• The Korea Journal of Herbology
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• v.22 no.4
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• pp.253-260
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• 2007

Objectives : Intracerebral hemorrhage (ICH) is characterized by breakdown of blood vessels within the brain parenchyma. Fundamental therapeutic strategies for ICH, particularly those aimed at neuroprotection, have to be established. So in this experiment, the effects of Woowhangchongshim-won, a traditional prescription formula for treating Cerebral Apoplexy in Asian countries, were investigated. Methods : After intraperitoneal injection of chloralhydrate, rats were placed in a stereotaxic frame. ICH was induced by injection of 1 U collagenase type IV and drug was administered orally for 10 days. The molecular profile of cerebral hemorrhage in rat brain tissue was measured using micro array technique to identify up- or down- regulated genes in brain tissue. These genes induced by brain damage were mainly concerned with general metabolic process such as primary metabolic process, cellular metabolic process, macromolecule metabolic process, and biosynthetic process. Results : The number of genes increased in control and not-changed in experiment was 374, and decreased in control and not-changed in experiment was 527. We are concerned with genes that can be recovered by treatment with medicine, it is especially interesting to above types of genes. Conclusions : Upon medicine treatment to the rat having cerebral hemorrhage, expressions of some genes were restored to normal level. Further analysis using protein interaction database identified some key molecules that can be used for elucidation of therapeutical mechanism of medicine in future.

• Tuberculosis and Respiratory Diseases
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• v.44 no.5
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• pp.992-1000
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• 1997

Background : Since up to 90% of a theophylline dose is biotransformed, probably by interaction with one or more the variants of the cytochrome P-450 drug metabolism system, anti-tuberculosis agents including drugs influencing microsomal enzyme systems, such as isoniazid and rifampicin. may be affect the elimination of theophylline. Method : The effect of combination therapy with isoniazid(INH), rifampicin(RFP), ethambutol(EMB) and pyrazinamide(PZA) on the pharmacokinetics of theophylline was evaluated by a computer program using Bayesian method. Three group were divided as follows. Group I is control, Group II is treated with INH. RFP, EMB and PZA and Group III is treated with INH, RFP and EMB. All of them were ilon-smoker who were normal in liver and renal functions, and not administered drugs affecting on the clearance of theophylline with exception of anti-tuberculous agents. Results : When it compared control with test groups, the clearance of theophylline in Group II and Group III was significantly decreased(p<0.001), and half life in Group II and Group III showed significant elevation(p<0.001). However there were no significant differences in clearance and half life between the Group II and Group III. Conclusion : These results suggest that theophylline dose may be need of readjustment in concurrent medication of anti-tuberculous agents including INH, RFP, and EMB.

• Analytical Science and Technology
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• v.24 no.6
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• pp.533-543
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• 2011

The hERG (human ether-a-go-go related gene) ion channel is a main factor for cardiac repolarization, and the blockade of this channel could induce arrhythmia and sudden death. Therefore, potential hERG ion channel inhibitors are now a primary concern in the drug discovery process, and lots of efforts are focused on the minimizing the cardiotoxic side effect. In this study, $IC_{50}$ data of 202 organic compounds in HEK (human embryonic kidney) cell from literatures were used to develop predictive 2D-QSAR model. Multiple linear regression (MLR), Support Vector Machine (SVM), and artificial neural network (ANN) were utilized to predict inhibition concentration of hERG ion channel as machine learning methods. Population based-forward selection method with cross-validation procedure was combined with each learning method and used to select best subset descriptors for each learning algorithm. The best model was ANN model based on 14 descriptors ($R^2_{CV}$=0.617, RMSECV=0.762, MAECV=0.583) and the MLR model could describe the structural characteristics of inhibitors and interaction with hERG receptors. The validation of QSAR models was evaluated through the 5-fold cross-validation and Y-scrambling test.

• Korean Journal of Food Science and Technology
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• v.43 no.5
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• pp.641-647
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• 2011

Polyphenols in green tea are biologically active and may interact with commonly-consumed over-the-counter (OTC) drugs in the body. In this study, modulation of cytotoxicity of polyphenon 60 (PPE, tea polyphenol mixture) with co-treatment of several OTC drugs, including ibuprofen (Ibu), acetaminophen (AAP), and aspirin was investigated in intestinal cells. PPE showed more potent cytotoxic effects on colon cancer HCT 116 cells than on normal intestinal INT 407 cells. Ibu had the strongest cytotoxic effects on both cell types. Cytotoxicity of PPE on HCT 116 and INT 407 cells was not markedly altered by co-treated OTC drugs. Cytotoxicity of the OTC drugs was not affected by PPE. When HCT 116 cells were incubated with AAP before or after PPE treatment, cytotoxicity was slightly enhanced more than their additive effect. The present study may provide basic information of possible toxicity due to interaction of the polyphenols and the OTC drugs.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.10
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• pp.4331-4338
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• 2014

$N^1$-(2, 5-dimethoxyphenyl)-$N^8$-hydroxyoctanediamide (N25) is a novel SAHA cap derivative of HDACi, with a patent (No. CN 103159646). This invention is a hydroxamic acid compound with a structural formula of $RNHCO(CH_2)6CONHOH$ (wherein R=2, 5dimethoxyaniline), a pharmaceutically acceptable salt which is soluble. In the present study, we investigated the effects of N25 with regard to drug distribution and molecular docking, and anti-proliferation, apoptosis, cell cycling, and $LD_{50}$. First, we designed a molecular approach for modeling selected SAHA derivatives based on available structural information regarding human HDAC8 in complex with SAHA (PDB code 1T69). N25 was found to be stabilized by direct interaction with the HDAC8. Anti-proliferative activity was observed in human glioma U251, U87, T98G cells and human lung cancer H460, A549, H1299 cells at moderate concentrations ($0.5-30{\mu}M$). Compared with SAHA, N25 displayed an increased antitumor activity in U251 and H460 cells. We further analyzed cell death mechanisms activated by N25 in U251 and H460 cells. N25 significantly increased acetylation of Histone 3 and inhibited HDAC4. On RT-PCR analysis, N25 increased the mRNA levels of p21, however, decreased the levels of p53. These resulted in promotion of apoptosis, inducing G0/G1 arrest in U251 cells and G2/M arrest in H460 cells in a time-dependent and dose-dependent manner. In addition, N25 was able to distribute to brain tissue through the blood-brain barrier of mice ($LD_{50}$: 240.840mg/kg). In conclusion, our findings demonstrate that N25 will provide an invaluable tool to investigate the molecular mechanism with potential chemotherapeutic value in several malignancies, especially human glioma.

• Journal of Life Science
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• v.30 no.5
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• pp.483-490
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• 2020

The ubiquitin system uses ligases and deubiquitinases (DUBs) to regulate ubiquitin position on protein substrates and is involved in many biological processes which determine stability, activity, and interaction of the target substrate. DUBs are classified in six groups according to catalytic domain, namely ubiquitin-specific proteases (USPs); ubiquitin C-terminal hydrolases (UCHs); ovarian tumor proteases (OTUs); Machado Joseph Disease proteases (MJDs); motif interacting with Ub (MIU)-containing novel DUB family (MINDY); and Jab1/MPN/MOV34 metalloenzymes (JAMMs). Otubain 1 (OTUB1) is a DUB in the OTU family which possesses both canonical and non-canonical activity and can regulate multiple cellular signaling pathways. In this review, we describe the function of OTUB1 through regulation of its canonical and non-canonical activities in multiple specifically cancer-associated pathways. The canonical activity of OTUB1 inhibits protein ubiquitination by cleaving Lys48 linkages while its non-canonical activity prevents ubiquitin transfer onto target proteins through binding to E2-conjugating enzymes, resulting in the induction of protein deubiquitination. OTUB1 can therefore canonically and non-canonically promote tumor cell proliferation, invasion, and drug resistance through regulating FOXM1, ERα, KRAS, p53, and mTORC1. Moreover, clinical research has demonstrated that OTUB1 overexpresses with high metastasis in many tumor types including breast, ovarian, esophageal squamous, and glioma. Therefore, OTUB1 has been suggested as a diagnosis marker and potential therapeutic target for oncotherapy.

• Journal of Yeungnam Medical Science
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• v.16 no.2
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• pp.326-332
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• 1999

Background: In korea the agricultural community widely uses organophosphorous, and organophosphorous poisonings are increasing every year. We compared change in activity of acetylcholinesterase and pseudocholinesterase by organophosphorous and by the interaction of ethanol and organophosphorous. We also compared the effect of reversible anticholinesterase drugs, physostigmine and neostigmine The object of this study is to investigate the effects of several anticholinesterase drugs and on how ethanol influences the activity of cholinesterase. Materials and Methods: Fifteen male university students were randomly selected, and blood samples were taken from the antecubital vein. The acetylcholinesterase in the RBC and the pseudocholinesterase in the serum were extracted and separated. The enzyme activity change was measured by the electrometric method. After adding acetylcholine, the pH change was measured with a pH meter. Results and Conclusion: Our results indicated that reversible anticholinesterase drugs decreased the cholinesterase activity more efficiently than organophosphorous. The acetyl cholinesterase and pseudocholinosterase activity were decreased by ethanol. When ethanol was added, oxime a cholinesterase activator, increased acetylcholinesterase activity but does not increased pseudocholinesterase activity.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.12
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• pp.6191-6196
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• 2012

Aims and Background: Traditional chemotherapy strategies for human leukemia commonly use drugs based on cytotoxicity to eradicate cancer cells. One predicament is that substantial damage to normal tissues is likely to occur in the course of standard treatments. Obviously, it is urgent to explore therapies that can effectively eliminate malignant cells without affecting normal cells. Our previous studies indicated that ginsenoside $Rg_1$ ($Rg_1$), a major active pharmacological ingredient of ginseng, could delay normal hematopoietic stem cell senescence. However, whether $Rg_1$ can induce cancer cell senescence is still unclear. Methods: In the current study, human leukemia K562 cells were subjected to $Rg_1$ exposure. The optimal drug concentration and duration with K562 cells was obtained by MTT colorimetric test. Effects of $Rg_1$ on cell cycle were analyzed using flow cytometry and by SA-${\beta}$-Gal staining. Colony-forming ability was measured by colony-assay. Telomere lengths were assessed by Southern blotting and expression of senescence-associated proteins P21, P16 and RB by Western blotting. Ultrastructural morphology changes were observed by transmission electron microscopy. Results: K562 cells demonstrated a maximum proliferation inhibition rate with an $Rg_1$ concentration of $20{\mu}\;mol{\cdot}L^{-1}$ for 48h, the cells exhibiting dramatic morphological alterations including an enlarged and flat cellular morphology, larger mitochondria and increased number of lysosomes. Senescence associated-${\beta}$-galactosidase (SA-${\beta}$-Gal) activity was increased. K562 cells also had decreased ability for colony formation, and shortened telomere length as well as reduction of proliferating potential and arrestin $G_2$/M phase after $Rg_1$ interaction. The senescence associated proteins P21, P16 and RB were significantly up-regulated. Conclusion: Ginsenoside $Rg_1$ can induce a state of senescence in human leukemia K562 cells, which is associated with p21-Rb and p16-Rb pathways.

• YAKHAK HOEJI
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• v.34 no.4
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• pp.224-237
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• 1990

A single uniform population of specific, saturable, high affinity binding site of $[^3H]QNB$ guinuclidinyl benzilate(QNB) was identified in the rat cerebral microsomes. The Kd value(37.2 pM) for $[^3H]QNB$ calculated from the kinetically derived rate constants was in agreement with the Kd value(48.9 pM) determined by analysis of saturation isotherms at various receptor concentrations. Dimenhydrinate(DMH), histamine $H_1-blocker$, increased Kd value for $[^3H]QNB$ QNB without affecting the binding site concentrations and this effect resulted from the ability of DMH to slow $[^3H]QNB-receptor$ association. Pirenzepine inhibition curve of $[^3H]QNB$ binding was shallow(nH = 0.52) indicating the presence of two receptor subtypes with high ($M_1-site$) and low($M_2-site$) affinity for pirenzepine. Analysis of these inhibition curves yielded that 68% of the total receptor populations were of the $M_1-subtype$ and the remaining 32% of the $M_2-subtype$. Ki values for the $M_1-$ and $M_2-subtypes$ were 2.42 nM and 629.3 nM, respectively. Ki values for $H_1-blockers$ that inhibited $[^3H]QNB$ binding varied with a wide range ($0.02-2.5\;{\mu}M$). The Pseudo-Hill coefficients for inhibition of $[^3H]QNB$ binding by most of $H_1-blockers$ examined except for oxomemazine inhibition of $[^3H]QNB$ binding were close to one. The inhibition curve for oxomemazine in competition with $[^3H]QNB$ was shallow(nH = 0.74) indicating the presence of two receptor populations with different affinities for this drug. The proportion of high and low affinity was 33:67. The Ki values for oxomemazine were $0.045{\pm}0.016\;{\mu}M$ for high affinity and $1.145{\pm}0.232\;{\mu}M$ for low affinity sites. These data indicate that muscarinic receptor blocking potency of $H_1-blockers$ varies widely between different drugs and that most of $H_1-blockers$ examined are nonselective antagonist for the muscarinic receptor subtypes, whereas oxomemazine might be capable of distinguishing between subclasses of muscarinic receptor.

• Archives of Pharmacal Research
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• v.28 no.9
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• pp.1002-1012
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• 2005

5-Substituted 4-oxo-2-thioxo-1,,2,3,4-tetrahydropyrimidine were synthesized by interaction of 4­oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-sulfonylhydrazide with some aldehydes to give the corresponding Schiff-bases, which after cyclization gave corresponding thiazolidinones. For some of the thiazolidinones, Mannich bases reaction was carried out. All the derivatives were tested for their possible inhibitory effect on Schistosoma mansoni cercarial elastase (CE). Only, N'-(4-methylbenzyledine)-4-oxo-2-thioxo-1,2 ,3,4-tetrahydropyrimidine-5-sulfonylhydrazide was found to have potent inhibitory effect on the CE activity with $IC_{50} = 264{\mu}M.$ Upon its use as a paint for mice tails before infection with S. mansoni cercariae, the compound formulated in jojoba oil caused a significant reduction ($93\%$; P-value = 0.0002) in the worm burden. IgG & IgM in mice sera were measured by using several S. mansoni antigens by ELISA. Sera from treated infected mice (TIM) 2, 4, and 6 weeks (W) post infection (PI) showed 1.2 folds lower, 1.2 folds higher, 1.7 folds lower IgM reactivity against soluble cercarial antigenic preparation (CAP), respectively, when compared with sera collected from infected untreated mice (IUM). Sera from TIM 2, 4, and 6WPI showed 1.3, 1.6, and 1.7 folds higher IgG reactivity, respectively against CAP than the IgG reactivity from IUM. Sera from TIM 2, 4 and 6WPI showed 1.5, 1.2 folds lower and 1.4 folds higher IgM reactivity, respectively against soluble worm antigenic preparation (SWAP) when compared with sera collected from IUM. Sera from TIM 2, 4, and 6WPI showed 1.4, 1 folds lower and 1 fold higher IgG reactivity, respectivley to SWAP when compared with sera from IUM. Sera from TIM 2, 4, and 6WPI had generaly lower IgM and IgG reactivities against soluble egg antigen (SEA) when compared with sera from IUM.