Publications by authors named "Seok Ho Hong"

180 Publications

Perivascular Stem Cells Suppress Inflammasome Activation during Inflammatory Responses in Macrophages.

Int J Stem Cells 2019 Nov;12(3):419-429

Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, Korea.

Background And Objectives: Perivascular stem cells (PVCs) have been identified as precursors of mesenchymal stem cells (MSCs) that offer promising prospects for application in the development of cellular therapies. Although PVCs have been demonstrated to have greater therapeutic potential compared to bone marrow and adipose tissue-derived MSCs in various diseases, the regulatory role of PVCs on inflammasome activation during macrophage-mediated inflammatory responses has not been investigated.

Methods And Results: In this study, we found that the PVC secretome effectively alleviates secretion of both caspase-1 and interleukin-1 in lipopolysaccharide-primed and activated human and murine macrophages by blocking inflammasome activation and attenuating the production of mitochondrial reactive oxygen species (ROS). We further showed that the PVC secretome significantly reduces inflammatory responses and endoplasmic reticulum stress in peritoneal macrophages in a mouse model of monosodium urate-induced peritonitis. A cytokine antibody array analysis revealed that the PVC secretome contains high levels of serpin E1 and angiogenin, which may be responsible for the inhibitory effects on mitochondrial ROS generation as well as on inflammasome activation.

Conclusions: Our results suggest that PVCs may be therapeutically useful for the treatment of macrophage- and inflammation-mediated diseases by paracrine action via the secretion of various biological factors.
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http://dx.doi.org/10.15283/ijsc19115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881042PMC
November 2019

Maintenance of hPSCs under Xeno-Free and Chemically Defined Culture Conditions.

Int J Stem Cells 2019 Nov;12(3):484-496

Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea.

Previously, the majority of human embryonic stem cells and human induced pluripotent stem cells have been derived on feeder layers and chemically undefined medium. Those media components related to feeder cells, or animal products, often greatly affect the consistency of the cell culture. There are clear advantages of a defined, xeno-free, and feeder-free culture system for human pluripotent stem cells (hPSCs) cultures, since consistency in the formulations prevents lot-to-lot variability. Eliminating all non-human components reduces health risks for downstream applications, and those environments reduce potential immunological reactions from stem cells. Therefore, development of feeder-free hPSCs culture systems has been an important focus of hPSCs research. Recently, researchers have established a variety of culture systems in a defined combination, xeno-free matrix and medium that supports the growth and differentiation of hPSCs. Here we described detailed hPSCs culture methods under feeder-free and chemically defined conditions using vitronetin and TeSR-E8 medium including supplement bioactive lysophospholipid for promoting hPSCs proliferation and maintaining stemness.
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http://dx.doi.org/10.15283/ijsc19090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881038PMC
November 2019

Role of miRNA-181a-2-3p in cadmium-induced inflammatory responses of human bronchial epithelial cells.

J Thorac Dis 2019 Jul;11(7):3055-3069

Department of Internal Medicine and Environmental Health Center, Kangwon National University Hospital, Chuncheon, South Korea.

Background: Inflammation is an important priming event in the pathogenesis of pulmonary diseases, including chronic obstructive pulmonary disease (COPD). Increasing evidence indicates that microRNAs (miRNAs) contribute to the pathogenesis of COPD by regulating inflammatory response. Therefore, it is necessary to investigate novel molecular targets in COPD without any validation in COPD samples in airway inflammation. The aim of our study is to reveal novel miRNAs that can influence molecular targets for COPD and to examine the underlying mechanism in airway inflammation.

Methods: We identified the downregulation of miR-181a-2-3p in the serum of COPD patients and further investigated the role of miR-181a-2-3p in cadmium (Cd)-induced inflammation of a human bronchial epithelial cell line (BEAS-2B) and normal human bronchial epithelial (NHBE) cells.

Results: Our results showed that expression of miR-181a-2-3p was significantly decreased in Cd-treated cells and silencing of miR-181a-2-3p enhanced Cd-induced inflammatory responses and inflammasome activation. This negative regulatory effect of miR-181a-2-3p on inflammation is partly mediated by the calcium signaling pathway. Furthermore, global gene expression profiling revealed that Toll-like receptor 4 or sequestosome 1 genes were identified as potential targets of miR-181a-2-3p, which were significantly upregulated by knockdown of miR-181a-2-3p in Cd-treated cells.

Conclusions: Our results strongly suggest that miR-181a-2-3p has a critical role in Cd-induced inflammation of airway by regulating its potential target genes, which could be molecular targets for COPD.
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http://dx.doi.org/10.21037/jtd.2019.07.55DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687977PMC
July 2019

The vicious cycle between transglutaminase 2 and reactive oxygen species in hyperglycemic memory-induced endothelial dysfunction.

FASEB J 2019 11 28;33(11):12655-12667. Epub 2019 Aug 28.

Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, South Korea.

Clinical trials suggested that the vascular system can remember episodes of poor glycemic control through a phenomenon known as hyperglycemic memory (HGM). HGM is associated with long-term diabetic vascular complications in type 1 and type 2 diabetes, although the molecular mechanism of that association is not clearly understood. We hypothesized that transglutaminase 2 (TGase2) and intracellular reactive oxygen species (ROS) play a key role in HGM-induced vascular dysfunction. We found that hyperglycemia induced persistent oxidative stress, expression of inflammatory adhesion molecules, and apoptosis in the aortic endothelium of HGM mice whose blood glucose levels had been normalized by insulin supplementation. TGase2 activation and ROS generation were in a vicious cycle in the aortic endothelium of HGM mice and also in human aortic endothelial cells after glucose normalization, which played a key role in the sustained expression of inflammatory adhesion molecules and apoptosis. Our findings suggest that the TGase2-ROS vicious cycle plays an important role in HGM-induced endothelial dysfunction.-Lee, J.-Y., Lee, Y.-J., Jeon, H.-Y., Han, E.-T., Park, W. S., Hong, S.-H., Kim, Y.-M., Ha, K.-S. The vicious cycle between transglutaminase 2 and reactive oxygen species in hyperglycemic memory-induced endothelial dysfunction.
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http://dx.doi.org/10.1096/fj.201901358RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902669PMC
November 2019

Novel S-Bend Resonator Based on a Multi-Mode Waveguide with Mode Discrimination for a Refractive Index Sensor.

Sensors (Basel) 2019 Aug 19;19(16). Epub 2019 Aug 19.

Department of Electrical and Electronics Engineering, Chung-Ang University, 221 Heuksuk-Dong, Dongjak-ku, Seoul 156-756, Korea.

In this paper, a multi-mode waveguide-based optical resonator is proposed for an integrated optical refractive index sensor. Conventional optical resonators have been studied for single-mode waveguide-based resonators to enhance the performance, but mass production is limited owing to the high fabrication costs of nano-scale structures. To overcome this problem, we designed an S-bend resonator based on a micro-scale multi-mode waveguide. In general, multi-mode waveguides cannot be utilized as optical resonators, because of a performance degradation resulting from modal dispersion and an output transmission with multi-peaks. Therefore, we exploited the mode discrimination phenomenon using the bending loss, and the resulting S-bend resonator yielded an output transmission without multi-peaks. This phenomenon is utilized to remove higher-order modes efficiently using the difference in the effective refractive index between the higher-order and fundamental modes. As a result, the resonator achieved a Q-factor and sensitivity of 2.3 × 10 and 52 nm/RIU, respectively, using the variational finite-difference time-domain method. These results show that the multi-mode waveguide-based S-bend resonator with a wide line width can be utilized as a refractive index sensor.
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http://dx.doi.org/10.3390/s19163600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720186PMC
August 2019

Insulin prevents pulmonary vascular leakage by inhibiting transglutaminase 2 in diabetic mice.

Life Sci 2019 Sep 30;233:116711. Epub 2019 Jul 30.

Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Kangwon-do 24341, Republic of Korea. Electronic address:

Aims: Insulin is a central peptide hormone required for carbohydrate metabolism; however, its role in diabetes-associated pulmonary disease is unknown. Here, we investigated the preventative effect of insulin against hyperglycemia-induced pulmonary vascular leakage and its molecular mechanism of action in the lungs of diabetic mice.

Main Methods: Vascular endothelial growth factor (VEGF) activated transglutaminase 2 (TGase2) by sequentially elevating intracellular Ca and reactive oxygen species (ROS) levels in primary human pulmonary microvascular endothelial cells (HPMVECs).

Key Findings: Insulin inhibited VEGF-induced TGase2 activation, but did not affect intracellular Ca elevation and ROS generation. Insulin prevented VEGF-induced vascular leakage by inhibiting TGase2-mediated c-Src phosphorylation, disassembly of VE-cadherin and β-catenin, and stress fiber formation. Insulin replacement therapy prevented hyperglycemia-induced TGase2 activation, but not ROS generation, in the lungs of diabetic mice. Insulin also prevented vascular leakage and cancer metastasis in the diabetic lung. Notably, vascular leakage was not detectable in the lungs of TGase2-null (Tgm2) diabetic mice.

Significance: These findings demonstrate that insulin prevents hyperglycemia-induced pulmonary vascular leakage in diabetic mice by inhibiting VEGF-induced TGase2 activation rather than ROS generation.
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http://dx.doi.org/10.1016/j.lfs.2019.116711DOI Listing
September 2019

The anticholinergic drug oxybutynin inhibits voltage-dependent K channels in coronary arterial smooth muscle cells.

Clin Exp Pharmacol Physiol 2019 11 9;46(11):1030-1036. Epub 2019 Aug 9.

Department of Physiology, Institute of Medical Sciences, Kangwon National University, School of Medicine, Chuncheon, South Korea.

This study demonstrates the inhibitory effect of anticholinergic drug oxybutynin on voltage-dependent K (Kv) channels in rabbit coronary arterial smooth muscle cells. Oxybutynin inhibited vascular Kv channels in a concentration-dependent manner, with an IC value of 11.51 ± 0.38 μmol/L and a Hill coefficient (n) of 2.25 ± 0.12. Application of oxybutynin shifted the activation curve to the right and the inactivation curve to the left. Pretreatment with the Kv1.5 subtype inhibitor DPO-1 and the Kv2.1 subtype inhibitor guangxitoxin suppressed the oxybutynin-induced inhibition of the Kv current. However, application of the Kv7 subtype inhibitor linopirdine did not affect the inhibition by oxybutynin of the Kv current. The anticholinergic drug atropine did not inhibit the Kv current nor influence oxybutynin-induced inhibition of the Kv current. From these results, we concluded that oxybutynin inhibited the vascular Kv current in a concentration-dependent manner by influencing the steady-state activation and inactivation curves independent of its anticholinergic effect.
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http://dx.doi.org/10.1111/1440-1681.13138DOI Listing
November 2019

Preventive Effects of Thermosensitive Biopolymer-Conjugated C-Peptide against High Glucose-Induced Endothelial Cell Dysfunction.

Macromol Biosci 2019 09 16;19(9):e1900129. Epub 2019 Jul 16.

Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Kangwon-Do, 200-701, Korea.

C-peptide has emerged as a potential drug for treating diabetic complications. However, clinical application of C-peptide is limited by its short half-life during circulation and costly synthesis methods. To overcome these limitations, a biocompatible and thermosensitive biopolymer-C-peptide conjugate composed of human C-peptide genetically conjugated at the C-terminus of nine repeats of lysine-containing elastin-like polypeptide (K9-C-peptide) is generated. K9-C-peptide exhibits reversible thermal phase behavior with a transition temperature dependent on polypeptide concentration. Degradation of K9-C-peptide hydrogel depends on the concentration of four cleavage enzymes as well as the reaction time and frequency of treatments with elastase-2. The preventive effect of K9-C-peptide against high glucose-induced human aortic endothelial cell dysfunction is further investigated. K9-C-peptide inhibits high glucose-induced intracellular reactive oxygen species generation, transglutaminase 2 activation, and apoptosis, similar to the inhibitory effects of human C-peptide. Thus, K9-C-peptide is a potential drug depot for the sustained delivery of C-peptide to treat diabetic complications.
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http://dx.doi.org/10.1002/mabi.201900129DOI Listing
September 2019

Malignant Transformation of a Rosette-Forming Glioneuronal Tumor to Glioblastoma.

World Neurosurg 2019 Oct 14;130:271-275. Epub 2019 Jun 14.

Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Background: A rosette-forming glioneuronal tumor (RGNT), a rare brain tumor, presents as a benign feature with a favorable outcome. To date, a few cases with aggressive behaviors, such as recurrence or dissemination, but none with malignant transformation, have been reported. We describe 1 case that recurred as glioblastoma after complete resection of the benign RGNT.

Case Description: A man aged 58 years presented with headache and dizziness without neurologic symptoms. Magnetic resonance imaging showed a 4 × 2.5 cm, well-demarcated mass in the left cerebellar hemisphere. The patient underwent gross total resection of the tumor and a diagnosis of RGNT was made. There was no evidence of recurrence on serial follow-up. However, a recurrent heterogeneous enhancing mass in the previous surgical cavity was observed on a 7-year postoperative magnetic resonance imaging scan. Reoperation was performed and a histopathological study revealed a glioblastoma.

Conclusions: To the best of our knowledge, this is the first case of spontaneous malignant transformation of an RGNT. Our case may be helpful in better understanding the biological behavior and clinical outcome of RGNT. We emphasize the malignant potential of this rare tumor and the necessity of future large-scaled research for most appropriate therapeutic strategies.
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http://dx.doi.org/10.1016/j.wneu.2019.06.042DOI Listing
October 2019

Growth rate and fate of untreated hemangioblastomas: clinical assessment of the experience of a single institution.

J Neurooncol 2019 Aug 14;144(1):147-154. Epub 2019 Jun 14.

Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea.

Background: The growth rate and natural history of untreated hemangioblastomas remain unclear. This study investigated the natural history of untreated intracranial hemangioblastomas and predictors of tumor growth using volumetric assessment.

Method: This study retrospectively enrolled 31 patients with untreated hemangioblastomas between 2004 and 2017 who were followed up for at least 12 months. The 31 patients had a total of 52 hemangioblastomas.

Results: The 31 patients included 11 (35.5%) men and 20 (64.5%) women, of mean age 42.5 years. Seventeen (54.8%) patients were genetically diagnosed with Von Hippel-Lindau (VHL) disease. Of the 52 lesions, 33 (63.5%) grew during the follow-up period, whereas 19 (36.5%) remained stable. Overall mean actual growth rate (AGR) was 1.94 cm/year, 2.38 cm/year in the VHL and 1.79 cm/year in the non-VHL group (p = 0.31). Overall mean relative growth rate (RGR) was 21%/year, 26%/year in the VHL and 19%/year in the non-VHL group. Time to 50% treatment probability was 34 months. The 1, 3, 5, and 7-year treatment probabilities were 11.5%, 50.1%, 52.7%, and 73%, respectively. The presence of only symptomatic lesions was significantly predictive of the growth of intracranial hemangioblastoma (odds ratio: 5.0, p = 0.02).

Conclusion: The overall growth rate of intracranial hemangioblastoma was faster than that of other benign intracranial tumors, with symptomatic lesions being the only meaningful predictor of tumor growth. Because of their rapid growth rate and high probability of treatment, a wait and scan management strategy should be carefully applied to intracranial hemangioblastomas.
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http://dx.doi.org/10.1007/s11060-019-03213-zDOI Listing
August 2019

A Primer on Magnetic Resonance-Guided Laser Interstitial Thermal Therapy for Medically Refractory Epilepsy.

J Korean Neurosurg Soc 2019 May 1;62(3):353-360. Epub 2019 May 1.

Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Epilepsy surgery that eliminates the epileptogenic focus or disconnects the epileptic network has the potential to significantly improve seizure control in patients with medically intractable epilepsy. Magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) has been an established option for epilepsy surgery since the US Food and Drug Administration cleared the use of MRgLITT in neurosurgery in 2007. MRgLITT is an ablative stereotactic procedure utilizing heat that is converted from laser energy, and the temperature of the tissue is monitored in real-time by MR thermography. Real-time quantitative thermal monitoring enables titration of laser energy for cellular injury, and it also estimates the extent of tissue damage. MRgLITT is applicable for lesion ablation in cases that the epileptogenic foci are localized and/or deep-seated such as in the mesial temporal lobe epilepsy and hypothalamic hamartoma. Seizure-free outcomes after MRgLITT are comparable to those of open surgery in well-selected patients such as those with mesial temporal sclerosis. Particularly in patients with hypothalamic hamartoma. In addition, MRgLITT can also be applied to ablate multiple discrete lesions of focal cortical dysplasia and tuberous sclerosis complex without the need for multiple craniotomies, as well as disconnection surgery such as corpus callosotomy. Careful planning of the target, the optimal trajectory of the laser probe, and the appropriate parameters for energy delivery are paramount to improve the seizure outcome and to reduce the complication caused by the thermal damage to the surrounding critical structures.
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http://dx.doi.org/10.3340/jkns.2019.0105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514321PMC
May 2019

Identification of Putative Regulatory Alterations Leading to Changes in Gene Expression in Chronic Obstructive Pulmonary Disease.

Mol Cells 2019 Apr;42(4):333-344

Division of Biomedical Convergence, College of Biomedical Science, Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon 24341, Korea.

Various genetic and environmental factors are known to be associated with chronic obstructive pulmonary disease (COPD). We identified COPD-related differentially expressed genes (DEGs) using 189 samples accompanying either adenocarcinoma (AC) or squamous cell carcinoma (SC), comprising 91 normal and 98 COPD samples. DEGs were obtained from the intersection of two DEG sets separately identified for AC and SC to exclude the influence of different cancer backgrounds co-occurring with COPD. We also measured patient samples named group 'I', which were unable to be determined as normal or COPD based on alterations in gene expression. The Gene Ontology (GO) analysis revealed significant alterations in the expression of genes categorized with the 'cell adhesion', 'inflammatory response', and 'mitochondrial functions', i.e., well-known functions related to COPD, in samples from patients with COPD. Multi-omics data were subsequently integrated to decipher the upstream regulatory changes linked to the gene expression alterations in COPD. COPD-associated expression quantitative trait loci (eQTLs) were located at the upstream regulatory regions of 96 DEGs. Additionally, 45 previously identified COPD-related miRNAs were predicted to target 66 of the DEGs. The eQTLs and miRNAs might affect the expression of 'respiratory electron transport chain' genes and 'cell proliferation' genes, respectively, while both eQTLs and miRNAs might affect the expression of 'apoptosis' genes. We think that our present study will contribute to our understanding of the molecular etiology of COPD accompanying lung cancer.
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http://dx.doi.org/10.14348/molcells.2019.2442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6530641PMC
April 2019

Identification and characterization of Pv50, a novel Plasmodium vivax merozoite surface protein.

Parasit Vectors 2019 Apr 18;12(1):176. Epub 2019 Apr 18.

Department of Medical Environmental Biology and Tropical Medicine, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, Republic of Korea.

Background: Plasmodium vivax contains approximately 5400 coding genes, more than 40% of which code for hypothetical proteins that have not been functionally characterized. In a previous preliminary screening using pooled serum samples, numerous hypothetical proteins were selected from among those that were highly transcribed in the schizont-stage of parasites, and highly antigenic P. vivax candidates including hypothetical proteins were identified. However, their immunological and functional activities in P. vivax remain unclear. From these candidates, we investigated a P. vivax 50-kDa protein (Pv50, PVX_087140) containing a highly conserved signal peptide that shows high transcription levels in blood-stage parasites.

Results: Recombinant Pv50 was expressed in a cell-free expression system and used for IgG prevalence analysis of patients with vivax malaria and healthy individuals. Immune responses were analyzed in immunized mice and mouse antibodies were used to detect the subcellular localization of the protein in blood-stage parasites by immunofluorescence assay. A protein array method was used to evaluate protein-protein interactions to predict protein functional activities during the invasion of parasites into erythrocytes. Recombinant Pv50 showed IgG prevalence in patient samples with a sensitivity of 42.9% and specificity of 93.8% compared to that in healthy individuals. The non-cytophilic antibodies IgG1 and IgG3 were the major components involved in the antibody response in Pv50-immunized mice. Pv50 localized on the surface of merozoites and a specific interaction between Pv50 and PvMSP1 was detected, suggesting that Pv50-PvMSP1 forms a heterodimeric complex in P. vivax.

Conclusions: Increased immune responses caused by native P. vivax parasites were detected, confirming its immunogenic effects. This study provides a method for detecting new malaria antigens, and Pv50 may be a vivax malaria vaccine candidate with PvMSP1.
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http://dx.doi.org/10.1186/s13071-019-3434-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474066PMC
April 2019

Inhibition of parasite invasion by monoclonal antibody against epidermal growth factor-like domain of Plasmodium vivax merozoite surface protein 1 paralog.

Sci Rep 2019 03 7;9(1):3906. Epub 2019 Mar 7.

Department of Medical Environmental Biology and Tropical Medicine, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, Republic of Korea.

The Plasmodium vivax merozoite surface protein 1 paralog (PvMSP1P), which has epidermal growth factor (EGF)-like domains, was identified as a novel erythrocyte adhesive molecule. This EGF-like domain (PvMSP1P-19) elicited high level of acquired immune response in patients. Antibodies against PvMSP1P significantly reduced erythrocyte adhesion activity to its unknown receptor. To determine PvMSP1P-19-specific antibody function and B-cell epitopes in vivax patients, five monoclonal antibodies (mAbs) and 18-mer peptides were generated. The mAb functions were determined by erythrocyte-binding inhibition assay and invasion inhibition assay with P. knowlesi. B-cell epitopes of PvMSP1P-19 domains were evaluated by peptide microarray. The pvmsp1p-19 sequences showed limited polymorphism in P. vivax worldwide isolates. The 1BH9-A10 showed erythrocyte binding inhibitory by interaction with the N-terminus of PvMSP1P-19, while this mAb failed to recognize PkMSP1P-19 suggesting the species-specific for P. vivax. Other mAbs showed cross-reactivity with PkMSP1P-19. Among them, the 2AF4-A2 and 2AF4-A6 mAb significantly reduced parasite invasion through C-terminal recognition. The linear B-cell epitope in naturally exposed P. vivax patient was identified at three linear epitopes. In this study, PvMSP1P-19 N-terminal-specific 1BH9-A10 and C-terminal-specific 2AF4 mAbs showed functional activity for epitope recognition suggesting that PvMSP1P may be useful for vaccine development strategy for specific single epitope to prevent P. vivax invasion.
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http://dx.doi.org/10.1038/s41598-019-40321-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405985PMC
March 2019

Inhibitory effect of immunosuppressive drug tacrolimus on voltage-gated K current in rabbit coronary arterial smooth muscle cells.

Eur J Pharmacol 2019 Apr 2;849:59-66. Epub 2019 Feb 2.

Department of Physiology, Kangwon National University School of Medicine, Chuncheon 24341, South Korea. Electronic address:

In the present study, we investigated the inhibitory effect of tacrolimus, a macrolide immunosuppressive drug that acts through calcineurin inhibition, on voltage-gated K (Kv) channels expressed in native smooth muscle cells isolated from the coronary arteries of rabbits. Tacrolimus reduced the amplitude of Kv currents in a dose-dependent manner with an IC value and Hill coefficient of 7.80 ± 3.01 μM and 1.07 ± 0.25, respectively. Tacrolimus caused a shift in the activation curve toward a more positive potential and in the inactivation curve toward a more negative potential. Tacrolimus-induced inhibition of Kv current was increased by the application of train pulses (1 or 2 Hz). Furthermore, the recovery time constant of inactivation was extended in the presence of tacrolimus, suggesting that tacrolimus inhibited Kv channels in a use-dependent manner. Two kinds of Kv subtype inhibitors, DPO-1 and guangxitoxin did not affect the degree of tacrolimus-induced inhibition of Kv current. Furthermore, pretreatment with another calcineurin inhibitor, cyclosporine A, did not affect the Kv current, and did not alter the inhibitory effect of tacrolimus. Using perforated-patch clamp experiments, inhibition of Kv channels by tacrolimus caused membrane depolarization. From these results, we concluded that tacrolimus inhibited the vascular Kv currents in a dose, state (open and closed)-dependent manner.
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http://dx.doi.org/10.1016/j.ejphar.2019.01.069DOI Listing
April 2019

Human pluripotent stem cell-derived alveolar epithelial cells are alternatives for in vitro pulmotoxicity assessment.

Sci Rep 2019 01 24;9(1):505. Epub 2019 Jan 24.

Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, 24341, South Korea.

Human pluripotent stem cell (hPSC)-derived alveolar epithelial cells (AECs) provide new opportunities for understanding lung development and the treatment of pulmonary diseases. However, toxicity assessments using hPSC-AECs have not been undertaken. In this study, we generated functional AECs from hPSCs and evaluated their inflammatory and apoptotic responses to cadmium (Cd) exposure (1, 5, and 10 μM) for 24 h compared with the human bronchial epithelial cell line (BEAS-2B) and primary AECs as controls. Our data showed that Cd (10 μM) treatment induced substantial inflammatory responses and apoptosis in BEAS-2B cells, but not in both hPSC-AECs and primary AECs. Interestingly, conditioned medium from AEC cultures significantly alleviated apoptotic and inflammatory responses to Cd exposure in BEAS-2B cells. Using cytokine arrays, several potential factors secreted from hPSC-AECs and primary AECs were detected and may be involved in reducing Cd-induced cytotoxicity. We also observed higher expression of surfactant proteins B and C in both hPSC-AECs and primary AECs, which may contribute to protection against Cd-induced cytotoxicity. These results suggested that hPSC-AECs phenotypically and functionally resemble primary AECs and could be more biologically relevant alternatives for evaluating the pathological contribution of confirmed or potential pulmotoxic materials included in smoking and microdust.
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http://dx.doi.org/10.1038/s41598-018-37193-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346100PMC
January 2019

Perivascular Cells and NADPH Oxidase Inhibition Partially Restore Hyperglycemia-Induced Alterations in Hematopoietic Stem Cell and Myeloid-Derived Suppressor Cell Populations in the Bone Marrow.

Int J Stem Cells 2018 Mar;12(1):63-72

Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, Korea.

Background And Objectives: Patients suffer from long-term diabetes can result in severe complications in multiple organs through induction of vascular dysfunctions. However, the effects of chronic hyperglycemic conditions on hematopoiesis and the microenvironment in the bone marrow (BM) are not yet well understood.

Methods: BM cells were harvested from femurs of mice and analyzed using flow cytometry. Human PVCs were cultured in serum-free -MEM. After 24hrs, PVC-CM was collected and filtered through a 0.22 m filter.

Results: In this study, we showed that hyperglycemia alters hematopoietic composition in the BM, which can partially be restored via paracrine mechanisms, including perivascular cells (PVCs) and NADPH oxidase (NOX) inhibition in mice with streptozotocin-induced diabetes. Prolonged hyperglycemic conditions resulted in an increase in the frequency and number of long-term hematopoietic stem cells as well as the number of total BM cells. The altered hematopoiesis in the BM was partially recovered by treatment with PVC-derived conditioned medium (CM). Long-term diabetes also increased the number of myeloid-derived suppressor cells in the BM, which was partially restored by the administration of PVC-CM and diphenyleneiodonium (DPI), a NOX inhibitor. We further showed the downregulation of ERK and p38 phosphorylation in BM cells of diabetic mice treated with PVC-CM and DPI. This may be associated with dysfunction of hematopoietic cells and promotion of subsequent diabetic complications.

Conclusions: Our data suggested that alterations in BM hematopoietic composition due to prolonged hyperglycemic conditions might be restored by improvement of the hematopoietic microenvironment and modulation of NOX activity.
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http://dx.doi.org/10.15283/ijsc18097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457702PMC
March 2018

Treatment and Survival Outcomes of Primary Intracranial Squamous Cell Carcinoma.

World Neurosurg 2019 05 18;125:e1-e9. Epub 2018 Dec 18.

Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Background: Primary intracranial squamous cell carcinoma (SCC) is a rare neoplasm associated with malignant transformation of benign epidermoid or dermoid cysts. The optimal treatment and prognosis of this rare disease are unclear.

Methods: A comprehensive literature review identified all reports relevant to clinical presentation, treatment, and outcome of primary intracranial SCC. All available data were extracted from the included literature. Two patients diagnosed with malignant transformation of an epidermoid cyst in our institute were also included in the study. Survival analysis was conducted to determine the factors affecting patient outcomes.

Results: A total of 62 cases were identified and selected for the present study. The median survival regardless of treatment was 12.8 months. Median survival for patients treated with surgery alone and surgery with radiotherapy was 5 months and 35 months, respectively (P = 0.037). Patients who underwent gross total resection showed relatively increased survival compared with those who underwent subtotal resection (median, 48 months vs. 25 months; P = 0.067). Patients with leptomeningeal carcinomatosis had a significantly decreased median survival of 10 months, as opposed to 41 months (P = 0.005).

Conclusions: Primary intracranial SCC shows poor prognosis, with controversial management. The results of this study indicate that complete resection of tumor when possible, followed by radiotherapy, is the optimal treatment for improving patient outcome.
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http://dx.doi.org/10.1016/j.wneu.2018.11.252DOI Listing
May 2019

The stability and oncogenic function of LIN28A are regulated by USP28.

Biochim Biophys Acta Mol Basis Dis 2019 03 10;1865(3):599-610. Epub 2018 Dec 10.

Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea; College of Medicine, Hanyang University, Seoul 04763, South Korea. Electronic address:

RNA-binding protein LIN28A is often highly expressed in human malignant tumors and is involved in tumor metastasis and poor prognosis. Knowledge about post-translational regulatory mechanisms governing LIN28A protein stability and function is scarce. Here, we investigated the role of ubiquitination and deubiquitination on LIN28A protein stability and report that LIN28A protein undergoes ubiquitination. Ubiquitin-specific protease 28 (USP28), a deubiquitinating enzyme, interacts with and stabilizes LIN28A protein to extend its half-life. USP28, through its deubiquitinating activity, antagonizes LIN28A protein turnover by reversing its proteasomal degradation. Our study describes the consequential impacts of USP28-mediated stabilization of LIN28A protein on enhancing cancer cell viability, migration and ultimately augmenting LIN28A-mediated tumor progression. Overall, our data suggest that a synergistic, combinatorial approach of targeting LIN28A with USP28 would contribute to effective cancer therapeutics.
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http://dx.doi.org/10.1016/j.bbadis.2018.12.006DOI Listing
March 2019

Vildagliptin, an Anti-diabetic Drug of the DPP-4 Inhibitor, Induces Vasodilation via Kv Channel and SERCA Pump Activation in Aortic Smooth Muscle.

Cardiovasc Toxicol 2019 06;19(3):244-254

Department of Physiology, Kangwon National University School of Medicine, 1 Kangwondaehak-gil, Chuncheon, 24341, South Korea.

This study investigated vildagliptin-induced vasodilation and its related mechanisms using phenylephrine induced precontracted rabbit aortic rings. Vildagliptin induced vasodilation in a concentration-dependent manner. Pretreatment with the large-conductance Ca-activated K channel blocker paxilline, ATP-sensitive K channel blocker glibenclamide, and inwardly rectifying K channel blocker Ba did not affect the vasodilatory effects of vildagliptin. However, application of the voltage-dependent K (Kv) channel inhibitor 4-aminopyridine significantly reduced the vasodilatory effects of vildagliptin. In addition, application of either of two sarcoplasmic/endoplasmic reticulum Ca-ATPase (SERCA) inhibitors, thapsigargin or cyclopiazonic acid, effectively inhibited the vasodilatory effects of vildagliptin. These vasodilatory effects were not affected by pretreatment with adenylyl cyclase, protein kinase A (PKA), guanylyl cyclase, or protein kinase G (PKG) inhibitors, or by removal of the endothelium. From these results, we concluded that vildagliptin induced vasodilation via activation of Kv channels and the SERCA pump. However, other K channels, PKA/PKG-related signaling cascades associated with vascular dilation, and the endothelium were not involved in vildagliptin-induced vasodilation.
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http://dx.doi.org/10.1007/s12012-018-9496-5DOI Listing
June 2019

Inhibition of MicroRNA-221 and 222 Enhances Hematopoietic Differentiation from Human Pluripotent Stem Cells via c-KIT Upregulation.

Mol Cells 2018 Nov 1;41(11):971-978. Epub 2018 Nov 1.

Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon 24341, Korea.

The stem cell factor (SCF)/c-KIT axis plays an important role in the hematopoietic differentiation of human pluripotent stem cells (hPSCs), but its regulatory mechanisms involving microRNAs (miRs) are not fully elucidated. Here, we demonstrated that supplementation with SCF increases the hematopoietic differentiation of hPSCs via the interaction with its receptor tyrosine kinase c-KIT, which is modulated by miR-221 and miR-222. c-KIT is comparably expressed in undifferentiated human embryonic and induced pluripotent stem cells. The inhibition of SCF signaling via treatment with a c-KIT antagonist (imatinib) during hPSC-derived hematopoiesis resulted in reductions in the yield and multi-lineage potential of hematopoietic progenitors. We found that the transcript levels of miR-221 and miR-222 targeting c-KIT were significantly lower in the pluripotent state than they were in terminally differentiated somatic cells. Furthermore, suppression of miR-221 and miR-222 in undifferentiated hPSC cultures induced more hematopoiesis by increasing c-KIT expression. Collectively, our data implied that the modulation of c-KIT by miRs may provide further potential strategies to expedite the generation of functional blood cells for therapeutic approaches and the study of the cellular machinery related to hematologic malignant diseases such as leukemia.
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http://dx.doi.org/10.14348/molcells.2018.0244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277561PMC
November 2018

Reprogramming mechanisms influence the maturation of hematopoietic progenitors from human pluripotent stem cells.

Cell Death Dis 2018 10 24;9(11):1090. Epub 2018 Oct 24.

Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, Republic of Korea.

Somatic cell nuclear transfer (SCNT) or the forced expression of transcription factors can be used to generate autologous pluripotent stem cells (PSCs). Although transcriptomic and epigenomic comparisons of isogenic human NT-embryonic stem cells (NT-ESCs) and induced PSCs (iPSCs) in the undifferentiated state have been reported, their functional similarities and differentiation potentials have not been fully elucidated. Our study showed that NT-ESCs and iPSCs derived from the same donors generally displayed similar in vitro commitment capacity toward three germ layer lineages as well as proliferative activity and clonogenic capacity. However, the maturation capacity of NT-ESC-derived hematopoietic progenitors was significantly greater than the corresponding capacity of isogenic iPSC-derived progenitors. Additionally, donor-dependent variations in hematopoietic specification and commitment capacity were observed. Transcriptome and methylome analyses in undifferentiated NT-ESCs and iPSCs revealed a set of genes that may influence variations in hematopoietic commitment and maturation between PSC lines derived using different reprogramming methods. Here, we suggest that genetically identical iPSCs and NT-ESCs could be functionally unequal due to differential transcription and methylation levels acquired during reprogramming. Our proof-of-concept study indicates that reprogramming mechanisms and genetic background could contribute to diverse functionalities between PSCs.
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http://dx.doi.org/10.1038/s41419-018-1124-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200746PMC
October 2018

Comparison of Survival Outcomes Between Partial Resection and Biopsy for Primary Glioblastoma: A Propensity Score-Matched Study.

World Neurosurg 2019 Jan 11;121:e858-e866. Epub 2018 Oct 11.

Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Objectives: Gross total resection for glioblastoma (GBM) has been associated with better prognosis. However, it is not always feasible, and the threshold for the extent of resection required for better prognosis has been controversial. Therefore, we compared the survival and clinical outcomes of patients with GBM who had undergone partial resection (PR) or biopsy.

Methods: Of the 110 patients, 32 and 78, who had undergone PR and biopsy, respectively, were enrolled to identify any differences in clinical outcomes. No differences were found in patient demographics between the 2 groups, except for tumor location and mean tumor volume (P = 0.02 and P < 0.01, respectively). Propensity score matching between the PR and biopsy groups was performed, in which 20 patients each in the PR and biopsy groups were matched.

Results: The overall survival (OS) and progression-free survival (PFS) did not differ significantly between the PR and biopsy groups (P = 0.84 and P = 0.48, respectively). After propensity score matching, the differences in OS and PFS between the 2 groups were still not statistically significant (P = 0.51 and P = 0.75, respectively). The hazard ratios for OS and PFS for the PR group compared with biopsy were 0.98 and 0.73, respectively; however, the difference was not statistically significant (P = 0.96 and P = 0.39, respectively). The surgical complication rate was greater in the PR group (14 of 32; 43.7%) than in the biopsy group (9 of 78; 11.5%; P < 0.01).

Conclusions: PR failed to improve survival compared with biopsy for patients with GBM. Moreover, the surgical complication rate in the PR group was greater than that in the biopsy group.
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http://dx.doi.org/10.1016/j.wneu.2018.09.237DOI Listing
January 2019

Prognosis and treatment outcomes of central neurocytomas: clinical interrogation based on a single center experience.

J Neurooncol 2018 Dec 17;140(3):669-677. Epub 2018 Sep 17.

Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea.

Introduction: Central neurocytoma (CN) is a very rare neuronal neoplasm. The clinical implications of the potential prognostic factors for these lesions, including tumor atypia, have therefore not been clarified.

Methods: Forty CN patients were enrolled and reclassified as typical or atypical in accordance with an MIB-1 labeling index (LI) of above and below 2%.

Results: We classified our retrospective study cohort as 21 (52.5%) typical and 19 (47.5%) atypical CN cases. No significant differences were found in terms of sex, mean age, mean tumor size or tumor location between these groups. Recurrences occurred in 2 (9.5%) typical and 6 (33.3%) atypical cases. The typical CN 2-,3- and 5-year PFS rates were 100%, 100%, 92.3%, and those for the atypical group were 93.8%, 78.1%, 65.1%, respectively (p = 0.02). The PFS rates did not statistically differ by treatment modality (gross total resection alone, subtotal resection (STR) alone and STR plus radiation therapy (RT) or radiosurgery (RS)) either in the whole cohort (p = 0.75) or in the typical CN and atypical CN subgroups (p = 0.45 and 0.98, respectively). An atypical histology was the only prognostic indicator of recurrence by univariate analysis (hazard ratio: 5.40, p = 0.04).

Conclusions: An atypical lesion (MIB-LI > 2%) is an important prognostic indicator in CN. The clinical implications of the extent of resection for CN patients are still debatable. The use of STR plus RT or RS may be a viable treatment strategy for CN but different therapeutic and follow-up approaches for atypical CN will be needed.
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http://dx.doi.org/10.1007/s11060-018-2997-zDOI Listing
December 2018

High-throughput investigation of transglutaminase 2 kinase regulation using a novel cysteine-modified peptide array.

Anal Biochem 2018 10 27;559:62-70. Epub 2018 Aug 27.

Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Kangwon-Do, 200-701, South Korea. Electronic address:

Transglutaminase 2 (TGase2) kinase has emerged as an important regulator of apoptosis as well as chromatin structure and function; however, details about the pathophysiological functions of TGase2 kinase have been limited because of the lack of a suitable activity assay for systematic investigation of TGase2 kinase regulation in a high-throughput manner. Thus, we developed a novel on-chip TGase2 kinase activity assay using a cysteine-modified insulin-like growth factor-binding protein-3-derived peptide (CMI peptide) on an array platform. This peptide array-based activity assay was reproducible, with a detection limit of 2.127 μg/ml. We successfully applied this assay to investigate the effects of thiol-reactive compounds and divalent cations on TGase2 kinase by determining the half maximal inhibitory concentrations (IC). Thiol-reactive compounds inhibited TGase2 kinase activity in a concentration-dependent manner, with IC values ranging from 0.125 to 5.550 mM. Divalent metal cations also showed a concentration-dependent inhibition, with IC values ranging from 0.005 to 1.937 mM; however, Ca had no effect on TGase2 kinase activity. Thus, this novel kinase activity assay using the CMI peptide array described here is suitable for systematic investigation of TGase2 kinase regulation and may be useful for investigating the roles of TGase2 kinase in pathogenesis of kinase-mediated diseases.
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http://dx.doi.org/10.1016/j.ab.2018.08.022DOI Listing
October 2018

Inhibition of the voltage-dependent K current by the class Ic antiarrhythmic drug flecainide in rabbit coronary arterial smooth muscle cells.

Clin Exp Pharmacol Physiol 2018 12 12;45(12):1286-1292. Epub 2018 Aug 12.

Department of Physiology, Kangwon National University School of Medicine, Chuncheon, South Korea.

This study examined the inhibitory effect of flecainide, a class 1c antiarrhythmic agent (Na channel blocker), on voltage-dependent K (Kv) channels in smooth muscle cells isolated from coronary arteries. Flecainide decreased the vascular Kv channel current in a dose-dependent manner with an IC value of 5.90 ± 0.87 μmol/L and a Hill coefficient of 0.77 ± 0.06. Although the steady-state activation curve was not affected by flecainide, it shifted the steady-state inactivation curves toward a more negative potential. Application of train pulses such as 1 or 2 Hz did not change the flecainide-induced inhibition of Kv channels, indicating that the inhibitory effect of flecainide was not use-dependent. Using perforated-patch clamp experiments, we found that inhibition of Kv channels by flecainide caused membrane depolarization. Together, these results suggest that flecainide inhibits Kv channels in a concentration-dependent, but not use-dependent manner by changing the inactivation gating properties. Furthermore, Kv channel inhibition by flecainide occurs regardless of Na channel inhibition.
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http://dx.doi.org/10.1111/1440-1681.13015DOI Listing
December 2018

Proinsulin C-peptide prevents hyperglycemia-induced vascular leakage and metastasis of melanoma cells in the lungs of diabetic mice.

FASEB J 2019 01 18;33(1):750-762. Epub 2018 Jul 18.

Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Korea.

C-peptide has a beneficial effect against diabetic complications, but its role in hyperglycemia-induced metastasis is unknown. We investigated hyperglycemia-mediated pulmonary vascular leakage and metastasis and C-peptide inhibition of these molecular events using human pulmonary microvascular endothelial cells (HPMVECs) and streptozotocin-induced diabetic mice. VEGF, which is elevated in the lungs of diabetic mice, activated transglutaminase 2 (TGase2) in HPMVECs by sequential elevation of intracellular Ca and reactive oxygen species (ROS) levels. VEGF also induced vascular endothelial (VE)-cadherin disruption and increased the permeability of endothelial cells, both of which were prevented by the TGase inhibitors monodansylcadaverine and cystamine or TGM2-specific small interfering RNA. C-peptide prevented VEGF-induced VE-cadherin disruption and endothelial cell permeability through inhibiting ROS-mediated activation of TGase2. C-peptide supplementation inhibited hyperglycemia-induced ROS generation and TGase2 activation and prevented vascular leakage and metastasis in the lungs of diabetic mice. The role of TGase2 in hyperglycemia-induced pulmonary vascular leakage and metastasis was further demonstrated in diabetic Tgm2 mice. These findings demonstrate that hyperglycemia induces metastasis, and C-peptide prevents the hyperglycemia-induced metastasis in the lungs of diabetic mice by inhibiting VEGF-induced TGase2 activation and subsequent vascular leakage.-Jeon, H.-Y., Lee, Y.-J., Kim, Y.-S., Kim, S.-Y., Han, E.-T., Park, W. S., Hong, S.-H., Kim, Y.-M., Ha, K.-S. Proinsulin C-peptide prevents hyperglycemia-induced vascular leakage and metastasis of melanoma cells in the lungs of diabetic mice.
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http://dx.doi.org/10.1096/fj.201800723RDOI Listing
January 2019

Inhibition of RAGE Attenuates Cigarette Smoke-Induced Lung Epithelial Cell Damage via RAGE-Mediated Nrf2/DAMP Signaling.

Front Pharmacol 2018 2;9:684. Epub 2018 Jul 2.

Department of Thoracic and Cardiovascular Surgery, Kangwon National University, Chuncheon, South Korea.

The oxidative stress and cellular apoptosis by environmental factor including cigarette smoke induces alveolar airway remodeling leading to chronic obstructive pulmonary disease (COPD). Recently, the receptor for advanced glycan end products (RAGE) which is highly expressed in alveolar epithelium is emerging as a biomarker for COPD susceptibility or progression. However, it still remains unknown how RAGE plays a role in cigarette smoke extract (CSE)-exposed human alveolar type II epithelial cell line. Therefore, we determined the efficacy of RAGE-specific antagonist FPS-ZM1 in response to CSE-induced lung epithelial cells. CSE induced the elevated generation of RONS and release of pro-inflammatory cytokines, and impaired the cellular antioxidant defense system. Further, CSE induced the alteration of RAGE distribution via the activation of redox-sensitive DAMP (Damage-associated molecular patterns) signaling through Nrf2 in cells. Although pre-treatment with SB202190 (p38 inhibitor) or SP600125 (JNK inhibitor) failed to recover the alteration of RAGE distribution, treatment of FPS-ZM1 significantly exhibited anti-inflammatory and anti-oxidative/nitrosative effects, also inhibited the activation of redox-sensitive DAMP signaling through Nrf2 (nuclear factor erythroid 2-related factor 2) migration in the presence of CSE. Taken together, our data demonstrate that RAGE and Nrf2 play a pivotal role in maintenance of alveolar epithelial integrity.
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http://dx.doi.org/10.3389/fphar.2018.00684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036614PMC
July 2018

Plasmodium vivax Merozoite Surface Protein 1 Paralog as a Mediator of Parasite Adherence to Reticulocytes.

Infect Immun 2018 09 22;86(9). Epub 2018 Aug 22.

Department of Medical Environmental Biology and Tropical Medicine, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, Republic of Korea

parasites preferentially invade reticulocytes in human beings. merozoite surface protein 1 (PvMSP1) and PvMSP1 paralog (PvMSP1P) may have important functions in reticulocyte adherence during invasion. These proteins share similar structures, including the presence of two epidermal growth factor (EGF)-like and glycosylphosphatidylinositol (GPI)-anchored domains at the C terminus. However, there have been no reports concerning the functional activity of PvMSP1P in reticulocyte adherence during invasion. In this study, the ability of PvMSP1P-19 to bind to reticulocytes and normocytes was analyzed. The reticulocyte binding activity of PvMSP1P-19 was 4.0-fold higher than its normocyte binding activity. The binding of PvMSP1P-19 to reticulocytes and normocytes was inhibited in a dose-dependent manner by antibodies from immunized rabbits and by antibodies from vivax parasite-infected patients. Consistently, antibodies against PvMSP1P inhibited parasite invasion during short-term cultivation. Similar to the case for PvDBPII binding activity, PvMSP1P-19 binding activity was reduced in chymotrypsin-treated reticulocytes. However, no significant difference between the binding of PvMSP1P-19 to Duffy-positive and Duffy-negative erythrocytes was found. The minimal binding motif of PvMSP1P-19 was characterized using synthetic peptides. The results showed that the residues at amino acid positions 1791 to 1808 may have an important function in mediating merozoite adherence to reticulocytes. The positively charged residues within the EGF-like domain were shown to constitute a key binding motif. This work presents strong evidence supporting the role of PvMSP1P in host target cell selection and invasion of Duffy-independent pathway in Moreover, PvMSP1P-19-specific antibodies may confer protection against reinvasion.
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http://dx.doi.org/10.1128/IAI.00239-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105898PMC
September 2018

Plasma CRABP2 as a Novel Biomarker in Patients with Non-Small Cell Lung Cancer.

J Korean Med Sci 2018 Jun 16;33(26):e178. Epub 2018 May 16.

Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea.

Background: Lung cancer is the most common cause of cancer-related mortality worldwide. We previously reported the identification of a new genetic marker, cellular retinoic acid binding protein 2 (CRABP2), in lung cancer tissues. The aim of this study was to assess plasma levels of CRABP2 from patients with non-small cell lung cancer (NSCLC).

Methods: Blood samples that were collected from 122 patients with NSCLC between September 2009 and September 2013 were selected for the analysis, along with samples from age- (± 5 years), sex-, and cigarette smoking history (± 10 pack-years [PY])-matched controls from the Korea Biobank Network. The control specimens were from patients who were without malignancies or pulmonary diseases. We measured plasma levels of CRABP2 using commercially available enzyme-linked immunosorbent assay kits.

Results: The mean age of the NSCLC patients was 71.8 ± 8.9 years, and the median cigarette smoking history was 32 PY (range, 0-150 PY). Plasma CRABP2 levels were significantly higher in patients with NSCLC than in the matched controls (37.63 ± 28.71 ng/mL vs. 24.09 ± 21.09 ng/mL, < 0.001). Higher plasma CRABP2 levels were also correlated with lower survival rates in NSCLC patients ( = 0.014).

Conclusion: Plasma CRABP2 levels might be a novel diagnostic and prognostic marker in NSCLC.
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http://dx.doi.org/10.3346/jkms.2018.33.e178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010740PMC
June 2018
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