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Eun-Joo Kim

Publications and source records attributed to Eun-Joo Kim.

At least 19 recordsLinked to original sources
PubMed2006

Electrophysiological effects of brompheniramine on cardiac ion channels and action potential.

Some antihistamines (mainly terfenadine and astemizole) have been demonstrated to cause QT interval prolongation and, in some cases, torsade-de-pointes. We investigated the cardiac electrophysiological effects of brompheniramine, a conventional antihistamine. Brompheniramine was reported to prolong QT interval in isolated hearts. To evaluate the electrophysiological effects of brompheniramine, we used whole-cell patch clamp techniques in human ether-a-go-go related gene (hERG)-stably transfected CHO cells, the SCN5A sodium channel transiently transfected CHO cells, and rat myocytes and conventional microelectrode recording techniques in isolated guinea pig papillary muscles. As for the I(hERG), the IC(50) value of brompheniramine was found to be 0.90+/-0.14microM with a Hill coefficient (n(H)) of 1.75+/-0.42. Action potential duration at 90% repolarization (APD(90)) was slightly prolonged by brompheniramine at 10 and 100microM, but APD(50) was shortened by 100microM. Moreover, despite the potent hERG current block, reductions of the V(max) and total amplitude of action potential were observed at high concentrations of brompheniramine. The change in action potential parameters and poor correlations between hERG and APD assay indicated additional effects of brompheniramine on non-hERG channels. In agreement with this hypothesis, the inhibition of I(Na) (IC(50) values: 21.26+/-2.52microM) and I(Ca) (IC(50) values: 16.12+/-9.43microM) by brompheniramine was observed. The results of this study suggest that brompheniramine may possess classes III, Ib and IV properties, especially at high concentrations and that additional studies on non-hERG channels will be necessary to elucidate the complex electrophysiological effects of brompheniramine on the heart.

Action Potentials↗
PubMed2006

Secondary mania in a patient with delayed anoxic encephalopathy after carbon monoxide intoxication.

Mania is a rare clinical manifestation of delayed anoxic encephalopathy (DAE). Prior case reports on mania after hypoxic injury involved patients with a previous history of mania or depression, potentially reflecting a recurrence of premorbid mood disorders after hypoxia rather than pure secondary mania. Herein, we report a 55-year-old woman with no past history of neurological or psychiatric illness, who developed mania as a symptom of DAE after carbon monoxide intoxication. Brain magnetic resonance imaging showed diffuse white matter lesions, particularly visible in the frontal white matter. This frontal lesion may have prevented frontal inhibition from being transmitted to the basotemporal limbic area, resulting in mania manifested as a burst of limbic activity.

Bipolar Disorder↗
PubMed2006

Additional sex comb-like 1 (ASXL1), in cooperation with SRC-1, acts as a ligand-dependent coactivator for retinoic acid receptor.

Additional sex comb-like 1 (ASXL1, 170 kDa), a mammalian homolog of Drosophila ASX, was identified as a protein that interacts with retinoic acid receptor (RAR) in the presence of retinoic acid (RA). Systematic binding assays showed that the C-terminal nuclear receptor box (LVMQLL) of ASXL1 and the activation function-2 activation domain (AF-2 AD) core of the RAR are critical for ligand-dependent interaction. The interaction was confirmed using in vitro glutathione S-transferase pulldown and in vivo immunoprecipitation (IP) assays. Confocal microscopy revealed that ASXL1 localizes in the nucleus. In addition to the intrinsic transactivation function of ASXL1, its cotransfection together with an RA-responsive luciferase reporter increased the RAR activity. This ASXL1 activity appears to be mediated through the functional cooperation with SRC-1, as shown by GST pulldown, IP, chromatin IP, and transcription assays. In the presence of ASXL1, more acetylated histone H3 was accumulated on the RA-responsive promoter in response to RA. Finally, stable expression of ASXL1 increased the expression of endogenous RA-regulated genes and enhanced the antiproliferative potential of RA. Overall, these results suggest that ASXL1 is a novel coactivator of RAR that cooperates with SRC-1 and implicates it as a potential antitumor target of RA in RA-resistant cancer cells.

Amino Acid Sequence↗
PubMed2006

Protective effect of anthocyanins in middle cerebral artery occlusion and reperfusion model of cerebral ischemia in rats.

Ischemic stroke results from a transient or permanent reduction in cerebral blood flow that is restricted to the territory of a major brain artery. The major pathobiological mechanisms of ischemia/reperfusion injury include excitotoxicity, oxidative stress, inflammation, and apoptosis. In the present report, we first investigated the protective effects of anthocyanins against focal cerebral ischemic injury in rats. The pretreatment of anthocyanins (300 mg/kg, p.o.) significantly reduced the brain infarct volume and a number of TUNEL positive cells caused by middle cerebral artery occlusion and reperfusion. In the immunohistochemical observation, anthocyanins remarkably reduced a number of phospho-c-Jun N-terminal kinase (p-JNK) and p53 immunopositive cells in the infarct area. Moreover, Western blotting analysis indicated that anthocyanins suppressed the activation of JNK and up-regulation of p53. Thus, our data suggested that anthocyanins reduced neuronal damage induced by focal cerebral ischemia through blocking the JNK and p53 signaling pathway. These findings suggest that the consumption of anthocyanins may have the possibility of protective effect against neurological disorders such as brain ischemia.

Animals↗
PubMed2006

Electrophysiological safety of novel fluoroquinolone antibiotic agents gemifloxacin and balofloxacin.

Some fluoroquinolones have been reported to induce QT interval prolongation associated with the onset of torsades de pointes (TdP), resulting in a life-threatening ventricular arrhythmia. We investigated the cardiac electrophysiological effects of two new fluoroquinolones, gemifloxacin and balofloxacin, by using conventional microelectrode recording techniques in isolated rabbit Purkinje fiber and whole-cell patch-clamp techniques in human ether-á-go-go related gene (hERG)-transient transfected CHO cells. Gemifloxacin had no significant effects on the resting membrane potential, total amplitude, action potential, and Vmax of phase 0 depolarization at concentrations up to 30 microM, but gemifloxacin at 100 microM significantly decreased total amplitude (p < 0.01). These values of gemifloxacin (30 and 100 microM) were approximately 25- and 83-fold more than the free plasma concentration of 1.2 microM in a single therapeutic injection in humans. For I(hERG), the IC(50) value was about 300 microM. Balofloxacin had also no significant effects on the resting membrane potential, total amplitude, action potential duration, and Vmax of phase 0 depolarization at concentrations up to 30 microM, but balofloxacin at 100 microM significantly (p < 0.01) prolonged action potentials at both 50% repolarization (APD(50)) and 90% repolarization (APD(90)). These values of balofloxacin (30 and 100 microM) were approximately 6.8- and 23-fold more than the free plasma concentration of 4.4 microM in a single therapeutic injection in humans. For I(hERG), the IC(50) value was 214 +/- 14 microM. Therefore, our data suggested that in the electrophysiological aspect, gemifloxacin and balofloxacin may have no torsadogenic potenties up to 30 microM.

Action Potentials↗
PubMed2005

FHL2 mediates p53-induced transcriptional activation through a direct association with HIPK2.

To understand the molecular mechanism underlying HIPK2 regulation of the transcriptional activation by p53, we sought to identify the protein that interacts with HIPK2. From our yeast two-hybrid screen, we found that four and a half LIM domains 2 (FHL2) could bind to the C-terminal half of HIPK2. Further assays in yeast mapped the minimal interaction domain to amino acids 812-907 in HIPK2. The interaction was confirmed using a GST pull-down assay in vitro, and an immunoprecipitation (IP) assay and fluorescence microscopy in vivo. FHL2 alone spread throughout both the cytoplasm and nucleus but was redistributed to dot-like structures in the nucleus when HIPK2 was coexpressed in HEK293 cells. When tethered to the Gal4-responsive promoter through the Gal4 DBD fusion, FHL2 showed autonomous transcriptional activity that was enhanced by wild-type HIPK2, but not by the kinase-defective mutant. In addition, FHL2 increased the p53-dependent transcriptional activation and had an additive effect on the activation when coexpressed with HIPK2, which was again not observed with the kinase-defective mutant of HIPK2. Finally, we found a ternary complex of p53, HIPK2, and FHL2 using IP, and their recruitment to the p53-responsive p21Waf1 promoter in chromatin IP assays. Overall, our findings indicate that FHL2 can also regulate p53 via a direct association with HIPK2.

Binding Sites↗
PubMed2005

Micrographia on free writing versus copying tasks in idiopathic Parkinson's disease.

BACKGROUND: Only a few studies have reported on the frequency of micrographia in idiopathic Parkinson's disease (IPD), and the definition of micrographia in these studies was based simply on the visual inspection of the patients' free writing. OBJECTIVES: We investigated the frequency of consistent (CM) and progressive (PM) micrographia by quantifying the patients' copying of a target letter or figure. METHODS: Seventy-five IPD patients and 30 sex/age matched healthy controls were assigned the tasks of free writing and letter/figure copying. CM was defined by the average size of the letter or figure written or copied by the patients below the controls' mean-2SD. PM was defined by the slope of reduction in size as a function of the serial positioning of the letters/figures below the mean-2SD of the controls. RESULTS: In the free writing, of 75 patients, only one met the criteria for the definition of CM and two met the criteria for the definition of PM definition. In contrast, letter/figure copying tasks identified 33 (44%) patients with CM and 19 (25%) with PM. CONCLUSION: Our study suggests that the prior definition of CM or PM by visual inspection in free writing task is less valid, and that the definition of CM and PM, based on the letter/figure copying tasks rather than free writing tests, could be more objective.

Aged↗
PubMed2005

Left hemispatial visual neglect associated with a combined right occipital and splenial lesion: another disconnection syndrome.

Damage to the left occipital lobe and the splenium or forceps major is often associated with pure alexia, thought to be an occipital-temporoparietal disconnection syndrome. A patient with the parallel lesion, a combined right occipital and splenial lesion, showed severe left-sided visual spatial neglect, but no significant neglect in other sensory modalities. This visual neglect might be related to a disconnection between the visual information processed by the left occipital lobe and the right posterior temporal-inferior parietal areas that mediate attention in the left hemispace.

Aged↗
PubMed2005

The phenothiazine drugs inhibit hERG potassium channels.

Cardiovascular adverse effects from phenothiazine drugs are common. The most serious consequences of treatment, arrhythmias and sudden death, are probably rare and most likely to be caused primarily by blockade of cardiac potassium channels such as the human ether-a-go-go-related gene (hERG) channel, which plays a central role in arrhythmogenesis. This phenomenon has been previously reported to occur with a few phenothiazine drugs. However, phenothiazine drugs are composed of pharmacologically and structurally diverse groups. The effects of many of the phenothiazine drugs on hERG channels expressed in mammalian cell lines remain unknown. Therefore, we investigated the effects of four distinct phenothiazine drugs (thioridazine, chlorpromazine, trifluoperazine, and perphenazine) on hERG channel expressed in chinese hamster ovary (CHO) cells. HERG channels were expressed in CHO cells, and ion currents were measured using the patch-clamp technique. Thioridazine, perphenazine, trifluoperazine, and chlorpromazine blocked hERG potassium channels with the following IC(50) values: IC(50) values were 224 +/- 42 nM for thioridazine, 1003 +/- 71 nM for perphenazine, 1406 +/- 124 nM for trifluoperazine, and 1561 +/- 281 nM for chloropromazine. Inhibition of hERG channels by thioridazine was characterized by significant changes in voltage dependence, the value of V(1/2), the half-maximal activation potential, and shift into negative potential, that is, the amount of block was greater at more positive potential. No significant changes were noted in other drugs.

Animals↗
PubMed2005

Effects of combined treatment with sildenafil and itraconazole on the cardiovascular system in telemetered conscious dogs.

Sildenafil, a potent PDE5 inhibitor, is widely prescribed as a treatment of erectile dysfunction. Itraconazole is an inhibitor of CYP3A4, a metabolic enzyme of sildenafil. In the current study, we investigated the effects of single treatment with sildenafil and combined treatment with sildenafil and itraconazole on blood pressure, heart rate, and QT interval in conscious beagle dogs. After a transmitter was implanted to beagle dogs for conscious state experiments, a single oral dose of sildenafil was administered to the beagle dogs at dose levels of 3, 15, and 30 mg/kg. Blood pressure, heart rate, and lead II ECG were measured prior to dosing and at 0.5, 1, 2, 4, 6, and 24 h postdosing. In the study of combined treatment with sildenafil and itraconazole, the 100 mg/kg dose of itraconazole was orally administered 1 h prior to oral administration of sildenafil. No changes in blood pressure were observed at any doses in animals receiving either single treatment with sildenafil or combined treatment with sildenafil and itraconazole. Increased heart rate from 0.5 h to 6 h postdosing and decreased QT interval were observed in animals receiving single treatment with sildenafil at 15 or 30 mg/kg. When 30 mg/kg of sildenafil was coadministered with 100 mg/kg of itraconazole, drug-related effects such as increased heart rate and decreased QT interval were significantly enhanced as compared to sildenafil-alone administration at 6 h postadministration. These results demonstrated that increased heart rate and decreased QT interval, the adverse effects of sildenafil, were enhanced and prolonged when sildenafil was coadministered with itraconazole. Therefore, caution should be taken when sildenafil is coadministered with itraconazole, a CYP3A4 inhibitor, or when administered to elderly patients or patients with hepatic or renal impairment who cannot metabolize and excrete sildenafil normally.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2005

Electrophysiological safety of DW-286a, a novel fluoroquinolone antibiotic agent.

Inhibition of the potassium current I(Kr) and QT prolongation has been known to be associated with drug-induced torsades de pointes arrhythmias (TdP) and sudden cardiac death. We investigated the cardiac electrophysiological effects of DW-286a, a new class of fluoroquinolone antibiotics reported to prolong the QT interval. To investigate the electrophysiological safety of DW-286a, we used conventional microelectrode recording techniques in isolated guinea pig papillary muscles, whole-cell patch clamp techniques in human ether-à-go-go related gene (hERG)-transient transfected Chinese hamster ovary cells, and in vivo electrocardiogram (ECG) measurements in Sprague-Dawley (SD) rats by the use of a telemetry system. DW-286a at 300 microM significantly (P<0.01) prolonged action potentials at 50% repolarization (APD50) and 90% repolarization (APD90). For IHERG, the IC50 value was 89.00+/-37.85 microM with a Hill coefficient (nH) of -0.97+/-0.49. However, when DW-286a was orally administered to conscious SD rats at a high dose (1000 mg/kg), no significant effect on ECG in vivo was detected. From a previous study, we know that concentration at 19.8 microM is the antimicrobial end-point of DW-286a. Therefore, our data suggest that in the electrophysiological aspect, it can be thought that the effective concentrations of DW-286a are between 19.8 and 100 microM (concentration in serum).

Action Potentials↗
PubMed2005

Safety pharmacology of sibutramine mesylate, an anti-obesity drug.

Sibutramine mesylate is a new anti-obesity drug. It is a crystalline salt of sibutramine developed to improve the solubility of sibutramine hydrochloride. Methanesulfonic acid was used as a salt-forming acid instead of hydrochloric acid, resulting in a greatly improved solubility of 1000 mg/mL in water. Sibutramine mesylate was administered orally to ICR mice, Sprague-Dawley rats, and beagle dogs at dose levels of 1.15, 3.45, and 11.50 mg/kg to measure its effects on the central nervous system (CNS), general behaviour, cardiovascular-respiratory system and the other organ systems. Following administration of sibutramine mesylate, spontaneous locomotor activity was significantly increased from 120 min to 24 hours at 3.45 mg/kg and from 30 min to 24 hours at 11.50 mg/kg. Furthermore, there were a decrease in hexobarbital-induced sleep time, an increase in respiratory rate at 120 min, increases in intestinal transport capacity and gastric pH at 11.50 mg/kg, and decreases in gastric volume and total acidity at 3.45 and 11.50 mg/kg. However sibutramine mesylate caused no effects on general behaviour, motor coordination, body temperature, analgesia, convulsion, blood pressure, heart rate, electrocardiogram, cardiac functions of the isolated rat heart, isolated smooth muscles and renal function. Based on the above results, it was concluded that sibutramine mesylate caused effects on the spontaneous locomotor activity, hexobarbital-induced sleep time, respiration, gastrointestinal transport, and gastric secretion at a dose level of 3.45 mg/kg or greater but caused no effects on other general pharmacological reactions.

Administration, Oral↗
PubMed2005

General pharmacology of CKD-732, a new anticancer agent: effects on central nervous, cardiovascular, and respiratory system.

CKD-732 [6-O-(4-dimethylaminoethoxy) cinnamoyl fumagillol hemioxalate] is a new fumagillin anticancer drug that belongs to an angiogenesis inhibitor. Its effect on the central nervous system (CNS), general behavior, cardiovascular-respiratory system and the other organ systems were studied. CKD-732 was intravenously administered with the dosages of 10, 30, 40 or 50 mg/kg and the highest dosage of 50 mg/kg prolonged the hexobarbital-induced sleep time. CKD-732 at the dosage of 50 mg/kg, also, caused the decrease of body temperature from 15 to 120 min after the administration, which was recovered at 240 min. In the study of the effects on gastric secretion, CKD-732 induced the increase of pH and decrease of total acidity. However, CKD-732 showed no effect on general behavior, spontaneous locomotor activity, motor coordination, analgesia, convulsion, mean arterial pressure, and cardiac functions except for heart rate of isolated rat heart, respiration, isolated smooth muscle, intestinal charcoal transport and renal function. Based on the results, we suggested that CKD-732 is safe general pharmacologically at clinical supposed dose (1.75 mg/kg) and demonstrated to have much better safety than other fumagillin derivatives.

Animals↗
PubMed2004

IFI16 is an essential mediator of growth inhibition, but not differentiation, induced by the leukemia inhibitory factor/JAK/STAT pathway in medullary thyroid carcinoma cells.

Activation of Ras or Raf in the human medullary thyroid carcinoma (MTC) cell line, TT, induces growth arrest and differentiation via two parallel, yet independent, pathways. One of these pathways is intracellular and the other is a cell-extrinsic, autocrine/paracrine pathway mediated by the leukemia inhibitory factor (LIF)/JAK/STAT pathway. Here, we show that IFI16 is a necessary and sufficient downstream effector for LIF effects in MTC cells, specifically required for the LIF/JAK/STAT pathway-induced growth inhibition in these cells. IFI16 was induced by Raf or LIF. Dominant-negative STAT3 could block the induction, indicating that Raf can induce IFI16 only via the cell-extrinsic pathway. Knock-down of IFI16 using siRNA abrogated LIF-induced changes in cellular levels of E2F1, cyclin D1, and p21WAF/CIP1, and cell cycle arrest. In addition, adenovirus-mediated overexpression of IFI16 was sufficient to induce growth arrest. In contrast to its essential role for LIF-mediated growth arrest, IFI16 was not required for differentiation induced by LIF. Knock-down of IFI16 could not block changes in differentiation markers of the MTC cells, including calcitonin, RET, and cell morphology. Our study identifies IFI16 as an essential growth-specific effector of the cell-extrinsic growth inhibitory pathway of Ras/Raf signaling in MTC cells.

Adenoviridae↗
PubMed2004

Potent effect of 5-HPBR, a butanoate derivative of 4-HPR, on cell growth and apoptosis in cancer cells.

Fenretinide, 4-(N-hydroxyphenyl) retinamide (4-HPR), has demonstrated anticancer activity associated with a favorable toxicity profile and is now being investigated in several clinical trials. However, its plasma levels in patients have been far lower than the effective concentration required to induce apoptosis (usually 10 microM). This result has led to the synthesis of derivatives with better efficacy. Sodium butyrate's potential as an anticancer agent prompted us to synthesize a butanoate derivative of 4-HPR, 5-hydroxyphenyl butanoate retinamide (5-HPBR) and compare it to the parent compound for antitumor potential in vitro. The cytotoxicity of 5-HPBR was 2- to 6-fold greater than that of 4-HPR against cancer cell lines derived from various tissues. In premalignant bronchial cells (BEAS2B), 5-HPBR exhibited about a 10-fold stronger cytotoxicity than did 4-HPR. Normal CHANG liver cells were unaffected by either 4-HPR or 5-HPBR. Subsequent assays using DNA fragmentation, DAPI staining, FACS and Western blotting suggested that the potent inhibitory effect of 5-HPBR is mediated by apoptosis; the exact mechanism appears to differ among cancer cell types. In transcription assays with COS-1 cells, 5-HPBR selectively activated RARbeta and RARgamma but was a weaker ligand for all 3 subtypes of RAR than either all-trans retinoic acid or 4-HPR. Overall, these data suggest that 4-BHPR may be a promising retinoid with enhanced antitumor activity and reduced toxicity.

Animals↗
PubMed2004

Mechanism of the closing-in phenomenon in a figure copying task in Alzheimer's disease patients.

The"closing-in phenomenon"in figure copying tasks refers to a tendency to copy near the target, or to overlap the target to be copied. The mechanisms underlying the closing-in phenomenon have not been fully elucidated. We posit that closing-in may be related to the patients'compensatory strategies to overcome visuospatial dysfunction or visuospatial working memory deficit. Thus, it is expected that as the complexity of the target figure or the distance from the target to the copying space is increased, the magnitude of closing-in will be increased. Thirteen patients with Alzheimer's disease (AD) who demonstrated closing-in on a screening test and 15 healthy controls participated in this study. Each subject copied figures in conditions that varied in terms of figure complexity and distance from the target to the copying space. Neither figure complexity nor distance between the target and copying space affected the degree of closing-in in normal subjects. In contrast, in AD patients, the magnitude of closing-in increased as a function of figure complexity; however closing-in was unchanged by varying the distance from the target to the copying space. Our results suggest that copying near the target figure might be the patients'strategy to compensate for their visuospatial dysfunction or visuospatial working memory deficits.

Aged↗