• Journal of Plant Biotechnology
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• v.37 no.1
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• pp.57-66
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• 2010

Programmed cell death systems are important for an active type of cell deaths. Among them, a type of programmed cell death, autophagy is activated in cancer cells in response to multiple stresses and has been demonstrated to promote tumor cell survival and drug resistance. Thus, in the area of cancer, over the time frame form around the 1940s to date, of the 155 small molecules, 73% are other than "synthetic", with 47% actually being either "natural products" or "directly derived therefrom". Autophagy has multiple physiological functions in multicellular organisms, including protein degradation and organelle turnover. Genes and proteins that constitute the basic machinery of the autophagic process were first identified in the yeast system and some of their mammalian orthologues have been characterized as well. Numerous oncogenes, including Akt1, Bcl-2, NF1, PDPK1, class I PI3K, PTEN, and Ras and oncosuppressors, inculuding Bec-1, Bif-1, DAPK-1, p53 and UVRAG suppress or promote the autophagy pathway. Regulation of autophagy in tumors is governed by similar principles of the normal cells, only in a much more complicated manner, given the frequently observed abnormal PI3K activation in cancer and the multitude of interactions between the PI3K/AKT/mTOR pathway and other cell signaling cascades, often also deregulated in tumor cells. Autophagy induction by some anticancer agents underlines the potential utility of its induction as a new cancer treatment modality of development for natural medicines.

• Development and Reproduction
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• v.18 no.4
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• pp.225-231
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• 2014

Autophagy is a homeostatic degradation process that is involved in tumor development and normal development. Autophagy is induced in cancer cells in response to chemotherapeutic agents, and inhibition of autophagy results in enhanced cancer cell death or survival. Chloroquine (CQ), an anti-malarial drug, is a lysosomotropic agent and is currently used as a potential anticancer agent as well as an autophagy inhibitor. Here, we evaluate the characteristics of these dual activities of CQ using human colorectal cancer cell line HCT15. The results show that CQ inhibited cell viability in dose- and time-dependent manner in the range between 20 to 80 uM, while CQ did not show any antiproliferative activity at 5 and 10 uM. Cotreatment of CQ with antitumor agent NVP-BEZ235, a dual inhibitor of PI3K/mTOR, rescued the cell viability at low concentrations meaning that CQ acted as an autophagy inhibitor, but CQ induced the lethal effect at high concentrations. Acridine orange staining revealed that CQ at high doses induced lysosomal membrane permeabilization (LMP). High doses of CQ produced cellular reactive oxygen species (ROS) and cotreatment of antioxidants, such as NAC and trolox, with high doses of CQ rescued the cell viability. These results suggest that CQ may exert its dual activities, as autophagy inhibitor or LMP inducer, in concentration-dependent manner.

• The Korean Journal of Zoology
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• v.20 no.4
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• pp.159-168
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• 1977

In order to evaluate the mutagenic potentential in mammalian system for those pesticides which were proved to be mutagenic in Salmonella microsome assay system, we have studied drug-resistant mutagenesis in cultured L5178Y cells and unscheduled DNA synthesis in human lymphocytes in vitro. We have tested five pesticides: insecticides DDVP and trichlorfon, fungicide TMTD and herbicides MO and NIP. Of these pesticides, TMTD induced weak mutation to MTX-resistance in L5178Y cells in vitro and gave positive responses in DNA repair assay system. Therefore, its potential genetic risks in human beings should be re-evaluated. DDVP and trichlorfon gave negative response in L5178Y mutagenesis test system but stimulated incorporation of $^{3}H$-TdR in DNA repar assay. MO and NIP gave also negative responses both in L5178Y mutagenesis test systemand in DNA repair assay system.

• YAKHAK HOEJI
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• v.55 no.6
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• pp.466-472
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• 2011

NF-E2-related factor 2 (Nrf2), a master regulator of antioxidant genes in animals, has been associated with the resistance of cancer cells to several cytotoxic chemotherapeutics. Bortezomib, a reversible inhibitor of the 26S proteasome, is a novel class anti-cancer therapeutics approved for the treatment of refractory multiple myeloma. However, the molecular mechanism of drug-resistance remains elusive. In the present study, bortezomib sensitivity has been investigated in Nrf2 knockdown ovarian cancer cells. When Nrf2 expression is stably repressed using interfering RNA expression, bortezomib-induced apoptosis and cell death were significantly enhanced compared to nonspecific RNA control cells. Knockdown cells showed elevated expression in the catalytic subunit PSMB5, PSMB6, and PSMB7 compared to the control, and failed to induce heme oxygenase-1 expression following bortezomib treatment. These indicate that differential proteasome levels and altered expression of stress-response genes could be underlying mechanisms of bortezomib sensitization in Nrf2-inhibited ovarian cancer cells.

• YAKHAK HOEJI
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• v.39 no.3
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• pp.314-328
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• 1995

This study was attempted to investigate the mechanism of retention of sodium and water by naproxen which is a drug among nonsteroidal anti-inflammatory drugs in dogs. Napoxen, when given intravenously in doses ranging from 30 mg to 100 mg/kg, elicited antidiuresis accompanied vath the decrease of osmolar clearance(Cosm) and amounts of sodium excreted in urine(E$_{Na}$), with the increase of sodium reabsorption rate in renal tubule(R$_{Na}$) and ratio of potassium against sodium (K/Na). Naproxen infused into a renal artery in doses ranging from 1.0mg to 3.0mg/kg/min produced both diuretic action in infused kidney and antidiuretic action in control kidney. Naproxen injected into carotid artery in doses ranging from 10.0 mg to 30.0 mg/kg exhibited antidiuretic action. Changes of renal function in the circumstances of above two antidiuresis were the same with aspect of intravenous naproxen. Antidiuretic action of naproxen injected into carotid artery was not affected by renal denervation, was blocked by pretreatment with i.v. arachidonic acid, prostaglandin precursor, or i.v. indomethacin, cyclooxygenase inhibitor. Naproxen injected into carotid artery abolished the diuretic action of i.v. spironolactone, aldosterone antagonist, and i.v. spironolactone blocked the antidiuretic action of naproxen given into carotid artery. The results suggest that naproxen produced antidiuresis, and sodium and water retention through the central system, the mechanism being related to the prostaglandin biosynthetic inhibition and aldostercfne like action.

• Bulletin of the Korean Chemical Society
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• v.24 no.1
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• pp.70-74
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• 2003

The heterogeneous bioluminescence immunoassay for digoxin was developed using photoprotein, native aequorin as a label and the site-directed immobilization technique based on avidin/biotin interaction. Aequorin is a bioluminescence protein, originally isolated from the jellyfish Aequoria Victoria and an attractive label in analytical applications because of sensitive detection due to virtually no background bioluminescent signal. Digoxin is a cardioactive drug, and its therapeutic level in serum is at low concentration with very narrow therapeutic index. The aequorin-digoxigenin conjugates were synthesized by the N-hydroxysuccinimide ester method and characterized in terms of bioluminescent residual activity. The resulting dose-response curve shows that the detection limit is $1.0\;{\times}\;10^{-10}\;M$ and a dynamic range is three orders of magnitude, which was obtained by $1.0\;{times}\;10^{-10}\;M$ conjugate and 0.9 μg/mL anti-digoxin antibody. Three structurally similar molecules to digoxin were examined for their cross-reactivity. None of these three compounds showed any crossreactivity with digoxin antibody employed in this study. Standard amounts of digoxin corresponding to the therapeutic range were spiked into the each serum solution. Study of the serum matrix effect indicated that correlation coefficient shows good agreement between luminescence light intensity between in buffer and in serum.

• Korean Journal of Clinical Pharmacy
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• v.21 no.4
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• pp.347-352
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• 2011

Health insurance review & Assessment service (HIRA) has enforced cutting the drug costs when physicians prescribe split extended release drugs, starting from December, 2010. The objective of this study is to analyze extended release and enteric coated drugs on pharmaceutical reimbursement list in Korea, and to investigate the impact and barriers of the health insurance review on splitting extended-release formulation drugs. By using the ingredient code, extended release and enteric coated formulations make up 7.8% of all drugs in April, 2011. The most frequently used drugs are agent affecting circulatory and digestive system. From the extended release and enteric coated formulations (n=112), 34.8% (n=39) were not available in other dosage forms. According to questionnaire survey for 169 pharmacists (response rate: 73.8%), the rate of splitting and crushing of extended release and enteric coated drugs decreased. When pharmacists correct physician's prescription errors, the biggest problem was lack of other dosage forms. So it is necessary to develop variety of other dosage forms, and computerized checking system for splitting extended-release drugs. It is also important to inform physicians and patients in regard to the problems of split prescription of extended release and enteric coated drugs.

• Journal of Haehwa Medicine
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• v.6 no.1
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• pp.331-347
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• 1997

In order to investigate the effects of YOOKMIJIHWANGTANG, GAMIJIHWANGTANG and PALMIJIHWANGTANG on the various immune responses, the chemotactic, adherent, nitric oxide release ability of macrophages were studied in vivo and in vitro. The results obtained were follows : 1. The total number of peritoneal exudate cells from mice injected with three drugs were 2~3 times more than those from the PBS. 2. The administration of three drugs enhanced significantly the Fc receptor mediated activity(phagocytosis, rosette formation activity). 3. The administration of three drugs enhanced significantly the chemotactic activity of peritoneal macrophages. 4. The administration of three drugs enhanced significantly the adherent activity of macrophages and neutrophils. 5. The administration of GAMIJIHWANGTANG and PALMIJIHWANGTANG enhanced significantly the chemotatic activity of macrophages (p<0.01). And also the administration of YOOKMIJIHWANGTANG enhanced significantly the chemotatic activity of macrophages(p<0.05). 6. The administration of GAMIJIHWANGTANG and enhanced significantly the chemotatic activity of neutrophils(p<0.01). And also the administration of YOOKMIJIHWANGTANG and PALMIJIHWANGTANG enhanced significantly the chemotatic activity of neutrophils(p<0.05). From above findings, it is suggested that YOOKMIJDTWANGTANG, GAMIJIHWANGTANG and PALMIJIHWANGTANG seems to produce the increase of immune response such as the Fc receptor activity, chemotactic activity, adherent activity, nitrate release of macrophages. From the above results, the GAMIJIHWANGTANG among three drugs may be the most useful drug having immunostimulating effects.

• Investigative Magnetic Resonance Imaging
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• v.20 no.2
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• pp.132-135
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• 2016

We report the case of a 43-year-old male with both giant left atrial appendage (LAA) aneurysm and drug-refractory atrial fibrillation (AF). The patient was treated with percutaneous electrical isolation of cardiac arrhythmogenic substrate, and has been free of AF symptom over one year. Although the surgical resection of giant LAA aneurysm is mostly used to prevent systemic thromboembolism, we have performed follow-up of the giant LAA aneurysm using cardiac magnetic resonance (CMR) imaging and transesophageal echocardiography (TEE) after the successful catheter ablation of refractory AF. At one-year follow-up CMR, the giant LAA aneurysm showed remarkable enlargement as well as decreased contractility. Additionally, one-year follow-up TEE showed spontaneous echo contrast as an indicator of blood stasis in the giant LAA aneurysm. Those findings of giant LAA aneurysm suggest that the risk of thromboembolism may be high despite termination of AF.

• IMMUNE NETWORK
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• v.13 no.1
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• pp.16-24
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• 2013

CTLA-4Ig is regarded as an inhibitory agent of the T cell proliferation via blocking the costimulatory signal which is essential for full T cell activation. To improve applicability, we developed the CTLA-4Ig-CTKC in which the c-terminal lysine had been replaced by cysteine through single amino acid change. The single amino acid mutation of c-terminus of CTLA-4Ig was performed by PCR and was checked by in vitro transcription and translation. DNA construct of mutant form was transfected to Chinese hamster ovary (CHO) cells by electroporation. The purified proteins were confirmed by Western blot and B7-1 binding assay for their binding ability. The suppressive capacity of CTLA-4Ig-CTKC was evaluated by the mixed lymphocyte reaction (MLR) and in the allogeneic pancreatic islet transplantation model. CTLA-4Ig-CTKC maintained binding ability to B7-1 molecule and effectively inhibits T cell proliferation in MLR. In the murine allogeneic pancreatic islet transplantation, short-term treatment of CTLA-4Ig-CTKC prolonged the graft survival over 100 days. CTLA-4Ig-CTKC effectively inhibits immune response both in MLR and in allogeneic islet transplantation model, indicating that single amino acid mutation does not affect the inhibitory function of CTLA-4Ig. CTLA-4Ig-CTKC can be used in vehicle-mediated drug delivery system such as liposome conjugation.