Min Goo Lee

Yonsei University Hospital, Sŏul, Seoul, South Korea

Are you Min Goo Lee?

Claim your profile

Publications (223)1042 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Dysferlinopathy comprises a group of autosomal recessive muscular dystrophies caused by mutations in the DYSF gene. Due to the large size of the gene and its lack of mutational hot spots, analysis of the DYSF gene is time-consuming and laborious using conventional sequencing methods. By next-generation sequencing (NGS), DYSF gene analysis has previously been validated through its incorporation in multi-gene panels or exome analyses. However, individual validation of NGS approaches for DYSF gene has not been performed. Here, we established and validated a hybridization capture-based target-enrichment followed by next-generation sequencing to detect mutations in patients with dysferlinopathy. With this approach, mean depth of coverage was approximately 450 fold and almost all (99.3%) of the targeted region had sequence coverage greater than 20 fold. When this approach was tested on samples from patients with known DYSF mutations, all known mutations were correctly retrieved. Using this method on 32 consecutive patient samples with dysferlinopathy, at least two pathogenic variants were detected in 28 (87.5%) samples and at least one pathogenic variant was identified in all samples. Our results suggested that the NGS-based screening method could facilitate efficient and accurate genetic diagnosis of dysferlinopathy. Copyright © 2015 Elsevier B.V. All rights reserved.
    Neuromuscular Disorders 03/2015; DOI:10.1016/j.nmd.2015.03.006 · 3.13 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Anoctamin 6 (ANO6) is a member of the recently identified TMEM16/anoctamin protein family comprising Ca(2+)-activated Cl(-) channels that generate outward-rectifying ionic currents in response to intracellular Ca(2+) increase. ANO6 is also essential for Ca(2+)-dependent phospholipid scrambling required for blood coagulation. Selective serotonin reuptake inhibitors (SSRIs)-fluoxetine, sertraline, and paroxetine-that are used for the treatment of major depressive disorders can increase the risk of upper gastrointestinal bleeding after chronic treatment. However, at the earlier stage of intake, which is 1-7 days after the treatment, the possibility of blood coagulation might also increase, but transiently. Therefore, in this study, we investigated whether therapeutic SSRI concentrations affected the Cl(-) current or phospholipid scrambling activity of ANO6 by assessing ANO6 currents (I ANO6), phosphatidylserine (PS) exposure, and platelet aggregation. In the whole-cell patch mode, SSRIs facilitated Ca(2+)-dependent activation of IANO6 in ANO6-transfected cells, as evidenced by a significant decrease in the delay of IANO6 generation. On the other hand, in the inside-out patch clamp configuration, SSRIs showed an inhibitory effect on ANO6 currents, suggesting that SSRIs activate ANO6 via an indirect mechanism in intact cells. SSRIs also facilitated Ca(2+)-dependent PS exposure and α-thrombin-induced platelet aggregation. These results indicate that SSRIs at clinically relevant concentrations promote Ca(2+)-dependent activation of ANO6, which may have potential clinical implications such as the underlying mechanism of SSRI-induced adverse drug reactions.
  • Jinsei Jung, Min Goo Lee
    The Journal of General Physiology 01/2015; 145(1):75-7. DOI:10.1085/jgp.201411283 · 4.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: The goals of this study were to investigate the clinical activity, safety and biomarkers of dacomitinib, an irreversible tyrosine kinase inhibitor of EGFR, HER2 and HER4, in recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M-SCCHN). Experimental Design: Patients were eligible if the diseases were not amenable to curative treatment and had progressed on platinum-based chemotherapy, and were treated with dacomitinib 45mg/day. The primary endpoint was objective response rate by RECISTv1.1. Exploratory analysis included the characterization of somatic mutation, gene copy number, gene expression, p16INK4A expression by immunohistochemistry, and investigation of their relationship with clinical outcomes. Results: Forty-eight patients were evaluable for efficacy and toxicity. Ten patients (20.8%) had partial responses and 31 patients (65%) had stable diseases. The median progression-free survival (PFS) and overall survival (OS) were 3.9 months (95% CI, 2.9-5.0) and 6.6 months (95% CI, 5.4-10.3). Adverse events were mostly grade 1-2. Mutations in PI3K-pathway (PIK3CA, PTEN) and high expression of inflammatory cytokines (IL6, IL8, IL1A, IL1B, IL4, and TNF) were significantly associated with shorter PFS (2.9 v 4.9 months without mutations, P=0.013; 2.8 v 9.9 months with low expression, P=0.004). Those harboring PI3K-pathway mutations or high inflammatory cytokine expression had shorter median OS (6.1 v 12.5 months lacking PI3K-pathway mutations and with low inflammatory cytokine expression, P=0.005). Conclusions: Dacomitinib demonstrated clinical efficacy with manageable toxicity in platinum-failed R/M-SCCHN patients. Screening of PI3K-pathway mutation and inflammatory cytokine expression may help identify which R/M-SCCHN patients are likely to gain benefit from dacomitinib. Copyright © 2014, American Association for Cancer Research.
    Clinical Cancer Research 11/2014; DOI:10.1158/1078-0432.CCR-14-1756 · 8.19 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Molecular inversion probe (MIP)-based capture is a scalable and effective target-enrichment technology that can use synthetic single-stranded oligonucleotides as probes. Unlike the straightforward use of synthetic oligonucleotides for low-throughput target capture, high-throughput MIP capture has required laborious protocols to generate thousands of single-stranded probes from DNA microarray because of multiple enzymatic steps, gel purifications and extensive PCR amplifications. Here, we developed a simple and efficient microarray-based MIP preparation protocol using only one enzyme with double-stranded probes and improved target capture yields by designing probes with overlapping targets and unique barcodes. To test our strategy, we produced 11 510 microarray-based duplex MIPs (microDuMIPs) and captured 3554 exons of 228 genes in a HapMap genomic DNA sample (NA12878). Under our protocol, capture performance and precision of calling were compatible to conventional MIP capture methods, yet overlapping targets and unique barcodes allowed us to precisely genotype with as little as 50 ng of input genomic DNA without library preparation. microDuMIP method is simpler and cheaper, allowing broader applications and accurate target sequencing with a scalable number of targets. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.
    Nucleic Acids Research 11/2014; 43(5). DOI:10.1093/nar/gku1188 · 8.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Microglia are immune effector cells in the central nervous system that participate in tissue repair, inflammatory responses, and neuronal degeneration. The most important signaling factor in the differentiation of immune-active cells after stimulation is the sustained high calcium concentration in the cytosol, which is called store-operated calcium entry (SOCE). Recently, the molecular identity of the store-operated channel (SOC) has revealed that Orai1, Orai2, Orai3, Stim1, and Stim2 constitute the most of SOC. In this study, we demonstrate that Orai1- and Stim1-mediated SOC regulated the phagocytic activity and cytokine release of primary isolated murine microglia.RT-PCR analysis revealed that primary cultured microglia from neonatal ICR mouse brains had Orai1, Orai2, Orai3, and Stim1. To elucidate the role of SOCE in the immune functions of microglia, pharmacological inhibitors or knockdown with Orai1 or Stim1 siRNA was applied, and UDP-induced phagocytic activity and LPS-induced cytokine secretion activity were compared. The pharmacological inhibition and siRNA effect was verified by measuring thapsigargin (TG)-, ATP-, or UDP-activated SOCE Ca2 + influx and proper siRNA-mediated knockdown was verified by western blot analysis. UDP-induced phagocytic activity was inhibited by pharmacological inhibitors of SOCE, such as SKF96365 or 2-APB, and knockdown of Orai1 and Stim1. Cytokine secretion of TNF-α and IL-6 by LPS treatment was also inhibited by SKF96365 and knockdown of Orai1 and Stim1. Meanwhile, LPS stimulation-induced NF-κB activation was not altered, but NFAT1 activity was attenuated with Stim1 knockdown. These results indicate that SOCE, which was composed of Orais and Stim1, regulates UDP-induced phagocytosis and LPS-stimulated cytokine secretion in microglia.
    Cellular Signalling 11/2014; 27(1). DOI:10.1016/j.cellsig.2014.11.003 · 4.47 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Squamous metaplasia in airway epithelium is a pathological process arising from abnormal remodeling/repair responses to injury. Proteolytic maturation of many growth and differentiation factors involved in tissue remodeling is controlled by proprotein convertases (PCs). However, the role of these convertases in airway remodeling remains poorly understood. Using a retinoic acid deficiency-induced squamous metaplasia model of cultured human nasal epithelial cells (HNECs), we observed a significant increase in the expression of PC5/6A, a PC member, and bone morphogenetic protein-2 (BMP-2), a candidate substrate for PC5/6A. Specific lentiviral shRNA-mediated PC5/6A knockdown decreased BMP-2 expression and maturation, decreased expression of squamous cell markers, and increased expression of ciliated cell markers. Dec-RVKR-CMK, a PC inhibitor, and LDN-193189, a BMP receptor inhibitor, suppressed squamous differentiation, promoted mucociliary differentiation, and down-regulated the BMP-2/Smad1/5/8/p38 signaling pathways. Dec-RVKR-CMK also decreased expression of PC5/6A, but not furin, another PC member, suggesting the involvement of PC5/6A in squamous differentiation of HNECs. Overexpression of PC5/6A and BMP-2 in the human nasal epithelial cell line RPMI-2650 demonstrated that PC5/6A can activate BMP-2. Under retinoic acid-sufficient culture conditions for mucociliary differentiation of HNECs, short-term expression of PC5/6A by the adenovirus system and addition of exogenous BMP-2 induced squamous differentiation. Furthermore, PC5/6A and BMP-2 were highly expressed in metaplastic squamous epithelium of human nasal polyps. Taken together, PC5/6A is involved in squamous differentiation of HNECs, possibly through up-regulation of the BMP-2/pSmad1/5/8/p38 signaling pathway, pointing to a potential therapeutic target for the prevention of chronic airway diseases that exhibit squamous metaplasia.
    American Journal of Respiratory Cell and Molecular Biology 10/2014; DOI:10.1165/rcmb.2014-0029OC · 4.11 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objectives: Our study aimed to identify the association of norepinephrine transporter gene (SLC6A2), synaptosomal-associated protein of the 25-kDa gene (SNAP-25), and latrophilin 3 gene (LPHN3) with osmotic-controlled release oral delivery system methylphenidate (OROS MPH) treatment response. Methods: One hundred thirty-nine children and adolescents with attention-deficit/hyperactivity disorder (ADHD) were recruited. We selected rs192303, rs3785143 in SLC6A2; rs3746544 (1065 T>G) in SNAP-25; and rs6551665, rs1947274, and rs2345039 in LPHN3 to examine the association of OROS MPH treatment response with each single nucleotide polymorphism. We first defined good response group when the Korean version of the ADHD rating scale score at 8 weeks was decreased for more than 50% of baseline scores and compared genotype frequencies in good response group with poor group. Second, we defined it when the Clinical Global Impression-Improvement score at 8 weeks was 1 or 2, and we also analyzed the genotype frequencies. Results: There was a significant association between the 1065 T>G of SNAP-25 gene and OROS MPH response, with the good response group defined by the Korean version of ADHD rating scale scores; 33.3% of the subjects with GG genotype showed a good response, whereas 74.7% of those with TT genotype and 72.5% of those with TG genotype showed good responses (P=0.034). SLC6A2 rs192303 was related with OROS MPH treatment response when we defined good treatment response by Clinical Global Impression-Improvement (P=0.009). Conclusions: Our study suggested that SNAP-25 gene and SLC6A2 were involved with OROS MPH response.
    Clinical Neuropharmacology 09/2014; 37(5):136-141. DOI:10.1097/WNF.0000000000000045 · 1.84 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: CFTR is a dynamically regulated anion channel. Intracellular WNK1-SPAK activation causes CFTR to change permeability and conductance characteristics from a chloride-preferring to bicarbonate-preferring channel through unknown mechanisms. Two severe CFTR mutations (CFTRsev) cause complete loss of CFTR function and result in cystic fibrosis (CF), a severe genetic disorder affecting sweat glands, nasal sinuses, lungs, pancreas, liver, intestines, and male reproductive system. We hypothesize that those CFTR mutations that disrupt the WNK1-SPAK activation mechanisms cause a selective, bicarbonate defect in channel function (CFTRBD) affecting organs that utilize CFTR for bicarbonate secretion (e.g. the pancreas, nasal sinus, vas deferens) but do not cause typical CF. To understand the structural and functional requirements of the CFTR bicarbonate-preferring channel, we (a) screened 984 well-phenotyped pancreatitis cases for candidate CFTRBD mutations from among 81 previously described CFTR variants; (b) conducted electrophysiology studies on clones of variants found in pancreatitis but not CF; (c) computationally constructed a new, complete structural model of CFTR for molecular dynamics simulation of wild-type and mutant variants; and (d) tested the newly defined CFTRBD variants for disease in non-pancreas organs utilizing CFTR for bicarbonate secretion. Nine variants (CFTR R74Q, R75Q, R117H, R170H, L967S, L997F, D1152H, S1235R, and D1270N) not associated with typical CF were associated with pancreatitis (OR 1.5, p = 0.002). Clones expressed in HEK 293T cells had normal chloride but not bicarbonate permeability and conductance with WNK1-SPAK activation. Molecular dynamics simulations suggest physical restriction of the CFTR channel and altered dynamic channel regulation. Comparing pancreatitis patients and controls, CFTRBD increased risk for rhinosinusitis (OR 2.3, p<0.005) and male infertility (OR 395, p<0.0001). WNK1-SPAK pathway-activated increases in CFTR bicarbonate permeability are altered by CFTRBD variants through multiple mechanisms. CFTRBD variants are associated with clinically significant disorders of the pancreas, sinuses, and male reproductive system.
    PLoS Genetics 07/2014; 10(7):e1004376. DOI:10.1371/journal.pgen.1004376 · 8.17 Impact Factor
  • Source
    Jinsei Jung, Min Goo Lee
    [Show abstract] [Hide abstract]
    ABSTRACT: Transepithelial bicarbonate secretion plays a key role in the maintenance of fluid and protein secretion from epithelial cells and the protection of the epithelial cell surface from various pathogens. Epithelial bicarbonate secretion is mainly under the control of cAMP and calcium signaling. While the physiological roles and molecular mechanisms of cAMP-induced bicarbonate secretion are relatively well defined, those induced by calcium signaling remain poorly understood in most epithelia. The present review summarizes the current status of knowledge on the role of calcium signaling in epithelial bicarbonate secretion. Specifically, this review introduces how cytosolic calcium signaling can increase bicarbonate secretion by regulating membrane transport proteins and how it synergizes with cAMP-induced mechanisms in epithelial cells. In addition, tissue-specific variations in the pancreas, salivary glands, intestines, bile ducts, and airways are discussed. We hope that the present report will stimulate further research into this important topic. These studies will provide the basis for future medicines for a wide spectrum of epithelial disorders including cystic fibrosis, Sjögren's syndrome, and chronic pancreatitis.
    Cell calcium 06/2014; DOI:10.1016/j.ceca.2014.02.002 · 4.21 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Lung adenocarcinoma is a highly heterogeneous disease with various etiologies, prognoses, and responses to therapy. Although genome-scale characterization of lung adenocarcinoma has been performed, a comprehensive somatic mutation analysis of EGFR/KRAS/ALK-negative lung adenocarcinoma in never-smokers has not been conducted. We analyzed whole exome sequencing data from 16 EGFR/KRAS/ALK-negative lung adenocarcinomas and additional 54 tumors in two expansion cohort sets. Candidate loci were validated by target capture and Sanger sequencing. Gene set analysis was performed using Ingenuity Pathway Analysis (IPA). We identified 27 genes potentially implicated in the pathogenesis of lung adenocarcinoma. These included targetable genes involved in PI3K/mTOR signaling (TSC1, PIK3CA, AKT2) and receptor tyrosine kinase signaling (ERBB4) and genes not previously highlighted in lung adenocarcinomas, such as SETD2 and PBRM1 (chromatin remodeling), CHEK2 and CDC27 (cell cycle), CUL3 and SOD2 (oxidative stress), and CSMD3 and TFG (immune response). In the expansion cohort (N = 70), TP53 was the most frequently altered gene (11%), followed by SETD2 (6%), CSMD3 (6%), ERBB2 (6%), and CDH10 (4%). In pathway analysis, the majority of altered genes were involved in cell cycle/DNA repair (P < 0.001) and cAMP-dependent protein kinase signaling (P < 0.001). The genomic makeup of EGFR/KRAS/ALK-negative lung adenocarcinomas in never-smokers is remarkably diverse. Genes involved in cell cycle regulation/DNA repair are implicated in tumorigenesis and represent potential therapeutic targets.
    Genome Medicine 02/2014; 6(2):18. DOI:10.1186/gm535 · 4.94 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Shank2 is a PDZ-based adaptor that has been suggested to regulate membrane transporting proteins in the brain and epithelial tissues. Here, we report that Shank2-mutant (Shank2-/-) mice exhibit aberrant fluid and ion transport in the intestine. Molecular characterization using epithelial tissues from Shank2+/+ and Shank2-/- mice revealed that a long spliceoform of Shank2 (Shank2E) is predominantly expressed in the pancreatic, renal, and intestinal epithelia. In functional assays, deletion of Shank2 increased the cystic fibrosis transmembrane conductance regulator (CFTR)-dependent short-circuit currents by 84% (P < 0.05) and 101% (P < 0.05) in the mouse colon and rectum, respectively. Disruption of the CFTR-Shank2-phosphodiesterase 4D protein complex appeared to be mostly responsible for the changes in the CFTR activities. Notably, Shank2 deletion profoundly increased cholera toxin-induced fluid accumulation in the mouse intestine (~90%, P < 0.01). Analyses with chemical inhibitors confirmed that the hyperactivation of CFTR channel function is responsible for the increased response to cholera toxin. These results suggest that Shank2 is a key molecule that participates in epithelial homeostasis, in particular to prevent overt secretory responses caused by epithelial pathogens.
    The Journal of Physiology 01/2014; DOI:10.1113/jphysiol.2013.268631 · 4.54 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Na(+)/H(+) exchanger regulatory factor 3 (NHERF3) is a PSD-95/discs large/ZO-1 (PDZ)-based adaptor protein that regulates several membrane-transporting proteins in epithelia. However, the in vivo physiologic role of NHERF3 in transepithelial transport remains poorly understood. Multidrug resistance protein 4 (MRP4) is an ATP binding cassette transporter that mediates the efflux of organic molecules, such as nucleoside analogs, in the gastrointestinal and renal epithelia. Here, we report that Nherf3 knockout (Nherf3(-/-)) mice exhibit profound reductions in Mrp4 expression and Mrp4-mediated drug transport in the kidney. A search for the binding partners of the COOH-terminal PDZ binding motif of MRP4 among several epithelial PDZ proteins indicated that MRP4 associated most strongly with NHERF3. When expressed in HEK293 cells, NHERF3 increased membrane expression of MRP4 by reducing internalization of cell surface MRP4 and consequently, augmented MRP4-mediated efflux of adefovir, a nucleoside-based antiviral agent and well known substrate of MRP4. Examination of wild-type and Nherf3(-/-) mice revealed that Nherf3 is most abundantly expressed in the kidney and has a prominent role in modulating Mrp4 levels. Deletion of Nherf3 in mice caused a profound reduction in Mrp4 expression at the apical membrane of renal proximal tubules and evoked a significant increase in the plasma and kidney concentrations of adefovir, with a corresponding decrease in the systemic clearance of this drug. These results suggest that NHERF3 is a key regulator of organic transport in the kidney, particularly MRP4-mediated clearance of drug molecules.
    Journal of the American Society of Nephrology 01/2014; 25(4). DOI:10.1681/ASN.2013040438 · 9.47 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Na(+)/H(+) exchanger-1 (NHE-1) activity is known to play a critical role in the neuronal injury caused by glutamate. However, the underlying mechanism is not clear. This study shows that NHE-1 activation and its phosphorylation during glutamate exposure were attenuated by the inhibition of protein kinase C (PKC)-βI and -βII, leading to reduced neuronal death. In addition, activations of PKC-βI and -βII by PKC-βI and -βII CAT plasmid or by PMA, PKC-β pharmacological activator stimulated the activity and phosphorylation of NHE-1, which were abolished by inhibition of PKC-β in neuronal cells. Furthermore, the inhibition of PKC-β mediated neuroprotective effect on glutamate-induced cells, which is similar to neuroprotective efficacy of siRNA NHE-1 transfection. Taken together, these results suggest that activation of the PKC-βI and -βII pathway by glutamate increases the activity and phosphorylation of NHE-1, and that these increases contribute to neuronal cell death. In this study, we demonstrate that PKC-βI and -βII are involved in the regulation of NHE-1 activation following glutamate exposure in neuron.
    Cellular Signalling 12/2013; DOI:10.1016/j.cellsig.2013.12.011 · 4.47 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The multidrug resistance protein 2 (MRP2, ABCC2) gene may determine individual susceptibility to adverse drug reactions (ADRs) in the central nervous system (CNS) by limiting brain access of antiepileptic drugs, especially valproic acid (VPA). Our objective was to investigate the effect of ABCC2 polymorphisms on ADRs caused by VPA in Korean epileptic patients. We examined the association of ABCC2 single-nucleotide polymorphisms and haplotype frequencies with VPA related to adverse reactions. In addition, the association of the polymorphisms with the risk of VPA related to adverse reactions was estimated by logistic regression analysis. A total of 41 (24.4%) patients had shown VPA-related adverse reactions in CNS, and the most frequent symptom was tremor (78.0%). The patients with CNS ADRs were more likely to have the G allele (79.3% vs. 62.7%, p = 0.0057) and the GG genotype (61.0% vs. 39.7%, p = 0.019) at the g.-1774delG locus. The frequency of the haplotype containing g.-1774Gdel was significantly lower in the patients with CNS ADRs than without CNS ADRs (15.8% vs. 32.3%, p = 0.0039). Lastly, in the multivariate logistic regression analysis, the presence of the GG genotype at the g.-1774delG locus was identified as a stronger risk factor for VPA related to ADRs (odds ratio, 8.53; 95% confidence interval, 1.04 to 70.17). We demonstrated that ABCC2 polymorphisms may influence VPA-related ADRs. The results above suggest the possible usefulness of ABCC2 gene polymorphisms as a marker for predicting response to VPA-related ADRs.
    12/2013; 11(4):254-62. DOI:10.5808/GI.2013.11.4.254
  • [Show abstract] [Hide abstract]
    ABSTRACT: A new leucine-rich glioma-inactivated 1 gene (LGI1) mutation inducing an amino acid sequence substitution was found in a Korean family with autosomal dominant lateral temporal lobe epilepsy (ADLTE). We report the clinical features and characteristics of this newly identified LGI1 mutation. Clinical data were collected from a large ADLTE family. All exons and flanking regions of the LGI1 gene were directly sequenced. 243 healthy controls were screened for the putative mutation. The 'Sorting Tolerant From Intolerant' algorithm was employed for the prediction of mutated LGI1 protein stability. LGI1 protein secretion was confirmed in vitro by immunoblotting assay. The main clinical characteristics included a young age at onset (mean, 12.4 years), diverse phenotypic manifestations, the occurrence of generalized tonic-clonic seizures, and a favorable prognosis. The genetic analysis detected a nonsynonymous single nucleotide polymorphism of c.137G>T coding for p.C46F in the five affected family members. This variant was not found in the normal control population and one unaffected family member. All the amino acids substituted for cysteine at position 46 of the LGI1 protein were predicted to damage protein stability in in silico analysis. Mutated C46F protein was retained within the cell at the immunoblotting assay. We identified a new LGI1 mutation in a large Korean ADLTE family which appeared to be involved in the development of epilepsy through suppressing LGI1 protein secretion.
    Seizure 10/2013; 23(1). DOI:10.1016/j.seizure.2013.10.001 · 2.06 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We sought to determine the hepatic fibrosis-reversal effects upon simultaneous administration of lithospermate B (LAB), an anti-oxidant, and nivocasan, a caspase inhibitor, to rats compared with each compound alone. Liver fibrosis was induced in Sprague-Dawley rats by thioacetamide (TAA). Rats were treated with TAA and then given LAB and (or) nivocasan. Fibrotic areas were evaluated quantitatively by computerized morphometry. Apoptosis was assessed using a TUNEL assay, and immunohistochemical staining for malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4HNE) was performed to assess oxidative stress levels. Real-time quantitative PCR was used to quantify expression of fibrosis-related genes. The degree of hepatic fibrosis was significantly reduced in rats treated with LAB and nivocasan compared to either treatment alone (P < 0.001). Treatment with each compound significantly decreased expression of fibrosis-related genes, such as type I collagen α1 (col1α1), α-SMA and TGF-β1 (P < 0.05). Co-treatment with LAB and nivocasan further reduced col1α1 expression compared to treatment with either compound. A TUNEL assay revealed that hepatocyte apoptosis was significantly decreased in the group treated with nivocasan compared to other groups (P < 0.01). Immunohistochemistry showed a decrease in MDA and 4HNE, reflecting amelioration of oxidative stress, when LAB or LAB+nivocasan was administered compared to nivocasan alone (P < 0.01). Nivocasan was found to inhibit caspase-1, -3, -7, -9 and gliotoxin-induced death of rat-derived hepatic stellate cells was inhibited by nivocasan administration without overexpression of α-SMA. Conclusions: Co-incidental administration of LAB and nivocasan suppressed oxidative stress and apoptosis, resulting in enhanced reversal of hepatic fibrosis in rat.
    Apoptosis 09/2013; DOI:10.1007/s10495-013-0896-5 · 3.61 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: WNK4, a serine/threonine kinase, plays a critical role in expression of membrane proteins in cell surface; however, the underlying mechanism of WNK4 is not clear. Here, we demonstrate that WNK4 inhibits the fusion of plasma membrane delivering vesicle with sorting/recycling endosome through disrupting SNARE formation of syntaxin13, an endosomal t-SNARE and VAMP2, the v-SNARE in plasma membrane delivering vesicle. Their interaction and co-localization was enhanced by hyperosmotic stimulation which is known for WNK4 activation. Kinase domain of WNK4 interacts with the transmembrane domain (TM) of syntaxin13 and this interaction was abolished when the TM was replaced with that of syntaxin16. Interestingly, cell fractionation using sucrose gradients revealed that WNK4 inhibited the formation of the syntaxin13/VAMP2 SNARE complex in endosomal compartment, but not syntaxin16/VAMP2 or syntaxin13/VAMP7. Syntaxin13 was not phosphorylated by WNK4 and WNK4(KI) also possessed binding and inhibiting in syntaxin13-SNARE complex regulation. Physiological relevance of this mechanism was proved with expression of NCC (Na(+) C1(-) co-transporter) in cell surface. The inhibiting activity of WNK4 on surface expression of NCC was abolished by syntaxin13 siRNA transfection. These results suggest that WNK4 attenuates PM targeting of NCC proteins through regulation of syntaxin13 SNARE complex formation with VAMP2 in recycling and sorting endosome.
    Cellular Signalling 08/2013; DOI:10.1016/j.cellsig.2013.08.006 · 4.47 Impact Factor
  • Shin Hye Noh, Heon Yung Gee, Min Goo Lee
    Pancreatology 07/2013; 13(4):S18. DOI:10.1016/j.pan.2013.07.111 · 2.50 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: ABSTRACTA mouse model of polymicrobial sepsis induced by cecal content injection (CCI) was developed with the aim of gaining a better understanding of the mechanism of sepsis. This model has a similar survival pattern to the conventional model with the added benefits of ability to vary the severity of sepsis and greater consistency. Administration of 1‐methyl‐D‐tryptophan (1‐MT) to inhibit indoleamine 2,3‐dioxygenase (IDO) in mice with CCI‐induced sepsis increased the survival rate and tended to up‐regulate IL‐10/IL‐12 serum concentrations. The effectiveness of 1‐MT was confirmed by increases in IL‐10 over IL‐12 in bone marrow‐derived dendritic cells (BMDCs) treated with LPS and 1‐MT and a superior survival rate 24 hr after injection of these double treated BMDCs in the CCI‐induced sepsis model. Therefore, CCI is both a useful and reliable technique for investigating polymicrobial sepsis. The present findings using this newly developed model suggest that inhibition of IDO alleviates the severity of polymicrobial sepsis and modulates the immune response even in cases of severe systemic septic inflammation.
    Microbiology and Immunology 07/2013; 57(9). · 1.31 Impact Factor

Publication Stats

3k Citations
1,042.00 Total Impact Points


  • 2001–2015
    • Yonsei University Hospital
      • Department of Internal Medicine
      Sŏul, Seoul, South Korea
  • 1997–2014
    • Yonsei University
      • • Department of Pharmacology
      • • Institute of Gastroenterology
      • • Department of Otorhinolaryngology
      Sŏul, Seoul, South Korea
    • University of Texas at Dallas
      Richardson, Texas, United States
  • 2013
    • CHA University
      • School of Medicine
      Sŏul, Seoul, South Korea
  • 2009–2013
    • Chonnam National University
      • • Department of Cardiology
      • • Department of Internal Medicine
      Gwangju, Gwangju, South Korea
  • 2010–2012
    • Chonnam National University Hospital
      Sŏul, Seoul, South Korea
  • 2011
    • Chung-Ang University Hospital
      Sŏul, Seoul, South Korea
  • 2000–2009
    • Korea University
      • • Department of Physiology
      • • Department of Biology
      Sŏul, Seoul, South Korea
  • 2007
    • University of Cincinnati
      Cincinnati, Ohio, United States
    • Stanford University
      • Department of Obstetrics and Gynecology
      Palo Alto, California, United States
  • 1999–2004
    • University of Texas Southwestern Medical Center
      • Department of Physiology
      Dallas, TX, United States