• Journal of Life Science
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• v.30 no.8
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• pp.661-671
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• 2020

The resistance of cancer cells to anti-cancer drugs is the leading cause of chemotherapy failure. The clinical use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been gradually extended to cancer treatment through combination with anti-cancer drugs. In the current study, we investigated whether NSAIDs including celecoxib (CCB), 2,5-dimethyl celecoxib (DMC), and ibuprofen (IBU) could enhance the cytotoxic effects of imatinib and TNF-related apoptosis inducing ligand (TRAIL) on human cancer cells. We found that the NSAIDs potentiated TRAIL and imatinib cytotoxicity against human hepatocellular carcinoma (HCC) cell lines SNU-354, SNU-423, SNU-449, and SNU-475/TR and against leukemic K562 cells with high level of CD44 (CD44^highK562), respectively. More specifically, CCB induced endoplasmic reticulum stress via up-regulation of ATF4/CHOP which is associated with the induction of autophagy against HCC and CD44^high K562 cells. NSAID-induced autophagic activity accelerated TRAIL cytotoxicity of HCC cells through up- and down-regulation of DR5 and c-FLIP, respectively. The NSAIDs also potentiated imatinib-induced cytotoxicity and apoptosis through down-regulation of markers in CD44^highK562 cells that express a stemness phenotype. Our results suggest that the ability of NSAIDs to induce autophagy could enhance the cytotoxicity of TRAIL and imatinib, leading to a reverse resistance to these drugs in the cancer cells. In conclusion, NSAIDs in combination with low-dose TRAIL or imatinib may constitute a novel clinical strategy that maximizes therapeutic efficacy of each drug and effectively reduces the toxic side effects.

• Proceedings of the Ginseng society Conference
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• 1993.09a
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• pp.102-109
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• 1993

Backgrounds Diabetes mellitus is associated with accelerated atherosc lerosis and predispose to specific microvascular problems. This study was performed to evaluate the usefulness of red ginseng as adjunctive therapeutic agent of NIDDM especially in preventing chronic diabetic complications. Materials and Methods We treated 50 patients with NIDDM for 5 month with 2 regimens: 1)oralhypoglycemic drug therapy only(the control group), 2)oral hypoglycemic group). The patients were recruited at Korea university hospital from June, 1992 to October, 1992 and the following inclusion criteria were used: l)age above 35 years 2)initial body weight within or above ideal body weight 3)fasting blood glucose level greater than 140mg/dl 4)no previous history of diabetes mellitus or no history of blood glucose control for recent 3 months of more. The patients were seen every 2 weeks for remaining 3 months. At every visit FBS and PP2hr blood glucose were measured with blood pressure and body weight. Lipid profiles were checked every 4 weeks and platelet function test was perfomed with aggregometer after administration of ADP, epineprine and collagen every 4 weeks. Free fatty acid were also analyzed every 8 weeks and glycosylated hemoglobin was measured every 12 weeks. Results The results were as follows: 1. The mean values for fasting and PP2hr blood glucose decreased significantly in the control group than in the ginseng group. 2. The weight gain was less in the ginseng group than in the control group. The levels of systolic blood pressure decreased' significantly in the ginseng group than in the control group. 3. There was no significant differences of lipid profiles in both groups. 4. The platelet hyperaggregation was improved more significantly in the ginseng group than in the control group. Conclusions In patients with NIDDM who were recieving oral hypoglycemic drug therapy, the addition of red ginseng improved platelet function and blood pressure, but induced less weight gain. The data suggests that red ginseng may be useful as a therapeutic adjunct especially in preventing chronic complications of NIDDM.

• Korean Journal of Clinical Pharmacy
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• v.6 no.2
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• pp.19-23
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• 1996

Carbamazepine is an anticonvulsant drug that has been shown to be as effective as phenytoin or phenobarbital in treatment of grand mal and complex partial seizures and is also approved as the drug of choice for treatment of the pain associated with trigerminal neuralgia. And the therapeutic or toxic effects of carbamazepine are better related to plasma concentration than to dosage, which can be attributed to interindividual variability in the pharmacokinetics. A slow rate of carbamazepine dissolution in the gastrointestinal tract is believed to be the cause of its relatively slow and erratic rate of absorption. For these reasons pharmacokinetic evaluation of newly formulated carbamazepine is neccessary. In this study, the bioequivalence in carbamazepine between the $TegretoI^{TM}$ CR tablet (Geigy Co.) and $Carmazepine^{TM}$ CR tablet (Myung In Co.) was evaluated. 12 normal volunteers (age $21\~27$ years old) was divided into two groups, and a randomized cross-over study was employed. The pharmacokinetic parameters ($C_{max},\;T_{max}$ and AUC) obtained of oral administration of each formulatim of carbamazepine 400 mg were evaluated and ANOVA was utilized for the statistical analysis of parameters. $C_{max}\;is\;8.26{\pm}3.1{\mu}g/ml\;(C.V.\;37.3\%)\;in\;TegretoI^{TM}\;and\;9.39\{pm}2.9{\mu}g/ml\;(C.V.\;30.5\%)$ in $Carmazepine^{TM},\;T_{max}\;is\;28.0{\pm}5.9\;hrs(C.V.\;21.1\%)$ in $Tegretol^{TM}\;and\;24.0{\pm}7.2\;hrs(C.V.\;30.2\%)$ in $Carmazepine^{TM}$ and AUC is $786.4{\pm}360.5{\mu}g{\cdot}hr/ml\;(C.V.\;45.8\%)$ in $TegretoI^{TM}\;and\;792.8{\pm}228.6{\mu}g{\cdot}hr/ml\;(C.V.\;28.8\%)$ in $Carmazepine^{TM}$, respectively. As the result of the data, two formulations are bioequvalent, and the lower C.V. of $Carmazepine^{TM}$ in every individual can be merit.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.7
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• pp.3123-3128
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• 2014

The liver is normally the major site of glucose metabolism in intact organisms and the most important target organ for the action of insulin. It has been widely accepted that insulin resistance (IR) is closely associated with postoperative recurrence of hepatocellular carcinoma (HCC). However, the relationship between IR and drug resistance in liver cancer cells is unclear. In the present study, IR was induced in HepG2 cells via incubation with a high concentration of insulin. Once the insulin-resistant cell line was established, the stability of HepG2/IR cells was further tested via incubation in insulin-free medium for another 72h. Afterwards, the biological effects of insulin resistance on adhesion, migration, invasion and sensitivity to cis-platinum (DDP) of cells were determined. The results indicated that glucose consumption was reduced in insulin-resistant cells. In addition, the expression of the insulin receptor and glucose transportor-2 was downregulated. Furthermore, HepG2/IR cells displayed markedly enhanced adhesion, migration, and invasion. Most importantly, these cells exhibited a lower sensitivity to DDP. By contrast, HepG2/IR cells exhibited decreased adhesion and invasion after treatment with the insulin sensitizer pioglitazone hydrochloride. The results suggest that IR is closely related to drug resistance as well as adhesion, migration, and invasion in HepG2 cells. These findings may help explain the clinical observation of limited efficacy for chemotherapy on a background of IR, which promotes the invasion and migration of cancer cells.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.8
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• pp.3213-3222
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• 2015

Background: Cancer metastasis depends on cell motility which is driven by cycles of actin polymerization and depolymerization. Reactive oxygen species (ROS) and metabolic oxidative stress have long been associated with cancer. ROS play a vital role in regulating actin dynamics that are sensitive to oxidative modification. The current work aimed at studying the effects of sub-lethal metabolic oxidative stress on actin cytoskeleton, focal adhesion and cell migration. Materials and Methods: T47D human breast cancer cells were treated with 2-deoxy-D-glucose (2DG), L-buthionine sulfoximine (BSO), or doxorubicin (DOX), individually or in combination, and changes in intracellular total glutathione and malondialdehyde (MDA) levels were measured. The expression of three major antioxidant enzymes was studied by immunoblotting, and cells were stained with fluorescent-phalloidin to evaluate changes in F-actin organization. In addition, cell adhesion and degradation ability were measured. Cell migration was studied using wound healing and transwell migration assays. Results: Our results show that treating T47D human breast cancer cells with drug combinations (2DG/BSO, 2DG/DOX, or BSO/DOX) decreased intracellular total glutathione and increased oxidized glutathione, lipid peroxidation, and cytotoxicity. In addition, the drug combinations caused a reduction in cell area and mitotic index, prophase arrest and a decreased ability to form invadopodia. The formation of F-actin aggregates was increased in treated T47D cells. Moreover, combination therapy reduced cell adhesion and the rate of cell migration. Conclusions: Our results suggest that exposure of T47D breast cancer cells to combination therapy reduces cell migration via effects on metabolic oxidative stress.

• Journal of Preventive Medicine and Public Health
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• v.42 no.3
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• pp.165-170
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• 2009

Objectives : We evaluated the risk of fracture associated with hypotension-related adverse drug reaction caused by taking alpha blockers to treat benign prostatic hyperplasia (BPH). Methods : We used the Health Insurance Review and Assessment Service database from January 1st 2005 to June 30th 2006 for this study. The male patients with BPH and who had a prescription for alpha blockers following any fractures were defined as the cases. We set the 20 day long hazard period prior to the index date and the four control periods whose lengths were same with hazard period. After 1:4 matching of the hazard and control periods, conditional logistic regression was used to calculate the odds ratios for the risk of fractures as related to the alpha blocker exposure. Results : Doxazosin and tamsulosin showed the increased risk of fractures, whereas terazosin did not. After stratification using the defined daily doses, a protective effect was shown for the patients who took terazosin at the doses lower than 0.4 DDD and the hazardous effect at the doses higher than or equal to 0.4 DDD. There was no significant difference for the risk of patients taking tamsulosin at the doses higher than 1.0 DDD but there was a statistically significant increase in the risk at the doses higher than or equal to 1.0 DDD. Conclusions : Alpha blockers for BPH may increase the risk of fracture in elderly patients who have comorbidities and take the concomitant medications. Alpha blockers need to be prescribed with caution, although some have high prostate specificity.

• Journal of Physiology & Pathology in Korean Medicine
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• v.19 no.4
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• pp.982-992
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• 2005

Acupuncture as a therapeutic intervention is widely used for the treatment of many functional disorders such as substance abuse and mental dysfunction. Clinical trials are currently underway to determine the effectiveness of acupuncture in the treatment of drug addiction. Yet, there are still many unanswered questions about the basic mechanism of acupuncture. Studies have shown that both the psychomotor stimulant effects and rewarding properties of addictive drugs, including morphine, are sensitized by repeated drug administration and raised the possibility that both of these effects may De linked to the same or closely overlapping the mesolimbic dopamine systems. Neiguan (PC6) point on the pericardium channel which is associated with the brain and its mental function, has been used to treat mental, psychosomatic disorders and gastroenterological disorders. The present study was designed to investigate the effect of acupuncture on repeated morphine-induced changes in extracellular dopamine levels using in vivo microdialysis and to measure the effect of acupuncture on repeated morphine-induced behavioral changes. Male Sprague-Dawley rats were treated twice a day for three days with increasing doses of morphine (10, 20 and 40 mg/kg, s.c.) or with saline. After 15 days of withdrawal, rats were challenged with morphine hydrochloride (5 mg/kg, s.c.). Acupuncture was applied at bilateral Neiguan (PC6) points for 1min after the morphine challenge. Results showed that acupuncture at the specific acupoint PC6, but not at control points (tail and HE8) significantly decreased both dopamine release, behavior induced by a systemic morphine challenge or a single s.c. morphine injection in the morphine-repeated animals. These results suggest that reduction in sensitization may be one mechanism whereby acupuncture alleviates morphine craving in addicts. Moreover, in a more general sense these results suggest that acupuncture can be used as a therapeutic intervention for correcting reversible malfunction of the body by direction of brain pathway and thus acupuncture can contribute to the biochemical balance in the central nervous system by regulating neurotransmitters.

• Tuberculosis and Respiratory Diseases
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• v.46 no.1
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• pp.25-35
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• 1999

Background : The treatment for multi-drug resistant tuberculosis(MDRTB) is encountered to be important clinically, but there are still a few reports about it all over the world. So, we evaluated the outcomes of only chemotherapy for the pulmonary MDRTB retrospectively. Method: We reviewed the clinical courses of 63 patients with pulmonary disease due to M.tuberculosis resistant to rifampin and isoniazid who were under follow-up between March 1996 and June 1996 after hospitalization at our hospital between January 1993 and January 1996. We performed cohort retrospective study for all these patient's records. Their regimens were selected individually and preferably included four medications that they had not been given previously and to which the strain was fully susceptible. Results: The 63 patients(mean age, 43.2 years) had previously received a median 5.1drugs. Fifty two(82.5%) patients responded to chemotherapy(as indicated by negative sputum cultures for at least three consecutive months) ; eleven patients(17.5 %) had no response, as shown by continually positive cultures. In a univariate analysis, an unfavorable response was significantly associated with greater number of resistant drugs before the current courses of therapy(relative risk 21.5 ; 95 percent confidence interval, 1.2-3.0; p<0.05). The mean period of follow-up was seventeen months. There was no relapse suooequently among the patients with responses. There was no death related to tuberculosis. Conclusion: In this report from National Masan Tuberculosis Hospital in Korea, multi-drug resistant pulmonary tuberculosis responded relatively well to carefully selected regimens.

• Korean Journal of Microbiology
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• v.46 no.3
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• pp.303-307
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• 2010

Acinetobacter baumannii 1625, a clinical isolate identified by Vitek and 16S rDNA sequence, showed an extended resistance to most ${\beta}$-lactams including imipenem, kanamycin, gentamicin, tobramycin, and cephalosporins of the third and fourth generations, and produced metallo-${\beta}$-lactamase (MBL) of IMP-1 type which is rare in Korea. The isolate contained a class 1 integron of about 2.5 kb in size and the integron included accA4 (aminoglycoside resistance gene), $bla_{IMP-1}$ (carbapenem resistance gene), and $bla_{OXA-2}$ (extended-spectrum ${\beta}$-lactam resistance gene) gene cassettes in order. The coexistence of IMP-1 type and OXA-2 type ${\beta}$-lactamase gene cassettes in an integron has not been reported in Korea. The transformed integron rendered the E. coli transformant resistant more than eight folds against imipenem, ampicilin, piperacillin, cefazolin, cefoperazone, and aztreonam comparing to the reference strain. This study clearly showed that the extended multi-drug resistance of A. baumannii 1625 was mainly due to the integron.

• Molecules and Cells
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• v.38 no.4
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• pp.373-379
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• 2015

Pyruvate kinase M2 isoform (PKM2), a rate-limiting enzyme in the final step of glycolysis, is known to be associated with the metabolic rewiring of cancer cells, and considered an important cancer therapeutic target. Herein, we report a novel PKM2 activator, PA-12, which was identified via the molecular docking-based virtual screening. We demonstrate that PA-12 stimulates the pyruvate kinase activity of recombinant PKM2 in vitro, with a half-maximal activity concentration of $4.92{\mu}M$, and effectively suppresses both anchorage-dependent and -independent growth of lung cancer cells in non-essential amino acid-depleted medium. In addition, PA-12 blocked the nuclear translocalization of PKM2 in lung cancer cells, resulting in the inhibition of hypoxia response element (HRE)-mediated reporter activity as well as hypoxia-inducible factor 1 (HIF-1) target gene expression, eventually leading to the suppression of cell viability under hypoxia. We also verified that the effects of PA-12 were dependent on PKM2 expression in cancer cells, demonstrating the specificity of PA-12 for PKM2 protein. Taken together, our data suggest that PA-12 is a novel and potent PKM2 activator that has therapeutic implications for lung cancer.