Publications by authors named "Incheol Seo"

13 Publications

  • Page 1 of 1

Melatonin ameliorates SGLT2 inhibitor-induced diabetic ketoacidosis by inhibiting lipolysis and hepatic ketogenesis in type 2 diabetic mice.

J Pineal Res 2020 Mar 6;68(2):e12623. Epub 2019 Dec 6.

Division of Endocrinology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are effective hypoglycemic agents that can induce glycosuria. However, there are increasing concerns that they might induce diabetic ketoacidosis. This study investigated the effect of melatonin on SGTL2i-induced ketoacidosis in insulin-deficient type 2 diabetic (T2D) mice. The SGLT2i dapagliflozin reduced blood glucose level and plasma insulin concentrations in T2D mice, but induced increases in the concentrations of plasma β-hydroxybutyrate, acetoacetate, and free fatty acid and a decrease in the concentration of plasma bicarbonate, resulting in ketoacidosis. Melatonin inhibited dapagliflozin-induced ketoacidosis without inducing any change in blood glucose level or plasma insulin concentration. In white adipose tissue, melatonin inhibited lipolysis and downregulated phosphorylation of PKA, HSL, and perilipin-1. In liver tissue, melatonin suppressed cellular cyclic AMP levels and downregulated phosphorylation of PKA, AMPK, and acetyl-CoA carboxylase (ACC). In addition, melatonin increased hepatic ACC activity, but decreased hepatic CPT1a activity and acetyl-CoA content. These effects of melatonin on lipolysis and hepatic ketogenesis were blocked by pretreatment with melatonin receptor antagonist or PKA activator. Collectively, these results suggest that melatonin can ameliorate SGLT2i-induced ketoacidosis by inhibiting lipolysis and hepatic ketogenesis though cyclic AMP/PKA signaling pathways in T2D mice. Thus, melatonin treatment may offer protection against SGLT2i-induced ketoacidosis.
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http://dx.doi.org/10.1111/jpi.12623DOI Listing
March 2020

Predicting transgenic markers of a neuron by electrophysiological properties using machine learning.

Brain Res Bull 2019 08 21;150:102-110. Epub 2019 May 21.

Department of Anatomy, Keimyung University School of Medicine, Daegu, Republic of Korea. Electronic address:

The task of classifying and identifying neurons, the essential components of the nervous system, has been undertaken in a variety of ways. The transcriptomic approach has become more accessible with the development of genetic engineering techniques. Considering the information processing function of the brain, however, it is necessary to consider the physiological characteristics of neurons. Recently, the Allen Institute for Brain Science has published the electrophysiological characteristics of neurons which were tagged with a transgenic reporter. We used these electrophysiological features to predict the transgenic markers of neurons. Using linear regression, random forest, and an artificial neural network, we assessed the performance of supervised machine learning models by comparing the prediction accuracy or the confusion matrix. As a result, in the binary classification problem of classifying excitatory and inhibitory neurons, the accuracy was 90% or more regardless of the model. The models showed better performance than merely distinguishing neurons by suprathreshold features such as the ratio of upstrokes and downstrokes of a single spike (ρ). However, when excitatory neurons were classified, the accuracy was 28˜47%, and the accuracy of classifying inhibitory neurons was 59˜73%. The present study was based on the results of electrophysiological experiments to determine whether transgenic markers of neurons could be predicted. Future research is needed to acquire electrophysiological data and transcriptomic data simultaneously on the single cell level to reveal the correlation between the gene expression and the physiological function of a neuron in building the neural network.
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http://dx.doi.org/10.1016/j.brainresbull.2019.05.012DOI Listing
August 2019

Clinical and Prognostic Value of Human Mammary Tumor Virus in Korean Patients with Breast Carcinoma.

Ann Clin Lab Sci 2019 Mar;49(2):171-174

Department of Anatomy, Keimyung University School of Medicine, Dongsan Medical Center, Daegu, Republic of Korea

Background: Human mammary tumor virus (HMTV) is 90-95% homologous to mouse mammary tumor virus, one of the causal agents of murine mammary tumors. Although HMTV has been frequently detected in human breast cancers, its clinical and prognostic value remains unknown.

Methods: In the present study, we analyzed HMTV infection using polymerase chain reaction (PCR) in 128 breast cancers.

Results: HMTV was found in 9.4% (12/128) of breast cancers and was significantly associated with breast pain (66.7% vs. 11.7%, =0.007). It had a tendency to be detected more frequently in breast cancer patients with lower BMI<25, although this result was not statistically significant (18.8% vs. 5.4%, =0.103). Kaplan-Meier survival analysis showed no prognostic value of HMTV in breast cancer (χ2=0.148, =0.700). For the first time, we investigated the clinical and prognostic value of HMTV in Korean patients with breast cancer.

Conclusion: Although our study revealed that HMTV infection does not have important clinical significance in breast cancer, the possibility remains that it may be a prominent causative agent of the disease.
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March 2019

Roles of Mitogen-Activated Protein Kinases in Osteoclast Biology.

Int J Mol Sci 2018 Oct 1;19(10). Epub 2018 Oct 1.

Department of Microbiology, Laboratory of Bone Metabolism and Control, Yeungnam University College of Medicine, Daegu 42415, Korea.

Bone undergoes continuous remodeling, which is homeostatically regulated by concerted communication between bone-forming osteoblasts and bone-degrading osteoclasts. Multinucleated giant osteoclasts are the only specialized cells that degrade or resorb the organic and inorganic bone components. They secrete proteases (e.g., cathepsin K) that degrade the organic collagenous matrix and establish localized acidosis at the bone-resorbing site through proton-pumping to facilitate the dissolution of inorganic mineral. Osteoporosis, the most common bone disease, is caused by excessive bone resorption, highlighting the crucial role of osteoclasts in intact bone remodeling. Signaling mediated by mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38, has been recognized to be critical for normal osteoclast differentiation and activation. Various exogenous (e.g., toll-like receptor agonists) and endogenous (e.g., growth factors and inflammatory cytokines) stimuli contribute to determining whether MAPKs positively or negatively regulate osteoclast adhesion, migration, fusion and survival, and osteoclastic bone resorption. In this review, we delineate the unique roles of MAPKs in osteoclast metabolism and provide an overview of the upstream regulators that activate or inhibit MAPKs and their downstream targets. Furthermore, we discuss the current knowledge about the differential kinetics of ERK, JNK, and p38, and the crosstalk between MAPKs in osteoclast metabolism.
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http://dx.doi.org/10.3390/ijms19103004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213329PMC
October 2018

Juglone induces cell death of Acanthamoeba through increased production of reactive oxygen species.

Exp Parasitol 2015 Dec 7;159:100-6. Epub 2015 Sep 7.

Department of Microbiology, Keimyung University School of Medicine, Daegu, Republic of Korea. Electronic address:

Juglone (5-hydroxy-1,4-naphthoquinone) is a major chemical constituent of Juglans mandshruica Maxim. Recent studies have demonstrated that juglone exhibits anti-cancer, anti-bacterial, anti-viral, and anti-parasitic properties. However, its effect against Acanthamoeba has not been defined yet. The aim of this study was to investigate the effect of juglone on Acanthamoeba. We demonstrate that juglone significantly inhibits the growth of Acanthamoeba castellanii at 3-5 μM concentrations. Juglone increased the production of reactive oxygen species (ROS) and caused cell death of A. castellanii. Inhibition of ROS by antioxidant N-acetyl-l-cysteine (NAC) restored the cell viability. Furthermore, our results show that juglone increased the uptake of mitochondrial specific dye. Collectively, these results indicate that ROS played a significant role in the juglone-induced cell death of Acanthamoeba.
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http://dx.doi.org/10.1016/j.exppara.2015.09.005DOI Listing
December 2015

Biofilm Formation and Colistin Susceptibility of Acinetobacter baumannii Isolated from Korean Nosocomial Samples.

Microb Drug Resist 2015 Aug 25;21(4):452-7. Epub 2015 Feb 25.

2 Department of Microbiology, Keimyung University School of Medicine , Daegu, Republic of Korea.

Biofilm formation, a virulence factor of Acinetobacter baumannii, is associated with long-term survival in hospital environments and provides resistance to antibiotics. Standard tests for antibiotic susceptibility involve analyzing bacteria in the planktonic state. However, the biofilm formation ability can influence antibiotic susceptibility. Therefore, here, the biofilm formation ability of A. baumannii clinical isolates from Korea was investigated and the susceptibility of biofilm and planktonic bacteria to colistin was compared. Of the 100 clinical isolates examined, 77% exhibited enhanced biofilm formation capacity relative to a standard A. baumannii strain (ATCC 19606). Differences between the minimal inhibitory concentrations and minimal biofilm-inhibitory concentrations of colistin were significantly greater in the group of A. baumannii that exhibited enhanced biofilm formation than the group that exhibited less ability for biofilm formation. Thus, the ability to form a biofilm may affect antibiotic susceptibility and clinical failure, even when the dose administered is in the susceptible range.
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http://dx.doi.org/10.1089/mdr.2014.0236DOI Listing
August 2015

Tigecycline inhibits proliferation of Acanthamoeba castellanii.

Parasitol Res 2015 Mar 7;114(3):1189-95. Epub 2015 Jan 7.

Department of Microbiology, Keimyung University School of Medicine, 1095 Dalgubeol-daero, Dalseo-gu, Daegu, 704-701, Republic of Korea.

Acanthamoeba is an opportunistic protozoan parasite responsible for different diseases in humans, such as granulomatous amoebic encephalitis and amoebic keratitis. Tigecycline, a third-generation tetracycline antibiotic, has potential activity to treat most of the antibiotic resistant bacterial infections. The effects of tigecycline in eukaryotic cells as well as parasites are less well studied. In the present study, we tested the effects of tigecycline on trophozoites of Acanthamoeba castellanii. The inhibitory effect of tigecycline on Acanthamoeba was determined by resazurin reduction and trypan blue exclusion assays. We found that tigecycline significantly inhibited the growth of Acanthamoeba (46.4 % inhibition at the concentration of 100 μM) without affecting cell viability and induction of encystation, whereas other tetracycline groups of antibiotics such as tetracycline and doxycycline showed no inhibitory effects. Furthermore, tigecycline decreased cellular adenosine triphosphate (ATP) level by 26 % than the control and increased mitochondrial mass, suggesting mitochondrial dysfunction in tigecycline-treated cells. These findings suggest that mitochondrial dysfunction with decreased ATP production might play an important mechanism of tigecycline in suppression of Acanthamoeba proliferation.
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http://dx.doi.org/10.1007/s00436-014-4302-1DOI Listing
March 2015

Improved application of the electrophoretic tissue clearing technology, CLARITY, to intact solid organs including brain, pancreas, liver, kidney, lung, and intestine.

BMC Dev Biol 2014 Dec 21;14:48. Epub 2014 Dec 21.

Department of Immunology, Keimyung University School of Medicine, 1095 Dalgubeoldae-Ro, Dalseo-Gu, Daegu, 704-701, South Korea.

Background: Mapping of tissue structure at the cellular, circuit, and organ-wide scale is important for understanding physiological and biological functions. A bio-electrochemical technique known as CLARITY used for three-dimensional anatomical and phenotypical mapping within transparent intact tissues has been recently developed. This method provided a major advance in understanding the structure-function relationships in circuits of the nervous system and organs by using whole-body clearing. Thus, in the present study, we aimed to improve the original CLARITY procedure and developed specific CLARITY protocols for various intact organs.

Results: We determined the optimal conditions for reducing bubble formation, discoloration, and depositing of black particles on the surface of tissue, which allowed production of clearer organ images. We also determined the appropriate replacement cycles of clearing solution for each type of organ, and convincingly demonstrated that 250-280 mA is the ideal range of electrical current for tissue clearing. We then acquired each type of cleared organs including brain, pancreas, liver, lung, kidney, and intestine. Additionally, we determined the images of axon fibers of hippocampal region, the Purkinje layer of cerebellum, and vessels and cellular nuclei of pancreas.

Conclusions: CLARITY is an innovative biochemical technology for the structural and molecular analysis of various types of tissue. We developed improved CLARITY methods for clearing of the brain, pancreas, lung, intestine, liver, and kidney, and identified the appropriate experimental conditions for clearing of each specific tissue type. These optimized methods will be useful for the application of CLARITY to various types of organs.
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http://dx.doi.org/10.1186/s12861-014-0048-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281481PMC
December 2014

Genome-wide association study of medication adherence in chronic diseases in the korean population.

Genomics Inform 2014 Sep 30;12(3):121-6. Epub 2014 Sep 30.

Department of Microbiology, Keimyung University School of Medicine, Daegu 704-701, Korea.

Medication adherence is generally defined as the extent of voluntary cooperation of a patient in taking medicine as prescribed. Adherence to long-term treatment with chronic disease is essential for reducing disease comorbidity and mortality. However, medication non-adherence in chronic disease averages 50%. This study was conducted a genome-wide association study to identify the genetic basis of medication adherence. A total of 235 medication non-adherents and 1,067 medication adherents with hypertension or diabetes were used from the Korean Association Resource project data according to the self-reported treatment status of each chronic disease, respectively. We identified four single nucleotide polymorphisms with suggestive genome-wide association. The most significant single nucleotide polymorphism was rs6978712 (chromosome 7, p = 4.87 × 10(-7)), which is located proximal to the GCC1 gene, which was previously implicated in decision-making capability in drug abusers. Two suggestive single nucleotide polymorphisms were in strong linkage disequilibrium (r(2) > 0.8) with rs6978712. Thus, in the aspect of decision-making in adherence behavior, the association between medication adherence and three loci proximal to the GCC1 gene seems worthy of further research. However, to overcome a few limitations in this study, defining the standardized phenotype criteria for self-reported adherence should be performed before replicating association studies.
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http://dx.doi.org/10.5808/GI.2014.12.3.121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196376PMC
September 2014

Chloroquine has a cytotoxic effect on Acanthamoeba encystation through modulation of autophagy.

Antimicrob Agents Chemother 2014 Oct 11;58(10):6235-41. Epub 2014 Aug 11.

Department of Microbiology, Keimyung University School of Medicine, Daegu, Republic of Korea

Encystation of Acanthamoeba castellanii is associated with resistance to chemotherapeutic agents. Blocking the encystation process could potentiate the efficacy of chemotherapeutic agents and biocides. During encystation, autophagy is highly stimulated and required for proper encystation of Acanthamoeba. In this study, the cytotoxic effect of chloroquine, a well-known autophagy-inhibitory drug, was tested in A. castellanii. Chloroquine was able to selectively reduce cell survival during the encystation of A. castellanii. However, A. castellanii trophozoites and mature cysts were resistant to chloroquine. Chloroquine treatment led to an increase in the number and size of lysosomes in encysting cells. Moreover, chloroquine inhibited the degradation of long-lived proteins in the encysting cells. Decreased autophagic flux, indicated by an increased number of lysosomes and decreased degradation of long-lived proteins, may be the mechanism by which cell death is induced by chloroquine in encysting Acanthamoeba. These results suggest a potential novel therapeutic application of chloroquine as an anti-Acanthamoeba drug. Our findings also suggest that targeting autophagy could be a therapeutic strategy against Acanthamoeba infection.
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http://dx.doi.org/10.1128/AAC.03164-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4187977PMC
October 2014

Translational suppression of HIF-1α by miconazole through the mTOR signaling pathway.

Cell Oncol (Dordr) 2014 Aug 29;37(4):269-79. Epub 2014 Jul 29.

Department of Microbiology, Keimyung University School of Medicine, 1095 Dalgubeol-daero, Dalseo-gu, Daegu, 704-701, Republic of Korea.

Background: Miconazole is an imidazole antifungal agent that has amply been used in the treatment of superficial mycosis. Preliminary data indicate that miconazole may also induce anticancer effects. As yet, however, little is known about the therapeutic efficacy of miconazole on cancer and the putative mechanism(s) involved. Here, we show that miconazole suppresses hypoxia inducible factor-1α (HIF-1α) protein translation in different cancer-derived cells.

Methods: The effect of miconazole on HIF-1α expression was examined by Western blotting and reverse transcriptase polymerase chain reaction assays in human U87MG and MCF-7 glioma and breast cancer-derived cell lines, respectively. The transcriptional activity of the HIF-1 complex was confirmed using a luciferase assay. To assess whether angiogenic factors are increased under hypoxic conditions in these cells, vascular endothelial growth factor (VEGF) levels were measured by ELISA. Metabolic labeling was performed to examine HIF-1α protein translation and global protein synthesis. The role of the mammalian target of rapamycin (mTOR) signaling pathway was examined to determine translation regulation of HIF-1α after miconazole treatment.

Results: Miconazole was found to suppress HIF-1α protein expression through post-transcriptional regulation in U87MG and MCF-7 cells. The suppressive effect of HIF-1α protein synthesis was found to be due to inhibition of mTOR. Miconazole significantly inhibited the transcriptional activity of the HIF-1 complex and the expression of its target VEGF. Moreover, miconazole was found to suppress global protein synthesis by inducing phosphorylation of the translation initiation factor 2α (eIF2α).

Conclusion: Our data indicate that miconazole plays a role in translational suppression of HIF-1α. We suggest that miconazole may represent a novel therapeutic option for the treatment of cancer.
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http://dx.doi.org/10.1007/s13402-014-0182-8DOI Listing
August 2014

Identification of lysosomotropic compounds based on the distribution and size of lysosomes.

Biochem Biophys Res Commun 2014 Jul 27;450(1):189-94. Epub 2014 May 27.

Department of Microbiology, School of Medicine, Keimyung University, Daegu, Republic of Korea; Institute for Cancer Research, School of Medicine, Keimyung University, Daegu, Republic of Korea. Electronic address:

Lysosomal accumulation of drugs with their specific physicochemical properties is of key importance to drug distribution in the body. Several attempts have been made to treat various human diseases by employing the accumulation of lysosomal drugs, and many methods to identify lysosomal accumulation of drugs have been proposed. Among those, the use of high-content screening has increased tremendously because of improved efficiency and accuracy as well as the development of automatic image acquisition and analytical techniques. Conventional methods to identify lysosomal accumulation of drugs by evaluating changes in the lysosomal area are unable to maximize the advantages of phenotypic high-content screening. Lysosomal distribution and the size of lysosomes are affected by lysosomal accumulating drugs. Therefore, we present image acquisition conditions and analytical methods to utilize lysosomal distribution and size as parameters for identifying lysosomal accumulating drugs. These two parameters will help to improve the reliability of the screening methods for identifying lysosomal accumulation of drugs by maximizing usage of information from image-based screening.
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http://dx.doi.org/10.1016/j.bbrc.2014.05.091DOI Listing
July 2014

Minocycline inhibits angiogenesis in vitro through the translational suppression of HIF-1α.

Arch Biochem Biophys 2014 Mar 8;545:74-82. Epub 2014 Jan 8.

Department of Microbiology, Keimyung University School of Medicine, Daegu, Republic of Korea. Electronic address:

Minocycline was recently found to be effective against cancer. However, the precise molecular mechanisms of minocycline in cancer are poorly understood. Hypoxia-inducible factor-1 (HIF-1, a heterodimeric transcription factor composed of HIF-1α and β) activates the transcription of genes that are involved in angiogenesis in cancer. In this study, we found that minocycline significantly inhibits HIF-1α protein expression and suppresses HIF-1 transcriptional activity. The tube formation assay showed that minocycline has anti-angiogenic activity and suppresses hypoxia-induced vascular endothelial growth factor (VEGF) expression. The metabolic labeling assay showed that minocycline reduces HIF-1α protein translation and global protein synthesis. In addition, minocycline suppresses mTOR signaling and increases the phosphorylation of eIF2α, which is known to be related to the translational regulation of HIF-1α expression. These findings collectively indicate that minocycline is a potential inhibitor of HIF-1α and provide new insight into the discovery of drugs for cancer treatment.
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http://dx.doi.org/10.1016/j.abb.2013.12.023DOI Listing
March 2014