alpha}$ expression, interaction of HIF-$1{\alpha}$ expression and p53, and relationship between HIF-$1{\alpha}$ expression and clinico-pathological prognostic parameters were investigated. Material and Method: Archival tissue blocks recruited in this study were retrieved from fifty-nine patients with primary non-small cell lung carcinoma, who underwent pneumonectomy or lobectomy from 1997 to 1999. HIF-$1{\alpha}$, VEGF(vascular endothelial growth factor), and p53 protein expression and Ki-67 labeling index in tumor tissues were evaluated, using a standard avidin-biotin-peroxidase complex(ABC) immunohistochemistry. Relationship between the HIF-$1{\alpha}$ expression and VEGF, p53 overexpression and correlation between the HIF-$1{\alpha}$ expresseion and Ki-67 index were analyzed. Clinico-pathologic prognostic parameters were also analyzed. Result: HIF-$1{\alpha}$ expression in cancer cells was found in 24 of 59 cases of non-small cell lung carcinoma(40.7%). High HIF-$1{\alpha}$ expression was significantly associated with several pathological parameters, such as pathological TMN stage(p=0.004), pT stage(p=0.020), pN stage (p=0.029), and lymphovascular invasion(p=0.019). High HIF-$1{\alpha}$ expression was also significantly associated with VEGF immunoreactivity(p<0.001), and aberrant p53 expression(p=0.040). but was marginally associated with Ki-67 labeling index(p=0.092). The overall 5-year survival rate was 42.3%. The survival curve of patients with a high HIF-$1{\alpha}$ expression was worse than that of patients with low-expression(p=0.002). High HIF-$1{\alpha}$ expression was independent unfavorable factors with a marginal significance in multivariate analysis performed by Cox regression. Conclusion: It is suggested that high HIF-$1{\alpha}$ expression may be associated with intratumoral neovascularization possibly through HIF-VEGF pathway, and high HIF-$1{\alpha}$ expression could be associated with lymph node metastasis and post operative poor prognosis in patients with non-small cell lung carcinoma.

• Journal of Life Science
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• v.29 no.5
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• pp.570-579
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• 2019

Diabetes is one of the serious chronic metabolic diseases caused by Westernized eating habits, and the goal of diabetes treatment is to keep blood glucose at a normal level and prevent diabetic complications. This study was designed to investigate the anti-diabetic effects of a mealworm (Tenebrio molitor larva) extract (MWE) on hyperglycemia in an animal model with type 2 diabetes. Diabetic C57BL/Ksj-db/db mice were divided into three groups: diabetic control, rosiglitazone, and MWE. The mice supplemented with MWE showed significantly lower blood levels of glucose and glycosylated hemoglobin when compared with the diabetic control mice. The homeostatic index of insulin resistance was significantly lower in mice supplemented with MWE than in diabetic control mice. MWE supplementation significantly stimulated the phosphorylation of insulin receptor substrate-1 and Akt, and activation of phosphatidylinositol 3-kinase in insulin signaling pathway of skeletal muscles. Eventually, MWE increased the expression of the plasma membrane glucose transporter 4 (GLUT4) via PI3K/Akt activation. These findings demonstrate that the increase in plasma membrane GLUT4 expression by MWE promoted the uptake of blood glucose into cells and relieved hyperglycemia in skeletal muscles of diabetic C57BL/Ksj-db/db mice. Therefore, mealworms are expected to prove useful for the prevention and treatment of diabetes, and further studies are needed to improve type 2 diabetes in the future.

• Asian-Australasian Journal of Animal Sciences
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• v.22 no.6
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• pp.819-826
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• 2009

An in vitro study was conducted to investigate the effect of malate or fumarate on fermentation characteristics, and production of conjugated linoleic acid (CLA) and methane ($CH_4$) by rumen microbes when incubated with linolenic acid (${\alpha}-C_{18:3}$). Sixty milligrams of ${\alpha}-C_{18:3}$ alone (LNA), or ${\alpha}-C_{18:3}$ with 24 mM malic acid (M-LNA) or ${\alpha}-C_{18:3}$ with 24 mM fumaric acid (F-LNA) were added to the 150 ml culture solution consisting of 75 ml strained rumen fluid and 75ml McDougall's artificial saliva. Culture solution for incubation was also made without malate, fumarate and ${\alpha}-C_{18:3}$ (Control). Two grams of feed consisting of 70% concentrate and 30% ground alfalfa (DM basis) were also added to the culture solution of each treatment. In vitro incubation was made anaerobically in a shaking incubator up to 12 h at $39^{\circ}C$. Supplementation of malate (M-LNA) or fumarate (F-LNA) increased pH at 6 h (p<0.01) and 12 h (p<0.001) incubation times compared to control and linolenic acid (LNA) treatments. Both malate and fumarate did not influence the ammonia-N concentration. Concentration of total VFA in culture solution was higher for M-LNA and F-LNA supplementation than for control and LNA treatments from 6 h (p<0.040) to 12 h (p<0.027) incubation times, but was not different between malate and fumarate for all incubation times. Molar proportion of $C_3$ was increased by F-LNA and M-LNA supplementation from 6 h (p<0.0001) to 12 h (p<0.004) incubation times compared to control and LNA treatments. No differences in $C_{3}$ proportion, however, were observed between M-LNA and F-LNA treatments. Accumulated total gas production for 12h incubation was increased (p<0.0002) by M-LNA or F-LNA compared to control or LNA treatment. Accumulated $CH_4$ production for 12 h incubation, however, was greatly reduced (p<0.0002) by supplementing malate or fumarate compared to the control, and its production from M-LNA or F-LNA treatment was smaller than that from LNA treatment. Methane production from LNA, M-LNA or F-LNA treatment was steadily lower (p<0.01 - p<0.001) from 3 h incubation time than that from the control, and was also lower for M-LNA or F-LNA treatment at incubation times of 6 h (p<0.01) and 9 h (p<0.001) than for LNA treatment. Methane production from LNA, however, was reduced (p<0.01 - p<0.001) from 3 h to 9 h incubation times compared to the control. Both malate and fumarate increased concentration of trans11-$C_{18:1}$ from 3 h to 12 h incubation (p<0.01), cis9,trans11-CLA up to 6 h incubation (p<0.01 - p<0.01), trans10,cis12-CLA at 3 h (p<0.05) and 12 h (p<0.01), and total CLA for all incubation times (p<0.05) compared to corresponding values for the ${\alpha}-C_{18:3}$ supplemented treatment (LNA). In conclusion, malate and fumarate rechanneled the metabolic $H_2 pathway to production of propionate and CLA, and depressed the process of biohydrogenation and methane generation. Linolenic acid alone would also be one of the optimistic alternatives to suppress the $CH_4$ generation.

• Journal of Life Science
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• v.24 no.11
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• pp.1180-1186
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• 2014

Autophagy, the lysosomal degradation pathway, is an intracellular recycling system that is necessary for the metabolic benefits of exercise and for producing lasting beneficial effects of exercise in various diseases. However, the most recent studies have only examined the effect of a single bout of exercise or resistance exercise on autophagic responses. To determine the differential effects of acute and chronic exercise on the expression of autophagy-related genes in D. melanogaster, white-eyed mutant D. melanogaster were assigned randomly to four groups: control, acute exercise, 2 hr chronic exercise, and 3 hr chronic exercise. The flies were exercised using a mechanized platform known as the Power Tower. Our results revealed that a single bout of exercise resulted in increased mRNA levels of the Atg8a gene (~20%, p<0.05). However, Atg1 and Atg6 mRNA expression were not induced by acute exercise. Transcript levels of Atg6 (~29%, p<0.05) related to the nucleation of autophagosomes were significantly induced by 2 hr of chronic exercise. However, this chronic exercise was not enough to increase Atg1 and Atg8a mRNA expression. On the other hand, 3 hr of exercise for 7 days significantly increased Atg1, Atg6, and Atg8a gene expression-about 57%, 37%, and 71%, respectively (p<0.05). These results suggest that a single bout of exercise is not enough to induce full activation of selected autophagy-related genes in D. melanogaster. Our results demonstrated that chronic regular exercise induced autophagy-related gene expression, suggesting that chronic regular exercise training might be required to activate autophagic responses important for producing beneficial effects of exercise in various diseases.

• Journal of the Korea Academia-Industrial cooperation Society
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• v.19 no.10
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• pp.243-253
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• 2018

This study aimed to investigate the effects of DCI on glucose control, quality of life(SF-36 Version 2.0, Korean) and SDSCA(Summary of Diabetes Self-Care Activities) in patients with type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled study was performed on 46 patients with HbA1c 7.0% taking triple anti-diabetic drug regimen who visited the department of Endocrinology and Metabolism in Chungnam National University Hospital between March 2015 and May 2016. As a result, DCI treatment in the intervention group resulted in significantly reduced HbA1c levels $8.75{\pm}0.79%$(baseline), $8.36{\pm}1.03%$(after 12weeks), and $8.65{\pm}0.81%$(after 24weeks). However, patients in the control group did not show any significant change. Interestingly, both DCI treatment group and the control group significantly showed improvements in SDSCA. Participants in the intervention group showed a small yet significant improvement in their only fasting blood glucose test in SDSCA and revealed significant increase in the quantitative levels of quality of life, from $73.05{\pm}16.85$ to $82.74{\pm}10.68$. By using pathway analysis, improvement of SDSCA scores(${\beta}=-0.505$, t=-2.743) was the most influential factor to the fasting blood glucose. The quality of life of patients with type 2 diabetes mellitus was affected by changes of SDSCA scores(${\beta}=0.411$, t=2.024) and fasting c-peptide(${\beta}=-0.445$, t=-2.668) in DCI treatment group. In conclusion, treatment of DCI effectively improved glucose control in patients with type 2 DM(HbA1c level>7.0%) after 12 weeks of treatment, although it had no impact on glucose control after 24 weeks of treatment. Improved glucose control may encourage diabetic patients to conduct self-care activities and improve the quality of life. Based on the present study, we suggest that diabetes self-management, as well as consideration of comprehensive laboratory findings, may be important factor in regulating the quality of life in type 2 DM patients.

• Tuberculosis and Respiratory Diseases
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• v.39 no.1
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• pp.42-54
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• 1992

Background:It has been suggested that the cyclooxygenase metabolites play an important role in changes of early hemodynamic parameters in the endotoxin-induced acute lung injury. But there have been many debates about their role in the late increase of alveolar-capillary permeability, and it is not known whether they act directly or indirectly through oxygen free radicals which have been known to be produced during the metabolic process of cyclooxygenase pathway. So we performed this study to identify the pathogenetic role of cyclooxygenase metabolites in the endotoxin-induced acute lung injury in domestic pigs. Method: We infused endotoxin into 8 domestic pigs; endotoxin only (n=3), and pretreatment with indomethacin (n=5). We observed the sequential changes in hemodynamic parameters, the concentration of plasma oxidized glutathione (GSSG) in pulmonary arterial and venous blood, and albumin content in bronchoalveolar lavage fluid (BALF). Results: 1) While cardiac output decreased, mean pulmonary arterial pressure, pulmonary vascular resistance, and alveolar-arterial oxygen difference increased over phase 1 (0-2hr) and phase 2 (2-4.5hr) by endotoxin, indomethacin attenuated the decrease in cardiac output during phase 1 and increase in mean pulmonary arterial pressure, pulmonary vascular resistance, and alveolar-arterial oxygen difference during both phases. 2) The increase in plasma GSSG content during phase 2 was not attenuated by indomethacin. 3) The content of BALF albumin was significantly lower in indomethacin groups than that of endotoxin group. Conclusion: These results suggest that it is likely that cyclooxygenase metabolites have an effect on endotoxin-induced acute lung injury during both phases probably through direct action.

• Horticultural Science & Technology
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• v.30 no.5
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• pp.509-518
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• 2012

The objective of this study was to determine the effect of heat shock treatments on the phytochemicals including antioxidants and anticancer materials in kale (Brassica oleracea L. var. acephala) sprouts. In study I, kale sprouts grown under the growing system for four days were soaked at 40, 50, or $60^{\circ}C$ distilled water for 10, 30, or 60 seconds, and in study II, kale sprouts were soaked at $50^{\circ}C$ distilled water for 10, 20, 30, 45, or 60 seconds. After the heat shock treatments, the sprouts were transferred into normal growing conditions and recovered there for two days. Fresh and dry weights, electrolyte leakage, total phenolic concentration, antioxidant capacity, total flavonoid concentration, phenylalanine ammonia-lyase (PAL) activity, and glucosinolates content of the sprouts were measured before and after the heat shock treatments. As a result, there was a significant decrease in the fresh and dry weight of kale sprouts treated with heat shock compared with control at harvest in study I. Especially, heat shock at $60^{\circ}C$ lead to more pronounced growth inhibition compared with heat treatments at 40 and $50^{\circ}C$. Electrolyte leakage by cell collapse was the highest in the sprouts exposed to $60^{\circ}C$ distilled water, which agreed with the growth results. Heat shock at $50^{\circ}C$ significantly induced the accumulation of phenolic compounds. In study II, fresh weight of kale sprouts at $50^{\circ}C$ heat shock showed a significant decrease compared with the control at one and two days after the treatment. However, the decrease was minimal and dry weight of kale sprouts was not significantly different from that in control. In contrast, the heat shock-treated kale sprouts had higher level of total phenolic concentration than control at harvest. Heat shock treatments at $50^{\circ}C$ for 20 seconds or more showed at least 1.5 and 1.2 times higher total phenolic concentration and antioxidants capacity than control, respectively. The change of the total flavonoid concentration was similar with that of antioxidants. PAL activity after 24 hours of heat shock was higher in all the heat shock-treated sprouts than that in control suggesting heat shock may stimulate secondary metabolic pathway in kale sprouts. Seven glucosinolates were identified in kale sprouts and soaking the sprouts with $50^{\circ}C$ water for 20 seconds had a pronounced impact on the accumulation of total glucosinolates as well as two major glucosinolates, progoitrin and sinigrin, at harvest. In conclusion, this study suggests that heat shock using hot water would be a potential strategy to improve nutritional quality of kale sprouts by inducing the accumulation of phytochemicals with antioxidant and anticancer properties.

• Journal of Plant Biotechnology
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• v.40 no.4
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• pp.210-216
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• 2013

Efficient regeneration methods and transformation system are a priority for successful application of genetic engineering to vegetative propagated plants such as grape (Vitis labrusca L.). This research is to establish shoot regeneration system from plant explants for 'Campbell Early', 'Tamnara', 'Heukgoosul', 'Heukbosek' using two types of plant growth regulators supplemented to medium. The highest adventitious shoot regeneration rate of 5% was achieved on a medium containing of Murashige and Skoog (MS) inorganic salts and Linsmaier and Skoog (LS) vitamins, 2 mg/L of TDZ and 0.1 mg/L of IBA. Leaf tissue of 'Campbell Early', was co-cultivated with Agrobacterium strains, LBA4404 containing the vector pBI121 carrying with CaMV 35S promoter, gus gene as reporter gene and resistance to kanamycin as selective agent, the other Agrobacterium strains, GV3101 containing the vector pB7 WG2D carrying with mPAP1-D gene. mPAP1-D is a regulatory genes of the anthocyanin biosynthetic pathway. 'Campbell Early' harboring mPAP1-D gene was readily able to be selected by red color due to anthocyanin accumulation in the transformed shoot. These results might be helpful for further studies to enhance the transformation efficiency in grape.

• Journal of the Korean Applied Science and Technology
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• v.29 no.1
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• pp.71-80
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• 2012

Vinca alkaloids produced from Catharanthus roseus are one of the most important natural product drugs in treatments of human cancers. These anticancer drugs are derived from coupling of the two monomeric indole alkaloids, catharanthine and vindoline. In order to investigate vindoline biosynthesis, tabersonine-$CD_3$ 1a is synthesized to use as a deuterium labeled precursor, which is distinguished clearly from the natural counterpart. We show that these deuterium labeled tabersonine 1a are successfully incorporated into the vindoline biosynthetic pathway to yield three deuterated vindoline intermediates. 16-Hydroxytabersonine-$CD_3$ (m/z 356) 2a, 16-Methoxytabersonine-$CD_3$ (m/z 370) 3a, 16-Methoxy-2,3-dihydro-3-hydroxytabersonine-$CD_3$ (m/z 388) 4a are produced from the cell suspension culture measured by UPLC/MS at 5 and 13 days after feeding tabersonine. The conversion rates from 1a to 2a and 2a to 3a are fast, whereas that from 3a to 4a is much slower. This indicates that the rate determining step among the first three vindoline biosynthesis is the last step. As a result of the slow conversion rate from 3a to 4a, the accumulation level of 16-Methoxytabersonine-$CD_3$ 3a is significantly increased up to 13 days. The accumulation ratio among 2a, 3a and 4a is 1, 2 and 0.1 at 5 days. However, the peaks of desacetoxyvindoline-$CD_3$ 5a, deacetylvindoline-$CD_3$ 6a and vindoline-$CD_3$ 7a are not found from the cell extracts even after 13 days of incubation which may indicate no presence of their corresponding enzymes.