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1.  A pediatric case of Bickerstaff's brainstem encephalitis 
Korean Journal of Pediatrics  2014;57(12):542-545.
Bickerstaff's brainstem encephalitis is characterized by ophthalmoplegia, ataxia, and disturbance of consciousness. It is similar to Miller Fisher syndrome, a variant of Guillain-Barre syndrome, in that they share features such as ophthalmoplegia and ataxia. The difference is that patients with Bickerstaff's brainstem encephalitis have impaired consciousness, whereas patients with Miller Fisher syndrome have alert consciousness and areflexia. Here, we report the case of a 3-year-old child who was diagnosed with Bickerstaff's brainstem encephalitis presenting typical clinical features and interesting radiological findings. The patient showed ophthalmoplegia, ataxia, and subsequent stuporous mentality. Brain magnetic resonance imaging revealed high signal intensity in the pons and cerebellum around the 4th ventricle on a T2-weighted image. He was successfully treated with intravenous immunoglobulin. Differentiation of Bickerstaff's brainstem encephalitis and Miller Fisher syndrome is often difficult because they possess many overlapping features. Brain magnetic resonance imaging may be helpful in diagnosing Bickerstaff's brainstem encephalitis, especially when lesions are definitely found.
PMCID: PMC4316599  PMID: 25653689
Encephalitis; Miller Fisher syndrome; Ophthalmoplegia; Ataxia
2.  Carbon Monoxide Protects against Hepatic Ischemia/Reperfusion Injury via ROS-Dependent Akt Signaling and Inhibition of Glycogen Synthase Kinase 3β 
Carbon monoxide (CO) may exert important roles in physiological and pathophysiological states through the regulation of cellular signaling pathways. CO can protect organ tissues from ischemia/reperfusion (I/R) injury by modulating intracellular redox status and by inhibiting inflammatory, apoptotic, and proliferative responses. However, the cellular mechanisms underlying the protective effects of CO in organ I/R injury remain incompletely understood. In this study, a murine model of hepatic warm I/R injury was employed to assess the role of glycogen synthase kinase-3 (GSK3) and phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathways in the protective effects of CO against inflammation and injury. Inhibition of GSK3 through the PI3K/Akt pathway played a crucial role in CO-mediated protection. CO treatment increased the phosphorylation of Akt and GSK3-beta (GSK3β) in the liver after I/R injury. Furthermore, administration of LY294002, an inhibitor of PI3K, compromised the protective effect of CO and decreased the level of phospho-GSK3β after I/R injury. These results suggest that CO protects against liver damage by maintaining GSK3β phosphorylation, which may be mediated by the PI3K/Akt signaling pathway. Our study provides additional support for the therapeutic potential of CO in organ injury and identifies GSK3β as a therapeutic target for CO in the amelioration of hepatic injury.
PMCID: PMC3880761  PMID: 24454979
3.  A Rare Case of Primary Hyperparathyroidism Associated with Primary Aldosteronism, Hürthle Cell Thyroid Cancer and Meningioma 
Journal of Korean Medical Science  2012;27(5):560-564.
Multiple endocrine neoplasia type 1 (MEN1) syndrome includes varying combinations of endocrine and non-endocrine tumors. There are also a considerable number of atypical MEN1 syndrome. In this case, a 68-yr-old woman was referred to the Department of Endocrinology for hypercalcemia. Five years ago, she had diagnosed as primary hyperaldosteronism and now newly diagnosed as parathyroid hyperplasia with laboratory and pathologic findings. Hürthle-cell thyroid cancer was also resected during the parathyroid exploration and small meningioma was found on brain MRI. Her general condition has markedly improved and her adrenal mass and meningioma are being closely observed now. We could find the loss of heterozygosity of the MEN1 locus in parathyroid glands, suggesting a MEN1-related tumor, but not a germline mutation. Considering a variety of phenotypic expression and a limitation of current molecular analysis, periodic follow up will be needed in patients with a MEN1-like phenotype.
PMCID: PMC3342551  PMID: 22563225
Hyperparathyroidism; Primary Hyperaldosteronism; Thyroid Cancer, Hürthle-cell; Meningioma
4.  Genetic and Epileptic Features in Rett Syndrome 
Yonsei Medical Journal  2012;53(3):495-500.
Rett syndrome is a severe neurodevelopmental disorder in females. Most have mutations in the methyl-CpG-binding protein 2 (MECP2) gene (80-90%). Epilepsy is a significant commonly accompanied feature in Rett syndrome. Our study was aimed at comprehensive analysis of genetic and clinical features in Rett syndrome patients, especially in regards to epileptic features.
Materials and Methods
We retrospectively reviewed 20 patients who were diagnosed with MECP2 mutations at Severance Children's Hospital between January 1995 and July 2010. All patients met clinical criteria for Rett syndrome. Evaluations included clinical features, epilepsy classification, electroencephalography analysis, and treatment of seizures.
Ages ranged from 3.6 to 14.3 years (7.7±2.6). Fourteen different types of MECP2 mutations were found, including a novel in-frame mutation (1153-1188 del36). Fourteen of these patients (70.0%) had epilepsy, and the average age of seizure onset was 3.0±1.8 years. Epilepsy was diverse, including partial seizure in four patients (28.5%), secondarily generalized seizure in six (42.8%), generalized tonic seizure in two (14.3%), Lennox-Gastaut syndrome in one (7.1%), and myoclonic status in non-progressive encephalopathy in one (7.1%). Motor functions were delayed so that only 10 patients (50.0%) were able to walk independently: five (35.8%) in the epilepsy group and five (83.3%) in the non-epilepsy group. Average developmental scale was 33.5±32.8 in the epilepsy group and 44.4±21.2 in the non-epilepsy group. A clear genotype-phenotype correlation was not found.
There is a tendency for more serious motor impairment and cognitive deterioration in Rett syndrome patients with epilepsy.
PMCID: PMC3343433  PMID: 22476991
Rett syndrome; epilepsy; MECP2 mutation
5.  Fracture Incidence and Risk of Osteoporosis in Female Type 2 Diabetic Patients in Korea 
Diabetes & Metabolism Journal  2012;36(2):144-150.
There are no published data regarding fracture risk in type 2 diabetic patients in Korea. In this study, we compared the fracture incidence and risk of osteoporosis of type 2 diabetic female patients with those in a non-diabetic hypertensive cohort.
The incidence of fracture in a type 2 diabetic cohort was compared with that in a non-diabetic hypertensive cohort over the course of 7 years. Female type 2 diabetic and non-diabetic hypertensive patients who visited Eulji General Hospital outpatient clinic from January 2004 to April 2004 were assigned to the diabetic cohort and the non-diabetic hypertensive cohort, respectively. Surveys on fracture event, use of anti-osteoporosis medications, and bone mineral density were performed.
The number of fractures was 88 in the female diabetic cohort (n=1,268, 60.6±11.5 years) and 57 in the female non-diabetic hypertensive cohort (n=1,014, 61.4±11.7 years). The RR in the diabetic cohort was 1.38 (P=0.064; 95% confidence interval [CI], 0.98 to 1.94) when adjusted for age. Diabetic patients with microvascular complications (61.0%) showed a higher RR of 1.81 (P=0.014; 95% CI, 1.13 to 2.92) compared with those without these complications. The prevalence of osteoporosis was comparable between the groups, while use of anti-osteoporosis medication was more common in the diabetic cohort (12.8%) than in the hypertensive cohort (4.5%) (P<0.001).
In our study, a higher fracture risk was observed in female type 2 diabetics with microvascular complications. Special concern for this risk group is warranted.
PMCID: PMC3335896  PMID: 22540051
Diabetes mellitus, type 2; Fracture; Osteoporosis
6.  Effect of Transdermal Estrogen Therapy on Bone Mineral Density in Postmenopausal Korean Women 
Journal of Menopausal Medicine  2014;20(3):111-117.
To evaluate the effects of transdermal estrogen therapy on bone mineral density (BMD) in postmenopausal Korean women.
A total of 149 healthy postmenopausal women were retrospectively evaluated: 100 were on hormone therapy (HT) and 49 were the control group. For the HT group, 54 applied estrogen transdermally using either a patch (n = 21) or gel (n = 33), and 46 took estrogen orally (conjugated estrogen 0.625 mg or equivalent). Demographic profiles and changes in BMD over two years were compared according to the route of the estrogen.
No differences were found in age, age at menopause, parity, body mass index, and type of menopause among the oral, transdermal and control groups. Compared with controls, HT significantly increased BMD after 2 years in both the lumbar spine and the total hip. The increases in BMD at both lumbar spine and hip were comparable between the oral and transdermal groups. There were also no differences in BMD changes according to progestogen addition in either the oral or transdermal groups.
Transdermal estrogen therapy increases BMD, comparable to oral estrogen, in postmenopausal Korean women.
PMCID: PMC4286655  PMID: 25580422
Administration cutaneous; Bone density; Hormone replacement therapy; Postmenopause
7.  Genetic, Cellular, and Functional Evidence for Ca2+ Inflow through Cav1.2 and Cav1.3 Channels in Murine Spiral Ganglion Neurons 
The Journal of Neuroscience  2014;34(21):7383-7393.
Spiral ganglion neurons (SGNs) of the eighth nerve serve as the bridge between hair cells and the cochlear nucleus. Hair cells use Cav1.3 as the primary channel for Ca2+ inflow to mediate transmitter release. In contrast, SGNs are equipped with multiple Ca2+ channels to mediate Ca2+-dependent functions. We examined directly the role of Cav1.3 channels in SGNs using Cav1.3-deficient mice (Cav1.3−/−). We revealed a surprising finding that SGNs functionally express the cardiac-specific Cav1.2, as well as neuronal Cav1.3 channels. We show that evoked action potentials recorded from SGNs show a significant decrease in the frequency of firing in Cav1.3−/− mice compared with wild-type (Cav1.3+/+) littermates. Although Cav1.3 is the designated L-type channel in neurons, whole-cell currents recorded in isolated SGNs from Cav1.3−/− mice showed a surprising remnant current with sensitivity toward the dihydropyridine (DHP) agonist and antagonist, and a depolarization shift in the voltage-dependent activation compared with that in the Cav1.3+/+ mice. Indeed, direct measurement of the elementary properties of Ca2+ channels, in Cav1.3+/+ neurons, confirmed the existence of two DHP-sensitive single-channel currents, with distinct open probabilities and conductances. We demonstrate that the DHP-sensitive current in Cav1.3−/− mice is derived from Cav1.2 channel activity, providing for the first time, to our knowledge, functional data for the expression of Cav1.2 currents in neurons. Finally, using shRNA gene knockdown methodology, and histological analyses of SGNs from Cav1.2+/− and Cav1.3+/− mice, we were able to establish the differential roles of Cav1.2 and Cav1.3 in SGNs.
PMCID: PMC4028507  PMID: 24849370
action potentials; calcium channels; deafness; hearing; neuronal degeneration; neuronal survival
8.  Mechanism of the pH-Induced Conformational Change in the Sensor Domain of the DraK Histidine Kinase via the E83, E105, and E107 Residues 
PLoS ONE  2014;9(9):e107168.
The DraR/DraK two-component system was found to be involved in the differential regulation of antibiotic biosynthesis in a medium-dependent manner; however, its function and signaling and sensing mechanisms remain unclear. Here, we describe the solution structure of the extracellular sensor domain of DraK and suggest a mechanism for the pH-dependent conformational change of the protein. The structure contains a mixed alpha-beta fold, adopting a fold similar to the ubiquitous sensor domain of histidine kinase. A biophysical study demonstrates that the E83, E105, and E107 residues have abnormally high pKa values and that they drive the pH-dependent conformational change for the extracellular sensor domain of DraK. We found that a triple mutant (E83L/E105L/E107A) is pH independent and mimics the low pH structure. An in vivo study showed that DraK is essential for the recovery of the pH of Streptomyces coelicolor growth medium after acid shock. Our findings suggest that the DraR/DraK two-component system plays an important role in the pH regulation of S. coelicolor growth medium. This study provides a foundation for the regulation and the production of secondary metabolites in Streptomyces.
PMCID: PMC4159317  PMID: 25203403
9.  Fecal calprotectin concentration in neonatal necrotizing enterocolitis 
Korean Journal of Pediatrics  2014;57(8):351-356.
Among the many factors associated with acute intestinal mucosal infection, numerous studies have proposed the usefulness of fecal calprotectin. The aim of this study was to evaluate the usefulness of fecal calprotectin in the diagnosis of necrotizing enterocolitis (NEC).
We collected 154 stool samples from 16 very low birth weight and premature newborns at the Konyang University Hospital neonatal intensive care unit or neonatal nursery. The stool samples were collected using the Calprest device, and the fecal calprotectin level was measured with the BÜHLMANN Calprotectin enzyme-linked immunosorbent assay kit.
Fecal calprotectin levels were significantly higher in the NEC group than in the non-NEC group (P=0.02). There was a significant positive linear relationship between the fecal calprotectin level and number of days after birth (P=0.00) in the gestational age <26 weeks group. There was a significant negative linear relationship between the calprotectin level and number of days after birth (P=0.03) in the gestational age ≥26 weeks and <30 weeks group. There was no difference in the calprotectin levels according to the type and method of feeding between the NEC and non-NEC groups.
Fecal calprotectin levels were significantly increased in premature infants with NEC. The fecal calprotectin test is a noninvasive, easy, and useful tool for the diagnosis of NEC.
PMCID: PMC4155179  PMID: 25210522
Necrotizing enterocolitis; Premature infant; Calprotectin; Fecal calprotectin
10.  Adenylyl Cyclase Subtype-Specific Compartmentalization: Differential Regulation of L-type Ca2+ Current in Ventricular Myocytes 
Circulation research  2013;112(12):1567-1576.
Adenylyl cyclase (AC) represents one of the principal molecules in the β-adrenergic receptor (βAR) signaling pathway, responsible for the conversion of ATP to the second messenger, cAMP. AC type 5 (ACV) and 6 (ACVI) are the two main isoforms in the heart. While highly homologous in sequence, these two proteins nevertheless play different roles during the development of heart failure. Caveolin-3 is a scaffolding protein, integrating many intracellular signaling molecules in specialized areas called caveolae. In cardiomyocytes, caveolin is predominantly located along invaginations of the cell membrane known as t-tubules.
We take advantage of ACV and ACVI knockout mouse models to test the hypothesis that there is distinct compartmentalization of these two isoforms in ventricular myocytes.
Methods and Results
We demonstrate that ACV and ACVI isoforms exhibit distinct subcellular localization. ACVI isoform is localized in the plasma membrane outside of the t-tubular region, and is responsible for β1AR signaling-mediated enhancement of the L-type Ca2+ current (ICa,L) in ventricular myocytes. In contrast, ACV isoform is localized mainly in the t-tubular region where its influence on ICa,L is restricted by phosphodiesterase (PDE). We further demonstrate that the interaction between caveolin-3 with ACV and PDE is responsible for the compartmentalization of ACV signaling.
Our results provide new insights into the compartmentalization of the two AC isoforms in the regulation of ICa,L in ventricular myocytes. Since caveolae are found in most mammalian cells, the mechanism of βAR and AC compartmentalization may also be important for βAR signaling in other cell types.
PMCID: PMC3751398  PMID: 23609114
Adenylyl cyclase type 5; adenylyl cyclase type 6; L-type Ca2+ current; ventricular myocytes; calcium channel; adrenergic receptor
11.  Precise Toxigenic Ablation of Intermediate Cells Abolishes the “Battery” of the Cochlear Duct 
The Journal of Neuroscience  2013;33(36):14601-14606.
The extracellular potential of excitable and nonexcitable cells with respect to ground is ∼0 mV. One of the known exceptions in mammals is the cochlear duct, where the potential is ∼80–100 mV, called the endocochlear potential (EP). The EP serves as the “battery” for transduction of sound, contributing toward the sensitivity of the auditory system. The stria vascularis (StV) of the cochlear duct is the station where the EP is generated, but the cell-specific roles in the StV are ill defined. Using the intermediate cell (IC)-specific tyrosinase promoter, under the control of diphtheria toxin (DT), we eliminated and/or halted differentiation of neural crest melanocytes after migration to the StV. The ensuing adult transgenic mice are profoundly deaf. Additionally, the EP was abolished. Expression of melanocyte early marker and Kir4.1 in ICs precedes the onset of pigment synthesis. Activation of DT leads to loss of ICs. Finally, in accord with the distinct embryology of retinal pigmented cells, transgenic mice with toxigenic ablation of neural crest-derived melanocytes have intact visual responses. We assert that the tyrosinase promoter is the distinct target for genetic manipulation of IC-specific genes.
PMCID: PMC3761058  PMID: 24005310
12.  Congenital muscular dystrophy type 1A with residual merosin expression 
Korean Journal of Pediatrics  2014;57(3):149-152.
Congenital muscular dystrophy type 1A (MDC1A) is an autosomal recessive disorder characterized by hypotonia, elevated serum creatine kinase level, delayed motor milestones, white matter changes observed by brain magnetic resonance imaging, and normal intelligence. A mutation in the laminin α2 (LAMA2) gene, located at 6q22-23, is a genetic cause of MDC1A. Patients have merosin (laminin α2)-deficient skeletal muscles. However, the degree of merosin expression ranges from total absence to partial reduction. Patients with residual merosin expression have more variable and milder phenotypes than those with absolute merosin deficiency. We observed a Korean girl with MDC1A with residual merosin expression. Clinical presentation of this patient was typical except for late onset of the disease and external capsule involvement. Immunohistochemical staining of muscle fibers including merosin, is important to evaluate patients with hypotonia, delayed motor development, and abnormal white matter changes.
PMCID: PMC4000761  PMID: 24778697
Merosin-deficient congenital muscular dystrophy; Laminin alpha2; Immunohistochemistry
13.  Tristetraprolin Mediates Anti-Inflammatory Effect of Carbon Monoxide against DSS-Induced Colitis 
PLoS ONE  2014;9(2):e88776.
Endogenous carbon monoxide (CO) exerts anti-inflammatory effects. Tristetraprolin (TTP) is known to destabilize pro-inflammatory transcripts. Here we found that exogenous CO enhanced the decay of TNF-α mRNA and suppressed TNF-α expression in LPS-activated macrophages from wild-type (WT) mice. However, TTP deficiency abrogated the effects of exogenous CO. While CO treatment prior to DSS administration in WT mice significantly reduced inflammatory cytokine levels and colitis, it failed to reduce the pro-inflammatory cytokine levels and colitis in TTP knockout (KO) mice. Our results demonstrate that TTP is a key factor mediating the anti-inflammatory action of CO in DSS-induced colitis.
PMCID: PMC3929600  PMID: 24586391
14.  Successful Treatment by Chemotherapy of Pineal Parenchymal Tumor with Intermediate Differentiation: A Case Report 
A 37-year-old male presented with a mass measuring 2.5 cm in size in the midbrain and obstructive hydrocephalus, which had manifested as a headache and dizziness. Magnetic resonance (MR) imaging of the brain showed intermediate enhancement on T1-weighted MR imaging and a high intensity of enhancement on T2-weighted MR. Neurosurgeons performed an occipital craniotomy with partial removal of the tumor and the postoperative diagnosis was a pineal parenchymal tumor with intermediate differentiation. He had undergone irradiation with 54 Gy of radiation on 27 fractions for removal of the remaining tumor approximately one month after surgery. However, in follow-up imaging performed four months after radiotherapy, a remnant mass in the superoposterior aspect of the midbrain was found to have extended to the hypothalamus and the third ventricle. He was treated with six cycles of procarbazine, lomustine, vincristine chemotherapy. At five months since the completion of chemotherapy, the brain MR imaging showed no evidence of any remaining tumor and he no longer displayed any of his initial symptoms.
PMCID: PMC3804738  PMID: 24155685
Pinealoma; Drug therapy; Radiotherapy; Surgery
15.  Post-hearing Ca2+ Currents and Their Roles in Shaping the Different Modes of Firing of Spiral Ganglion Neurons 
Whereas pre-hearing spiral ganglion neurons (SGNs) rely faithfully on outputs from spontaneously active developing hair cells, the electrical phenotypes of post-hearing neurons are shaped by distinct rapid and graded receptor potentials from hair cells. To date, technical difficulties in isolation of fragile post-hearing neurons from the rigid bony labyrinth of the inner ear have hindered analyses of the electrical phenotype of SGNs. Therefore, we have recently developed new strategies to isolate post-hearing mouse SGNs for functional analyses. Here, we describe the coarse and fine properties of Ca2+ currents, which sculpt the firing properties of post-hearing SGNs. Murine SGNs express multiple Ca2+ channel currents to confer diverse functions. We have demonstrated that suppression of Ca2+ currents results in significant hyperpolarization of the resting membrane potential (rmp) of basal SGNs, suggesting that Ca2+ influx primes rmp for excitation. In contrast, removal of external Ca2+ has modest effects on rmp of apical SGNs. The blockade of Ca2+ currents with a cocktail of specific blockers attenuates spontaneously active SGNs. Paradoxically, different subtypes of Ca2+ currents, such as R-type currents, may activate resting outward conductances since blockage of the current results in depolarization of rmp. In keeping with whole-cell current data, single channel records revealed multiple diverse Ca2+ channels in SGNs. Additionally, there were differential expressions of distinct Ca2+ current-densities in the apico-basal contour of the adult cochlea. This report provides invaluable insights into Ca2+-dependent processes in adult SGNs.
PMCID: PMC3535314  PMID: 23152615
Hearing; Development; Ca2+ channels; Voltage-dependent Ca2+ currents; and Spiral ganglion neurons
16.  Tumor suppressor p53 plays a key role in induction of both tristetraprolin and let-7 in human cancer cells 
Nucleic Acids Research  2013;41(11):5614-5625.
Tristetraprolin (TTP) and let-7 microRNA exhibit suppressive effects on cell growth through down-regulation of oncogenes. Both TTP and let-7 are often repressed in human cancers, thereby promoting oncogenesis by derepressing their target genes. However, the precise mechanism of this repression is unknown. We here demonstrate that p53 stimulated by the DNA-damaging agent doxorubicin (DOX) induced the expression of TTP in cancer cells. TTP in turn increased let-7 levels through down-regulation of Lin28a. Correspondingly, cancer cells with mutations or inhibition of p53 failed to induce the expression of both TTP and let-7 on treatment with DOX. Down-regulation of TTP by small interfering RNAs attenuated the inhibitory effect of DOX on let-7 expression and cell growth. Therefore, TTP provides an important link between p53 activation induced by DNA damage and let-7 biogenesis. These novel findings provide a mechanism for the widespread decrease in TTP and let-7 and chemoresistance observed in human cancers.
PMCID: PMC3675463  PMID: 23595149
17.  Pharmacogenetic Analysis of Pediatric Patients with Acute Lymphoblastic Leukemia: A Possible Association between Survival Rate and ITPA Polymorphism 
PLoS ONE  2012;7(9):e45558.
Genetic polymorphisms are important factors in the effects and toxicity of chemotherapeutics. To analyze the pharmacogenetic and ethnic differences in chemotherapeutics, major genes implicated in the treatment of acute lymphoblastic leukemia (ALL) were analyzed. Eighteen loci of 16 genes in 100 patients with ALL were analyzed. The distribution of variant alleles were CYP3A4*1B (0%), CYP3A5*3 (0%), GSTM1 (21%), GSTP1 (21%), GSTT1 (16%), MDR1 exon 21 (77%), MDR1 exon 26 (61%), MTHFR 677 (63%), MTHFR 1298 (29%), NR3C1 1088 (0%), RFC1 80 (68%), TPMT combined genotype (7%), VDR intron 8 (11%), VDR FokI (83%), TYMS enhancer repeat (22%) and ITPA 94 (30%). The frequencies of single nucleotide polymorphisms (SNPs) of 10 loci were statistically different from those in Western Caucasians. Dose percents (actual/planned dose) or toxicity of mercaptopurine and methotrexate were not related to any SNPs. Event free survival (EFS) rate was lower in ITPA variants, and ITPA 94 AC/AA variant genotypes were the only independent risk factor for lower EFS in multivariate analysis, which was a different pharmacogenetic implication from Western studies. This study is the first pharmacogenetic study in Korean pediatric ALL. Our result suggests that there are other possible pharmacogenetic factors besides TPMT or ITPA polymorphisms which influence the metabolism of mercaptopurine in Asian populations.
PMCID: PMC3454425  PMID: 23029095
18.  Anti-Breast Cancer Potential of SS5020, a Novel Benzopyran Antiestrogen 
Treatment with tamoxifen (TAM) increases the risk of developing endometrial cancer in women. The carcinogenic effect is thought to involve initiation and/or promotion resulting from DNA damage induced by TAM as well as its estrogenic action. To minimize this serious side-effect while increasing the anti-breast cancer potential, a new benzopyran antiestrogen, 2E-3-{4-[(7-hydroxy-2-oxo-3-phenyl-2H-chromen-4-yl)-methyl]-phenyl}-acrylic acid (SS5020), was synthesized. Unlike TAM, SS5020 exhibits no genotoxic activity to damage DNA. Furthermore, SS5020 does not present significant uterotrophic potential in rats; in contrast, the structurally related compounds, TAM, toremifene, raloxifene (RAL) and SP500263 all have uterotrophic activity. At the human equivalent molar dose of TAM (0.33 or 1.0 mg/kg), SS5020 had much stronger antitumor potential than those same antiestrogens against 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats. The growth of human MCF-7 breast cancer xenograft implanted into athymic nude mice was also effectively suppressed by SS5020. SS5020, lacking genotoxic and estrogenic actions, could be a safer and stronger antiestrogen alternative to TAM and RAL for breast cancer therapy and prevention.
PMCID: PMC3011858  PMID: 20824696
antiestrogen; breast cancer; antitumor; uterotrophic activity; DNA adduct
19.  CO/HO-1 Induces NQO-1 Expression via Nrf2 Activation 
Immune Network  2011;11(6):376-382.
Carbon monoxide (CO) is a cytoprotective and homeostatic molecule with important signaling capabilities in physiological and pathophysiological situations. CO protects cells/tissues from damage by free radicals or oxidative stress. NAD(P)H:quinone oxidoreductase (NQO1) is a highly inducible enzyme that is regulated by the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway, which is central to efficient detoxification of reactive metabolites and reactive oxygen species (ROS).
We generated NQO1 promoter construct. HepG2 cells were treated with CO Releasing Molecules-2 (CORM-2) or CO gas and the gene expressions were measured by RT-PCR, immunoblot, and luciferase assays.
CO induced expression of NQO1 in human hepatocarcinoma cell lines by activation of Nrf2. Exposure of HepG2 cells to CO resulted in significant induction of NQO1 in dose- and time-dependent manners. Analysis of the NQO1 promoter indicated that an antioxidant responsible element (ARE)-containing region was critical for the CO-induced Nrf2-dependent increase of NQO1 gene expression in HepG2 cells.
Our results suggest that CO-induced Nrf2 increases the expression of NQO1 which is well known to detoxify reactive metabolites and ROS.
PMCID: PMC3275707  PMID: 22346778
Carbon monoxide; Heme oxygenase-1; Nrf2; NQO1
20.  Acute treatment of hyperammonemia by continuous renal replacement therapy in a newborn patient with ornithine transcarbamylase deficiency 
Korean Journal of Pediatrics  2011;54(10):425-428.
Ornithine transcarbamylase (OTC) deficiency is well known as the most common inherited disorder of the urea cycle, and 1 of the most common causes of hyperammonemia in newborns. We experienced a case of a 3-day-old boy with OTC deficiency who appeared healthy in the first 2 days of life but developed lethargy and seizure soon afterwards. His serum ammonia level was measured as >1700 µg/dL (range, 0 to 45 µg/dL). Continuous renal replacement therapy (CRRT) in the mode of continuous venovenous hemodiafiltration was immediately applied to correct the raised ammonia level. No seizure occurred after the elevated ammonia level was reduced. Therefore, CRRT should be included as 1 of the treatment modalities for newborns with inborn errors of metabolism, especially hyperammonemia. Here, we report 1 case of successful treatment of hyperammonemia by CRRT in a neonate with OTC deficiency.
PMCID: PMC3250597  PMID: 22232626
Ornithine transcarbamylase deficiency; Hyperammonemia; Continuous renal replacement therapy; Infant; Newborn
21.  Determination of knockdown resistance allele frequencies in global human head louse populations using the serial invasive signal amplification reaction 
Pest management science  2010;66(9):1031-1040.
Pediculosis is the most prevalent parasitic infestation of humans. Resistance to pyrethrin- and pyrethroid-based pediculicides is due to knockdown (kdr)-type point mutations in the voltage-sensitive sodium channel α-subunit gene. Early detection of resistance is crucial for the selection of effective management strategies.
Kdr allele frequencies of lice from 14 countries were determined using serial invasive signal amplification reaction. Lice collected from Uruguay, UK and Australia had kdr allele frequencies of 100% while lice from Ecuador, Papua New Guinea, South Korea and Thailand had kdr allele frequencies of 0%. The remaining 7 countries investigated, including seven US populations, two Argentina, Brazil, Denmark, Czech Republic, Egypt and Israel, displayed variable kdr allele frequencies, ranging from 11% to 97%.
The newly developed and validated SISAR method is suitable for accurate monitoring of kdr allele frequencies in head lice. Proactive management is needed where kdr-type resistance is not yet saturated. Based on sodium channel insensitivity and its occurrence in louse populations resistant to pyrethrin- and pyrethroid-based pediculicides, the T917I mutation appears a key marker for resistance. Results from the Egyptian population, however, indicate that phenotypic resistance of lice with single or double mutations (M815I and/or L920F) should also be determined.
PMCID: PMC2926167  PMID: 20564731
genotyping; human head lice; kdr allele frequency; Pediculus humanus capitis; pyrethroid resistance; SISAR
22.  Equine estrogen-induced mammary tumors in rats 
Toxicology letters  2010;193(3):224-228.
Long-term hormone replacement therapy is associated with an increased risk of breast, ovarian and endometrial cancers in women. Equine estrogens are a principal component of hormone replacement therapy; however, their tumorigenic potential toward mammary tissue and reproductive organs has not been extensively explored. A pellet containing equilin was inserted under the skin of female ACI rats and the development of mammary tumors was monitored. Histological examination revealed premalignant lesions such as apocrine metaplasia in whole-mount preparations of mammary gland from the equilin-treated rats. ACI rats given 10 mg equilin developed palpable mammary tumors at 13 weeks of treatment, and 37.5% of the rats developed mammary tumors within 15 weeks. For 2.5 mg equilin, palpable tumors were observed in 8.3% of the rats after 8 weeks’ treatment; the frequency was lower than that (42.9%) observed with 2.5 mg E2. No tumors were observed in the untreated rats. Evidently, equilin is a mammary carcinogen, and this potential may be associated with development of breast and reproductive cancers in women receiving hormone replacement therapy.
PMCID: PMC2837116  PMID: 20096754
equine estrogen; mammary tumor; hormone replacement therapy; breast cancer
23.  Increasing Trend in the Number of Severe Hypoglycemia Patients in Korea 
Diabetes & Metabolism Journal  2011;35(2):166-172.
To investigate whether the number of subjects with severe hypoglycemia who are brought to a hospital emergency department is increasing and to identify whether there have been changes in the demographic and clinical characteristics of those subjects.
We analyzed data from the Emergency Departments of two general hospitals in Seoul, Korea. We included data from all adult subjects with type 2 diabetes who presented to an emergency department with severe hypoglycemia between January 1, 2004 and December 30, 2009.
A total of 740 cases of severe hypoglycemia were identified. The mean subject age was 69±12 years, mean duration of diabetes was 13.8±9.3 years, and 53.2% of subjects were receiving insulin therapy. We observed a sharp rise in the number of cases between 2006 and 2007. Stages 3-5 chronic kidney disease was diagnosed in 31.5% of subjects, and low C-peptide levels (<0.6 ng/mL) were found in 25.5%. The mean subject age, duration of diabetes, HbA1c level, and renal and insulin secretory function values did not change significantly during the study period. The proportion of glimepiride use increased, while use of gliclazide decreased among sulfonylurea users. Use of insulin analogues increased, while use of NPH/RI decreased among insulin users.
We identified a sharp increase in the number of subjects with severe hypoglycemia presenting to an emergency room since 2006. The clinical characteristics of these subjects did not change markedly during the study period. Nationwide studies are warranted to further clarify this epidemic of severe hypoglycemia.
PMCID: PMC3122892  PMID: 21738899
Emergency Department; Epidemiology; Severe hypoglycemia
24.  Interleukin-10 Prevents Diet-Induced Insulin Resistance by Attenuating Macrophage and Cytokine Response in Skeletal Muscle 
Diabetes  2009;58(11):2525-2535.
Insulin resistance is a major characteristic of type 2 diabetes and is causally associated with obesity. Inflammation plays an important role in obesity-associated insulin resistance, but the underlying mechanism remains unclear. Interleukin (IL)-10 is an anti-inflammatory cytokine with lower circulating levels in obese subjects, and acute treatment with IL-10 prevents lipid-induced insulin resistance. We examined the role of IL-10 in glucose homeostasis using transgenic mice with muscle-specific overexpression of IL-10 (MCK-IL10).
MCK-IL10 and wild-type mice were fed a high-fat diet (HFD) for 3 weeks, and insulin sensitivity was determined using hyperinsulinemic-euglycemic clamps in conscious mice. Biochemical and molecular analyses were performed in muscle to assess glucose metabolism, insulin signaling, and inflammatory responses.
MCK-IL10 mice developed with no obvious anomaly and showed increased whole-body insulin sensitivity. After 3 weeks of HFD, MCK-IL10 mice developed comparable obesity to wild-type littermates but remained insulin sensitive in skeletal muscle. This was mostly due to significant increases in glucose metabolism, insulin receptor substrate-1, and Akt activity in muscle. HFD increased macrophage-specific CD68 and F4/80 levels in wild-type muscle that was associated with marked increases in tumor necrosis factor-α, IL-6, and C-C motif chemokine receptor-2 levels. In contrast, MCK-IL10 mice were protected from diet-induced inflammatory response in muscle.
These results demonstrate that IL-10 increases insulin sensitivity and protects skeletal muscle from obesity-associated macrophage infiltration, increases in inflammatory cytokines, and their deleterious effects on insulin signaling and glucose metabolism. Our findings provide novel insights into the role of anti-inflammatory cytokine in the treatment of type 2 diabetes.
PMCID: PMC2768157  PMID: 19690064
25.  Biocompatible Polyhydroxyethylaspartamide-based Micelles with Gadolinium for MRI Contrast Agents 
Nanoscale Research Letters  2010;5(12):1970-1976.
Biocompatible poly-[N-(2-hydroxyethyl)-d,l-aspartamide]-methoxypoly(ethyleneglycol)-hexadecylamine (PHEA-mPEG-C16) conjugated with 1,4,7,10-tetraazacyclododecan-1,4,7,10-tetraacetic acid-gadolinium (DOTA-Gd) via ethylenediamine (ED) was synthesized as a magnetic resonance imaging (MRI) contrast agent. Amphiphilic PHEA-mPEG-C16-ED-DOTA-Gd forms micelle in aqueous solution. All the synthesized materials were characterized by proton nuclear magnetic resonance (1H NMR). Micelle size and shape were examined by dynamic light scattering (DLS) and atomic force microscopy (AFM). Micelles with PHEA-mPEG-C16-ED-DOTA-Gd showed higher relaxivities than the commercially available gadolinium contrast agent. Moreover, the signal intensity of a rabbit liver was effectively increased after intravenous injection of PHEA-mPEG-C16-ED-DOTA-Gd.
PMCID: PMC2991228  PMID: 21170410
MRI contrast agent; PHEA derivatives; Micelles; Nanoparticles; Gd contrast agent

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