Publications by authors named "Woo Jin Park"

111 Publications

Successful Management of Massive Congenital Hepatic Hemangioma and Systemic Hypertension With Sirolimus.

J Pediatr Hematol Oncol 2021 Mar 16. Epub 2021 Mar 16.

Department of Pediatrics, Chonnam National University Children's Hospital Department of Pediatrics, Chonnam National University Medical School Department of Radiology, Chonnam National University Hospital, Gwangju Department of Pediatrics Department of Pathology, Chonnam National University Hwasun Hospital, Hwasun, Korea.

Congenital hepatic hemangioma (CHH) is a common benign vascular tumor of the liver, seen in infancy. The clinical manifestations vary from incidental findings to life-threatening complications. The authors present here a case of an infant with massive CHH who developed systemic hypertension because of compression of the right renal artery by the CHH and did not respond to other lines of treatment. After sirolimus therapy, the CHH size decreased and antihypertensive drugs were no longer necessary. In a critical situation, if the embolization and/or steroids do not seem to control the situation, then adding sirolimus may be considered as secondary therapy with good additive effects.
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http://dx.doi.org/10.1097/MPH.0000000000002146DOI Listing
March 2021

Recyclable Transition Metal Catalysis using Bipyridine-Functionalized SBA-15 by Co-condensation of Methallylsilane with TEOS.

Chem Asian J 2021 Feb 4;16(3):197-201. Epub 2021 Jan 4.

Department of Chemistry, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.

Well-defined recyclable Pd- and Rh-bipyridyl group-impregnated SBA-15 catalysts were prepared for C-C bond coupling reaction and selective hydrogenation reactions, respectively. These SBA-15 derived ligands for the catalysts were prepared by direct and indirect co-condensation method using bipyridyl-linked methallylsilane. This indirect method, involving methoxysilane generated from methallylsilane shows higher loading efficiency of transition metal catalysts on SBA-15 than the direct use of methallylsilane.
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http://dx.doi.org/10.1002/asia.202001152DOI Listing
February 2021

Targets ATF3 to Reduce Calcium Deposition in Vascular Smooth Muscle Cells.

Mol Ther Nucleic Acids 2020 Dec 28;22:627-639. Epub 2020 Sep 28.

Department of Pharmacology, Chonnam National University Medical School, Hwasun, Jeollanamdo, Republic of Korea.

Vascular calcification, the ectopic deposition of calcium in blood vessels, develops in association with various metabolic diseases and atherosclerosis and is an independent predictor of morbidity and mortality associated with these diseases. Herein, we report that reduction of () causes an increase in activating transcription factor 3 (ATF3), a novel osteogenic transcription factor, in vascular smooth muscle cells. Both microRNA (miRNA) and mRNA microarrays were performed with rat vascular smooth muscle cells, and reciprocally regulated pairs of miRNA and mRNA were selected after bioinformatics analysis. Inorganic phosphate significantly reduced the expression of in A10 cells. The transcript level was also reduced in vitamin D-administered mouse aortas. reduced calcium deposition, whereas increased it. The Atf3 mRNA level was upregulated in a cellular vascular calcification model, and reduced the mRNA and protein levels. Transfection with could recover the -induced reduction of calcium deposition. Our results suggest that reduction of may contribute to the development of vascular calcification by de-repression of ATF3.
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http://dx.doi.org/10.1016/j.omtn.2020.09.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578555PMC
December 2020

The matricellular protein CCN5 prevents adverse atrial structural and electrical remodelling.

J Cell Mol Med 2020 10 4;24(20):11768-11778. Epub 2020 Sep 4.

College of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.

Atrial structural remodelling including atrial hypertrophy and fibrosis is a key mediator of atrial fibrillation (AF). We previously demonstrated that the matricellular protein CCN5 elicits anti-fibrotic and anti-hypertrophic effects in left ventricles under pressure overload. We here determined the utility of CCN5 in ameliorating adverse atrial remodelling and arrhythmias in a murine model of angiotensin II (AngII) infusion. Advanced atrial structural remodelling was induced by AngII infusion in control mice and mice overexpressing CCN5 either through transgenesis (CCN5 Tg) or AAV9-mediated gene transfer (AAV9-CCN5). The mRNA levels of pro-fibrotic and pro-inflammatory genes were markedly up-regulated by AngII infusion, which was significantly normalized by CCN5 overexpression. In vitro studies in isolated atrial fibroblasts demonstrated a marked reduction in AngII-induced fibroblast trans-differentiation in CCN5-treated atria. Moreover, while AngII increased the expression of phosphorylated CaMKII and ryanodine receptor 2 levels in HL-1 cells, these molecular features of AF were prevented by CCN5. Electrophysiological studies in ex vivo perfused hearts revealed a blunted susceptibility of the AAV9-CCN5-treated hearts to rapid atrial pacing-induced arrhythmias and concomitant reversal in AngII-induced atrial action potential prolongation. These data demonstrate the utility of a gene transfer approach targeting CCN5 for reversal of adverse atrial structural and electrophysiological remodelling.
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http://dx.doi.org/10.1111/jcmm.15789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579720PMC
October 2020

Characterization of Circular RNAs in Vascular Smooth Muscle Cells with Vascular Calcification.

Mol Ther Nucleic Acids 2020 Mar 14;19:31-41. Epub 2019 Nov 14.

Basic Research Laboratory for Vascular Remodeling, Chonnam National University Medical School, Jeollanam-do, Republic of Korea; Department of Biomedical Sciences, Center for Creative Biomedical Scientists at Chonnam National University, Jeollanam-do, Republic of Korea; Department of Biochemistry, Chonnam National University Medical School, Jeollanam-do, Republic of Korea. Electronic address:

Circular RNAs (circRNAs) are generally formed by back splicing and are expressed in various cells. Vascular calcification (VC), a common complication of chronic kidney disease (CKD), is often associated with cardiovascular disease. The relationship between circRNAs and VC has not yet been studied. Inorganic phosphate (Pi) was used to treat rat vascular smooth muscle cells to induce VC. circRNAs were identified by analyzing RNA sequencing (RNA-seq) data, and their expression change during VC was validated. The selected circRNAs, including circSamd4a, circSmoc1-1, circMettl9, and circUxs1, were resistant to RNase R digestion and mostly localized in the cytoplasm. While silencing circSamd4a promoted VC, overexpressing it reduced VC in calcium assay and Alizarin red S (ARS) staining. In addition, microRNA (miRNA) microarray, luciferase reporter assay, and calcium assay suggested that circSamd4a could act as a miRNA suppressor. Our data show that circSamd4a has an anti-calcification role by functioning as a miRNA sponge. Moreover, mRNAs that can interact with miRNAs were predicted from RNA-seq and bioinformatics analysis, and the circSamd4a-miRNA-mRNA axis involved in VC was verified by luciferase reporter assay and calcium assay. Since circSamd4a is conserved in humans, it can serve as a novel therapeutic target in resolving VC.
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http://dx.doi.org/10.1016/j.omtn.2019.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909180PMC
March 2020

Recent Advances in Anti-Aging Medicine.

Korean J Fam Med 2019 Sep 20;40(5):289-296. Epub 2019 Sep 20.

Department of Family Medicine, Yonsei University College of Medicine, Seoul, Korea.

A rapidly aging population in Korea has led to increased attention in the field of anti-aging medicine. The purpose of anti-aging medicine is to slow, stop, or reverse the aging process and its associated effects, such as disability and frailty. Anti-aging medicine is emerging as a growing industry, but many supplements or protocols are available that do not have scientific evidence to support their claims. In this review, the mechanisms of action and the clinical implications of anti-aging interventions were examined and explained. Calorie restriction mimetics define compounds that imitate the outcome of calorie restriction, including an activator of AMP protein kinase (metformin), inhibitor of growth hormone/insulin-like growth factor-1 axis (pegvisomant), inhibitor of mammalian target of rapamycin (rapamycin), and activator of the sirtuin pathway (resveratrol). Hormonal replacement has also been widely used in the elderly population to improve their quality of life. Manipulating healthy gut microbiota through prebiotic/probiotics or fecal microbiota transplantation has significant potential in anti-aging medicine. Vitamin D is expected to be a primary anti-aging medicine in the near future due to its numerous positive effects in the elderly population.
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http://dx.doi.org/10.4082/kjfm.19.0087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768834PMC
September 2019

Cardioprotective role of APIP in myocardial infarction through ADORA2B.

Cell Death Dis 2019 07 1;10(7):511. Epub 2019 Jul 1.

School of Biological Science, Seoul National University, Seoul, 08826, Korea.

In ischemic human hearts, the induction of adenosine receptor A2B (ADORA2B) is associated with cardioprotection against ischemic heart damage, but the mechanism underlying this association remains unclear. Apaf-1-interacting protein (APIP) and ADORA2B transcript levels in human hearts are substantially higher in patients with heart failure than in controls. Interestingly, the APIP and ADORA2B mRNA levels are highly correlated with each other (R = 0.912). APIP expression was significantly increased in primary neonatal cardiomyocytes under hypoxic conditions and this induction reduced myocardial cell death via the activation of the AKT-HIF1α pathway. Accordingly, infarct sizes of APIP transgenic mice after left anterior descending artery ligation were significantly reduced compared to those of wild-type mice. Strikingly, knockdown of APIP expression impaired the cytoprotective effects of ADORA2B during hypoxic damage. Immunoprecipitation and proximity ligation assays revealed that APIP interacts with ADORA2B, leading to the stabilization of both proteins by interfering with lysosomal degradation, and to the activation of the downstream PKA-CREB signaling pathways. ADORA2B levels in the hearts of APIP, APIP, and Apip mice were proportionally downregulated. In addition, ADORA2B D296G derived from the rs200741295 polymorphism failed to bind to APIP and did not exert cardioprotective activity during hypoxia. Moreover, Adora2b D296G knock-in mice were more vulnerable than control mice to myocardial infarction and intentional increases in APIP levels overcame the defective protection of the ADORA2B SNP against ischemic injury. Collectively, APIP is crucial for cardioprotection against myocardial infarction by virtue of binding to and stabilizing ADORA2B, thereby dampening ischemic heart injury.
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http://dx.doi.org/10.1038/s41419-019-1746-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602929PMC
July 2019

Long noncoding RNAs in vascular smooth muscle cells regulate vascular calcification.

Sci Rep 2019 04 10;9(1):5848. Epub 2019 Apr 10.

Basic Research Laboratory for Cardiac Remodeling Research Laboratory, Chonnam National University Medical School, Jeollanam-do, Republic of Korea.

Vascular calcification is characterized by the accumulation of hydroxyapatite crystals, which is a result of aberrant mineral metabolism. Although many clinical studies have reported its adverse effects on cardiovascular morbidity, the molecular mechanism of vascular calcification, especially the involvement of long noncoding RNAs (lncRNAs), is not yet reported. From the transcriptomic analysis, we discovered hundreds of lncRNAs differentially expressed in rat vascular smooth muscle cells (VSMCs) treated with inorganic phosphate, which mimics vascular calcification. We focused on Lrrc75a-as1 and elucidated its transcript structure and confirmed its cytoplasmic localization. Our results showed that calcium deposition was elevated after knockdown of Lrrc75a-as1, while its overexpression inhibited calcium accumulation in A10 cells. In addition, Lrrc75a-as1 attenuated VSMCs calcification by decreasing the expression of osteoblast-related factors. These findings suggest that Lrrc75a-as1 acts as a negative regulator of vascular calcification, and may serve as a possible therapeutic target in vascular calcification.
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http://dx.doi.org/10.1038/s41598-019-42283-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458154PMC
April 2019

Role of SIRT1 in Modulating Acetylation of the Sarco-Endoplasmic Reticulum Ca-ATPase in Heart Failure.

Circ Res 2019 04;124(9):e63-e80

From the Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York (P.A.G., D.J., A.L., P.L., J.G.O., V.C., R.J.H., C.K.).

Rationale: SERCA2a, sarco-endoplasmic reticulum Ca-ATPase, is a critical determinant of cardiac function. Reduced level and activity of SERCA2a are major features of heart failure. Accordingly, intensive efforts have been made to develop efficient modalities for SERCA2a activation. We showed that the activity of SERCA2a is enhanced by post-translational modification with SUMO1 (small ubiquitin-like modifier 1). However, the roles of other post-translational modifications on SERCA2a are still unknown.

Objective: In this study, we aim to assess the role of lysine acetylation on SERCA2a function and determine whether inhibition of lysine acetylation can improve cardiac function in the setting of heart failure.

Methods And Results: The acetylation of SERCA2a was significantly increased in failing hearts of humans, mice, and pigs, which is associated with the reduced level of SIRT1 (sirtuin 1), a class III histone deacetylase. Downregulation of SIRT1 increased the SERCA2a acetylation, which in turn led to SERCA2a dysfunction and cardiac defects at baseline. In contrast, pharmacological activation of SIRT1 reduced the SERCA2a acetylation, which was accompanied by recovery of SERCA2a function and cardiac defects in failing hearts. Lysine 492 (K492) was of critical importance for the regulation of SERCA2a activity via acetylation. Acetylation at K492 significantly reduced the SERCA2a activity, presumably through interfering with the binding of ATP to SERCA2a. In failing hearts, acetylation at K492 appeared to be mediated by p300 (histone acetyltransferase p300), a histone acetyltransferase.

Conclusions: These results indicate that acetylation/deacetylation at K492, which is regulated by SIRT1 and p300, is critical for the regulation of SERCA2a activity in hearts. Pharmacological activation of SIRT1 can restore SERCA2a activity through deacetylation at K492. These findings might provide a novel strategy for the treatment of heart failure.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.313865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483854PMC
April 2019

Role of the PRC2-Six1-miR-25 signaling axis in heart failure.

J Mol Cell Cardiol 2019 04 13;129:58-68. Epub 2019 Feb 13.

Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

The reduced expression of cardiac sarco-endoplasmic reticulum Ca ATPase (SERCA2a) is a hallmark of heart failure. We previously showed that miR-25 is a crucial transcriptional regulator of SERCA2a in the heart. However, the precise mechanism of cardiac miR-25 regulation is largely unknown. Literatures suggested that miR-25 is regulated by the transcriptional co-factor, sine oculis homeobox homolog 1 (Six1), which in turn is epigenetically regulated by polycomb repressive complex 2 (PRC 2) in cardiac progenitor cells. Therefore, we aimed to investigate whether Six1 and PRC2 are indeed involved in the regulation of the miR-25 level in the setting of heart failure. Six1 was up-regulated in the failing hearts of humans and mice. Overexpression of Six1 led to adverse cardiac remodeling, whereas knock-down of Six1 attenuated pressure overload-induced cardiac dysfunction. The adverse effects of Six1 were ameliorated by knock-down of miR-25. The epigenetic repression on the Six1 promoter by PRC2 was significantly reduced in failing hearts. Epigenetic repression of Six1 is relieved through a reduction of PRC2 activity in heart failure. Six1 up-regulates miR-25, which is followed by reduction of cardiac SERCA2a expression. Collectively, these data showed that the PRC2-Six1-miR-25 signaling axis is involved in heart failure. Our finding introduces new insight into potential treatments of heart failure.
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http://dx.doi.org/10.1016/j.yjmcc.2019.01.017DOI Listing
April 2019

Inhibition of heat shock protein 70 blocks the development of cardiac hypertrophy by modulating the phosphorylation of histone deacetylase 2.

Cardiovasc Res 2019 Nov;115(13):1850-1860

Department of Pharmacology, Chonnam National University Medical School, Hwasun, Republic of Korea.

Aims: Previously, we reported that phosphorylation of histone deacetylase 2 (HDAC2) and the resulting activation causes cardiac hypertrophy. Through further study of the specific binding partners of phosphorylated HDAC2 and their mechanism of regulation, we can better understand how cardiac hypertrophy develops. Thus, in the present study, we aimed to elucidate the function of one such binding partner, heat shock protein 70 (HSP70).

Methods And Results: Primary cultures of rat neonatal ventricular cardiomyocytes and H9c2 cardiomyoblasts were used for in vitro cellular experiments. HSP70 knockout (KO) mice and transgenic (Tg) mice that overexpress HSP70 in the heart were used for in vivo analysis. Peptide-precipitation and immunoprecipitation assay revealed that HSP70 preferentially binds to phosphorylated HDAC2 S394. Forced expression of HSP70 increased phosphorylation of HDAC2 S394 and its activation, but not that of S422/424, whereas knocking down of HSP70 reduced it. However, HSP70 failed to phosphorylate HDAC2 in the cell-free condition. Phosphorylation of HDAC2 S394 by casein kinase 2α1 enhanced the binding of HSP70 to HDAC2, whereas dephosphorylation induced by the catalytic subunit of protein phosphatase 2A (PP2CA) had the opposite effect. HSP70 prevented HDAC2 dephosphorylation by reducing the binding of HDAC2 to PP2CA. HSP70 KO mouse hearts failed to phosphorylate S394 HDAC2 in response to isoproterenol infusion, whereas Tg overexpression of HSP70 increased the phosphorylation and activation of HDAC2. 2-Phenylethynesulfonamide (PES), an HSP70 inhibitor, attenuated cardiac hypertrophy induced either by phenylephrine in neonatal ventricular cardiomyocytes or by aortic banding in mice. PES reduced HDAC2 S394 phosphorylation and its activation by interfering with the binding of HSP70 to HDAC2.

Conclusion: These results demonstrate that HSP70 specifically binds to S394-phosphorylated HDAC2 and maintains its phosphorylation status, which results in HDAC2 activation and the development of cardiac hypertrophy. Inhibition of HSP70 has possible application as a therapeutic.
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http://dx.doi.org/10.1093/cvr/cvy317DOI Listing
November 2019

The matricellular protein CCN5 inhibits fibrotic deformation of retinal pigment epithelium.

PLoS One 2018 20;13(12):e0208897. Epub 2018 Dec 20.

College of Life Sciences, Gwangju Institute of Science and Technology, Cheomdangwagi-ro, Buk-gu, Gwangju, Republic of Korea.

Retinal pigment epithelium (RPE) plays an essential role in maintaining retinal function, and its defect is thought to be critically implicated in various ocular disorders. This study demonstrated that the matricellular protein CCN5 was down-regulated in ARPE-19 cells treated with the pro-fibrotic agent transforming growth factor (TGF)-β. A recombinant adenovirus expressing CCN5 (AdCCN5) was used to restore the level of CCN5 in these cells. AdCCN5 prevented TGF-β-induced fibrotic changes, including disruption of tight junctions, up-regulation of mesenchymal marker proteins, and down-regulation of epithelial marker proteins. In addition, AdCCN5 prevented TGF-β-induced functional defects, including increased migratory activity and reduced phagocytic activity. Notably, AdCCN5 reversed morphological and functional defects pre-established by TGF-β prior to viral infection. The CCN5 level was down-regulated in RPE of 18-month-old Ccl2-/- mice, which exhibited retinal defects. Restoration of the CCN5 level via intravitreal injection of a recombinant adeno-associated virus expressing CCN5 (AAV9-CCN5) normalized the altered expression of mesenchymal, epithelial, and functional marker proteins, as assessed by western blotting and immunohistochemistry. Taken together, these data suggest that down-regulation of CCN5 is associated with fibrotic deformation of RPE under pathological conditions and that restoration of the CCN5 level effectively promotes recovery of deformed RPE.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208897PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301692PMC
May 2019

Costchondritis with necrotizing lymphadenopathy in an 11-month-old boy caused by BCG vaccination.

Pediatr Pulmonol 2019 01 3;54(1):7-9. Epub 2018 Dec 3.

Department of Pediatrics, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea.

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http://dx.doi.org/10.1002/ppul.24197DOI Listing
January 2019

CCN5 knockout mice exhibit lipotoxic cardiomyopathy with mild obesity and diabetes.

PLoS One 2018 28;13(11):e0207228. Epub 2018 Nov 28.

College of Life Sciences, Gwangju Institute of Science and Technology, Buk-gu, Gwangju, Republic of Korea.

Obesity is associated with various human disorders, such as type 2 diabetes, cardiovascular diseases, hypertension, and cancers. In this study, we observed that knockout (KO) of CCN5, which encodes a matricellular protein, caused mild obesity in mice. The CCN5 KO mice also exhibited mild diabetes characterized by high fasting glucose levels and impaired insulin and glucose tolerances. Cardiac hypertrophy, ectopic lipid accumulation, and impaired lipid metabolism in hearts were observed in the CCN5 KO mice, as determined using histology, quantitative RT-PCR, and western blotting. Fibrosis was significantly greater in hearts from the CCN5 KO mice both in interstitial and perivascular regions, which was accompanied by higher expression of pro-fibrotic and pro-inflammatory genes. Both systolic and diastolic functions were significantly impaired in hearts from the CCN5 KO mice, as assessed using echocardiography. Taken together, these results indicate that CCN5 KO leads to lipotoxic cardiomyopathy with mild obesity and diabetes in mice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207228PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261567PMC
April 2019

Effects of Heat-Treatment on Photoluminescence Spectra and Photocatalytic Properties of Solution-Combusted ZnO Nanopowders.

J Nanosci Nanotechnol 2019 Mar;19(3):1764-1767

Department of Materials Science and Engineering, Myongji University, Yongin, Kyunggi 17058, Korea.

ZnO nanopowders were prepared by a solution combustion method (SCM). The SCM ZnO nanopowders were heat-treated at 200, 400, 500, or 700 °C for 30 min in air and the photoluminescence (PL) of the nanopowders was evaluated. Two strong PL emission peaks are generally recognized as the unique PL signature of ZnO, one is from the band-edge emission and the other corresponds to green emission. The green emission is derived from crystalline defects, and is a critical obstacle for the electrooptical applications of ZnO. Surprisingly, the PL spectra of the SCM ZnO powders showed a single sharp peak near 390 nm. Furthermore, the intensity of this blue emission doubled when the synthesized ZnO powder was heat-treated at 400 °C. The green emission appeared for the sample treated at 500 °C, and was the highest for that treated at 700 °C. To comfirm the photocatalytic activity of the ZnO powder heat-treated at 400 °C, the removal of Ag ions from a used photofilm developer was evaluated, with complete removal within 10 min. The removal of the Ag ions by the ZnO powder heat-treated at 400 °C was more than two orders of magnitude faster than that achieved with the SCM ZnO powder. The relation between PL and photocatalytic activity was explained in terms of recombination of the photogenerated electrons. These results might be very useful for highly efficient photocatalyst applications.
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http://dx.doi.org/10.1166/jnn.2019.16156DOI Listing
March 2019

A one-step method for covalent bond immobilization of biomolecules on silica operated in aqueous solution.

Chem Sci 2018 Nov 24;9(41):7981-7985. Epub 2018 Aug 24.

Department of Chemistry , Yonsei University , 50 Yonsei-ro, Seodaemun-gu , Seoul 03722 , Republic of Korea . Email:

A simple, one-step method for covalent bond immobilization of biomolecules on silica operated in water is described. In the approach, an NHS-ester linked methallylsilane is utilized as a bifunctional linker to couple the biomolecule to the silica surface. Weak organic acid such as acetic acid activates the silica surface enough to react with bifunctional linker without destroying activity of biomolecule.
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http://dx.doi.org/10.1039/c8sc02565gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201817PMC
November 2018

Thyrocyte-specific deletion of insulin and IGF-1 receptors induces papillary thyroid carcinoma-like lesions through EGFR pathway activation.

Int J Cancer 2018 11 22;143(10):2458-2469. Epub 2018 Sep 22.

Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea.

Insulin and insulin-like growth factor (IGF)-1 signaling in the thyroid are thought to be permissive for the coordinated regulation by thyroid-stimulating hormone (TSH) of thyrocyte proliferation and hormone production. However, the integrated role of insulin receptor (IR) and IGF-1 receptor (IGF-1R) in thyroid development and function has not been explored. Here, we generated thyrocyte-specific IR and IGF-1R double knockout (DTIRKO) mice to precisely evaluate the coordinated functions of these receptors in the thyroid of neonates and adults. Neonatal DTIRKO mice displayed smaller thyroids, paralleling defective folliculogenesis associated with repression of the thyroid-specific transcription factor Foxe1. By contrast, at postnatal day 14, absence of IR and IGF-1R paradoxically induced thyrocyte proliferation, which was mediated by mTOR-dependent signaling pathways. Furthermore, we found elevated production of TSH during the development of follicular hyperplasia at 8 weeks of age. By 50 weeks, all DTIRKO mice developed papillary thyroid carcinoma (PTC)-like lesions that correlated with induction of the ErbB pathway. Taken together, these data define a critical role for IR and IGF-1R in neonatal thyroid folliculogenesis. They also reveal an important reciprocal relationship between IR/IGF-1R and TSH/ErbB signaling in the pathogenesis of thyroid follicular hyperplasia and, possibly, of papillary carcinoma.
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http://dx.doi.org/10.1002/ijc.31779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698377PMC
November 2018

Identification of long noncoding RNAs involved in muscle differentiation.

PLoS One 2018 2;13(3):e0193898. Epub 2018 Mar 2.

Basic Research Laboratory for Cardiac Remodeling Research Laboratory, Chonnam National University Medical School, Jeollanam-do, Republic of Korea.

Long noncoding RNAs (lncRNAs) are a large class of regulatory RNAs with diverse roles in cellular processes. Thousands of lncRNAs have been discovered; however, their roles in the regulation of muscle differentiation are unclear because no comprehensive analysis of lncRNAs during this process has been performed. In the present study, by combining diverse RNA sequencing datasets obtained from public database, we discovered lncRNAs that could behave as regulators in the differentiation of smooth or skeletal muscle cells. These analyses confirmed the roles of previously reported lncRNAs in this process. Moreover, we discovered dozens of novel lncRNAs whose expression patterns suggested their possible involvement in the phenotypic switch of vascular smooth muscle cells. The comparison of lncRNA expression change suggested that many lncRNAs have common roles during the differentiation of smooth and skeletal muscles, while some lncRNAs may have opposite roles in this process. The expression change of lncRNAs was highly correlated with that of their neighboring genes, suggesting that they may function as cis-acting lncRNAs. Furthermore, within the lncRNA sequences, there were binding sites for miRNAs with expression levels inversely correlated with the expression of corresponding lncRNAs during differentiation, suggesting a possible role of these lncRNAs as competing endogenous RNAs. The lncRNAs identified in this study will be a useful resource for future studies of gene regulation during muscle differentiation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193898PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834194PMC
June 2018

Connexin43 and zonula occludens-1 are targets of Akt in cardiomyocytes that correlate with cardiac contractile dysfunction in Akt deficient hearts.

Biochim Biophys Acta Mol Basis Dis 2018 Apr 31;1864(4 Pt A):1183-1191. Epub 2018 Jan 31.

Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Republic of Korea. Electronic address:

While deletion of Akt1 results in a smaller heart size and Akt2 mice are mildly insulin resistant, Akt1/Akt2 mice exhibit perinatal lethality, indicating a large degree of functional overlap between the isoforms of the serine/threonine kinase Akt. The present study aimed to determine the cooperative contribution of Akt1 and Akt2 on the structure and contractile function of adult hearts. To generate an inducible, cardiomyocyte-restricted Akt2 knockout (KO) model, Akt2 mice were crossed with tamoxifen-inducible MerCreMer transgenic (MCM) mice and germline Akt1 mice to generate the following genotypes:Akt1; Akt2 (WT), Akt2; α-MHC-MCM (iAkt2 KO), Akt1, and Akt1; Akt2; α-MHC-MCM mice (Akt1/iAkt2 KO). At 28 days after the first tamoxifen injection, Akt1/iAkt2 KO mice developed contractile dysfunction paralleling increased atrial and brain natriuretic peptide (ANP and BNP) levels, and repressed mitochondrial gene expression. Neither cardiac fibrosis nor apoptosis were detected in Akt1/iAkt2 KO hearts. To explore potential molecular mechanisms for contractile dysfunction, we investigated myocardial microstructure before the onset of heart failure. At 3 days after the first tamoxifen injection, Akt1/iAkt2 KO hearts showed decreased expression of connexin43 (Cx43) and connexin-interacting protein zonula occludens-1 (ZO-1). Furthermore, Akt1/2 silencing significantly decreased both Cx43 and ZO-1 expression in cultured neonatal rat cardiomyocytes in concert with reduced beating frequency. Akt1 and Akt2 are required to maintain cardiac contraction. Loss of Akt signaling disrupts gap junction protein, which might precipitate early contractile dysfunction prior to heart failure in the absence of myocardial remodeling, such as hypertrophy, fibrosis, or cell death.
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http://dx.doi.org/10.1016/j.bbadis.2018.01.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342503PMC
April 2018

Association of platelet count with sarcopenic obesity in postmenopausal women: A nationwide population-based study.

Clin Chim Acta 2018 Feb 5;477:113-118. Epub 2017 Dec 5.

Department of Family Medicine, Yong-In Severance Hospital, Yonsei University College of Medicine, Yong-In, Republic of Korea; Department of Medicine, Graduate School of Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address:

Objectives: The aim of this study was to examine the relationship between platelet count and sarcopenic obesity in postmenopausal women.

Method: This cross-sectional study was conducted using nationally representative data. A total of 2810 postmenopausal women who participated in the 2008-2011 Korea National Health and Nutrition Examination Survey were included in this study. Sarcopenic obesity was defined by a sarcopenia criterion and an obesity criterion. Platelet counts were divided into quartiles as follows: Q, 150-222; Q2, 223-257; Q3, 258-294, and Q4, 295-450 (10/μl). Multiple logistic regression analysis was performed to examine the association between platelet count quartile and sarcopenic obesity after adjusting for confounding factors.

Results: The prevalence of sarcopenic obesity in postmenopausal women was 14.8%. Compared to the lowest platelet quartile, the odds ratios and 95% confidence intervals for sarcopenic obesity in the highest quartile were 1.98 (1.36-2.89) in the unadjusted model; 1.93 (1.31-2.83) after adjusting for age; and 1.65 (1.23-2.65) after adjusting for age, systolic blood pressure, homeostatic model assessment insulin resistance (HOMA-IR), triglyceride, total cholesterol, total calorie intake, regular exercise, current smoking status, and education level.

Conclusions: Elevated platelet count (i.e. towards the upper end of the normal range) was significantly associated with sarcopenic obesity in postmenopausal women.
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http://dx.doi.org/10.1016/j.cca.2017.12.004DOI Listing
February 2018

Tenascin-C in Cardiac Hypertrophy and Fibrosis: Friend or Foe?

J Am Coll Cardiol 2017 09;70(13):1616-1617

Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.

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http://dx.doi.org/10.1016/j.jacc.2017.08.014DOI Listing
September 2017

Dry age-related macular degeneration like pathology in aged 5XFAD mice: Ultrastructure and microarray analysis.

Oncotarget 2017 Jun;8(25):40006-40018

Department of Biomedical Sciences, Seoul National University College of Medicine, Daehak-Ro, Jongno-Gu, Seoul, Republic of Korea.

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly. The two types of AMD are: dry and wet AMD. While laser-induced choroidal neovascularization has been used extensively in the studies of wet AMD, there is no established mouse model that fully recapitulates the cardinal features of dry AMD. A lack of appropriate mouse model for dry AMD has hampered the translational research on the pathogenesis of the disease and the development of therapeutic agents. We hypothesized that 5XFAD mice, an animal model for the study of Alzheimer's disease, can be used as a mouse model for dry AMD with regard to the amyloid beta (Aβ) related pathology. In this study, the ultrastructure of the retinal pigment epithelium (RPE) of 5XFAD mice was analyzed using transmission electron microscopy. Of importance, the aged 5XFAD mice show ultrastructural changes in the RPE and Bruch's membrane (BM) that are compatible with the cardinal features of human dry AMD, including a loss of apical microvilli and basal infolding of the RPE, increased BM thickness, basal laminar and linear deposits, and accumulation of lipofuscin granules and undigested photoreceptor outer segment-laden phagosomes. In microarray-based analysis, the RPE complex of the aged 5XFAD mice shows differential gene expression profiles consistent with dry AMD in the inflammation response, immune reaction pathway, and decreased retinol metabolism. Taken together, we suggest that aged 5XFAD mice can be used as a mouse model of dry AMD to study Aβ related pathology and develop a new therapeutic approaches.
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http://dx.doi.org/10.18632/oncotarget.16967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522269PMC
June 2017

Tauroursodeoxycholic acid (TUDCA) attenuates pressure overload-induced cardiac remodeling by reducing endoplasmic reticulum stress.

PLoS One 2017 20;12(4):e0176071. Epub 2017 Apr 20.

School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea.

Pressure overload in the heart induces pathological hypertrophy and is associated with cardiac dysfunction. Apoptosis and fibrosis signaling initiated by the endoplasmic reticulum stress (ERS) is known to contribute to these maladaptive effects. The aim of this study was to investigate whether reduction of ERS by a known chemical chaperone, tauroursodeoxycholic acid (TUDCA) can attenuate pressure overload-induced cardiac remodeling in a mouse model of transverse aortic constriction (TAC). Oral administration of TUDCA at a dose of 300 mg/kg body weight (BW) in the TUDCA-TAC group reduced ERS markers (GRP78, p-PERK, and p-eIf2α), compared to the Vehicle (Veh)-TAC group. TUDCA administration, for 4 weeks after TAC significantly reduced cardiac hypertrophy as shown by the reduced heart weight (HW) to BW ratio, and expression of hypertrophic marker genes (ANF, BNP, and α-SKA). Masson's trichrome staining showed that myocardial fibrosis and collagen deposition were also significantly reduced in the TUDCA-TAC group. We also found that TUDCA significantly decreased expression of TGF-β signaling proteins and collagen isoforms. TUDCA administration also reduced cardiac apoptosis and the related proteins in the TUDCA-TAC group. Microarray analysis followed by gene ontology (GO) and pathway analysis demonstrated that extracellular matrix genes responsible for hypertrophy and fibrosis, and mitochondrial genes responsible for apoptosis and fatty acid metabolism were significantly altered in the Veh-TAC group, but the alterations were normalized in the TUDCA-TAC group, suggesting potential of TUDCA in treatment of heart diseases related to pressure-overload.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0176071PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398705PMC
September 2017

PICOT alleviates myocardial ischemia-reperfusion injury by reducing intracellular levels of reactive oxygen species.

Biochem Biophys Res Commun 2017 04 28;485(4):807-813. Epub 2017 Feb 28.

College of Life Sciences, Gwangju Institute of Science and Technology, Gwangju Institute of Science and Technology, 123 Cheomdangwagi-ro, Buk-gu, Gwangju 61005, Republic of Korea. Electronic address:

Excessive generation of reactive oxygen species (ROS) is one of the main causes of myocardial ischemia-reperfusion (I/R) injury. In this study, we investigated the role of protein kinase C-interacting cousin of thioredoxin (PICOT; Grx3) during myocardial I/R using PICOT transgenic (TG) and knockdown (KD) mice. Infarction and apoptosis were attenuated in PICOT TG mice but exacerbated in PICOT KD mice upon I/R. In parallel, I/R-induced generation of ROS was attenuated in PICOT TG mice but exacerbated in PICOT KD mice. Angiotensin II (AngII)-mediated increases in ROS and free iron levels were also attenuated in cardiomyocytes isolated from PICOT TG mice but exacerbated in cardiomyocytes from PICOT KD mice. Accordingly, HO-mediated cell death was attenuated in cardiomyocytes isolated from PICOT TG mice but exacerbated in cardiomyocytes from PICOT KD mice. Taken together, these data show that PICOT alleviates myocardial I/R injury by regulating intracellular ROS and free iron levels. We suggest that PICOT presents a novel therapeutic strategy for myocardial I/R injury.
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http://dx.doi.org/10.1016/j.bbrc.2017.02.136DOI Listing
April 2017

Cardiac fibrosis and miR-433.

Ann Transl Med 2016 Dec;4(24):511

College of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.

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http://dx.doi.org/10.21037/atm.2016.11.28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5233473PMC
December 2016

Metal-Organic Cooperative Catalysis in C-H and C-C Bond Activation.

Chem Rev 2017 Jul 6;117(13):8977-9015. Epub 2017 Jan 6.

Department of Chemistry, Yonsei University , 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.

Transition-metal-catalyzed activation of C-H and C-C bonds is a challenging area in synthetic organic chemistry. Among various methods to accomplish these processes, the approach using metal-organic cooperative catalytic systems is one of the most promising. In this protocol, organic molecules as well as transition metals act as catalysts to bring about reactions, which proceed with high efficiencies and selectivities. Various metal-organic cooperative catalytic systems developed for C-H and C-C bond activation reactions are discussed in this review. Also discussed are how each metal-organic cooperative catalyst affects the reaction mechanism and what kinds of substrates can be applied in each of the catalytic processes.
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http://dx.doi.org/10.1021/acs.chemrev.6b00554DOI Listing
July 2017

MicroRNA-101b attenuates cardiomyocyte hypertrophy by inhibiting protein kinase C epsilon signaling.

FEBS Lett 2017 Jan 19;591(1):16-27. Epub 2016 Dec 19.

College of Life Sciences, Gwangju Institute of Science and Technology, Korea.

Previously, a surgical regression model identified microRNA-101b (miR-101b) as a potential inhibitor of cardiac hypertrophy. Here, we investigated the antihypertrophic mechanism of miR-101b using neonatal rat ventricular myocytes. miR-101b markedly suppressed agonist-induced cardiac hypertrophy as shown by cell size and fetal gene expression. By systems biology approaches, we identified protein kinase C epsilon (PKCε) as the major target of miR-101b. Our results from qRT-PCR, western blot, and luciferase reporter assays confirm that PKCε is a direct target of miR-101b. In addition, we found that effectors downstream of PKCε (p-AKT, p-ERK1/2, p-NFAT, and p-GSK3β) are also affected by miR-101b. Our study reveals a novel inhibitory mechanism for miR-101b as a negative regulator of cardiac hypertrophy.
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http://dx.doi.org/10.1002/1873-3468.12508DOI Listing
January 2017

Cytokine-Like 1 Regulates Cardiac Fibrosis via Modulation of TGF-β Signaling.

PLoS One 2016 11;11(11):e0166480. Epub 2016 Nov 11.

College of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Korea.

Cytokine-like 1 (Cytl1) is a secreted protein that is involved in diverse biological processes. A comparative modeling study indicated that Cytl1 is structurally and functionally similar to monocyte chemoattractant protein 1 (MCP-1). As MCP-1 plays an important role in cardiac fibrosis (CF) and heart failure (HF), we investigated the role of Cytl1 in a mouse model of CF and HF. Cytl1 was upregulated in the failing mouse heart. Pressure overload-induced CF was significantly attenuated in cytl1 knock-out (KO) mice compared to that from wild-type (WT) mice. By contrast, adeno-associated virus (AAV)-mediated overexpression of cytl1 alone led to the development of CF in vivo. The endothelial-mesenchymal transition (EndMT) and the transdifferentiation of fibroblasts (FBs) to myofibroblasts (MFBs) have been suggested to contribute considerably to CF. Adenovirus-mediated overexpression of cytl1 was sufficient to induce these two critical CF-related processes in vitro, which were completely abrogated by co-treatment with SB-431542, an antagonist of TGF-β receptor 1. Cytl1 induced the expression of TGF-β2 both in vivo and in vitro. Antagonizing the receptor for MCP-1, C-C chemokine receptor type 2 (CCR2), with CAS 445479-97-0 did not block the pro-fibrotic activity of Cytl1 in vitro. Collectively, our data suggest that Cytl1 plays an essential role in CF likely through activating the TGF-β-SMAD signaling pathway. Although the receptor for Cyt1l remains to be identified, Cytl1 provides a novel platform for the development of anti-CF therapies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0166480PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5105950PMC
June 2017

A Decoy Peptide Targeted to Protein Phosphatase 1 Attenuates Degradation of SERCA2a in Vascular Smooth Muscle Cells.

PLoS One 2016 28;11(10):e0165569. Epub 2016 Oct 28.

College of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.

Neointimal growth in the injured vasculature is largely facilitated by the proliferation of vascular smooth muscle cells (VSMC), which associates with reduced sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) activity. The gene transfer-mediated restoration of the SERCA2a level thus attenuates neointimal growth and VSMC proliferation. We previously reported that a peptide targeted to protein phosphatase 1, ψPLB-SE, normalizes SERCA2a activity in cardiomyocytes. In this study, we found that ψPLB-SE attenuated neointimal growth in balloon-injured rat carotid arteries, and the proliferation and migration of VSMC cultured in high-serum media (synthetic conditions). In parallel, ψPLB-SE inhibited the degradation of SERCA2a in the injured carotid arteries and VSMC under synthetic conditions. The calpain inhibitor MDL28170 also attenuated SERCA2a degradation and VSMC proliferation under synthetic conditions, indicating that calpain degrades SERCA2a. The Ca2+ ionophore A23187 induced SERCA2a degradation in VSMC, which was blocked by either ψPLB-SE or MDL28170. Additionally, ψPLB-SE normalized the cytosolic Ca2+ level in VSMC that was increased by either A23187 or synthetic stimulation. Collectively, these data indicate that ψPLB-SE corrects the abnormal Ca2+ handling by activating SERCA2a, which further protects SERCA2a from calpain-dependent degradation in VSMC. We conclude that ψPLB-SE may form the basis of a therapeutic strategy for vascular proliferative disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165569PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085086PMC
June 2017

Rapamycin ameliorates chitosan nanoparticle-induced developmental defects of preimplantation embryos in mice.

Oncotarget 2016 11;7(46):74658-74677

Department of Stem Cell and Regenerative Biotechnology, Humanized Pig Research Center (SRC), Konkuk University, Seoul, Republic of Korea.

Chitosan nanoparticles (CSNPs) are used as drug or gene delivery vehicles. However, a detailed understanding of the effects of CSNPs on embryonic development remains obscure. Here, we show that CSNPs can be internalized into mouse blastocysts, such as the zona pellucida, the perivitelline space, and the cytoplasm. Consequently, CSNPs-induced endoplasmic reticulum (ER) stress increases both of Bip/Grp78, Chop, Atf4, Perk, and Ire1a mRNAs expression levels, and reactive oxygen species. Moreover, CSNPs show double- and multi-membraned autophagic vesicles, and lead to cell death of blastocoels. Conversely, treatment with rapamycin, which plays an important role as a central regulator of cellular proliferation and stress responses, decreased CSNPs-induced mitochondrial Ca+2 overloading, apoptosis, oxidative stress, ER stress, and autophagy. In vivo studies demonstrated that CSNPs injection has significant toxic effect on primordial and developing follicles. Notably, rapamycin rescued oxidative stress-induced embryonic defects via modulating gene expression of sirtuin and mammalian target of rapamycin. Interestingly, CSNPs treatment alters epigenetic reprogramming in mouse embryos. Overall, these observations suggest that rapamycin treatment could ameliorate CSNPs-induced developmental defects in preimplantation embryos. The data from this study would facilitate to understand the toxicity of these CSNPs, and enable the engineering of safer nanomaterials for therapeutic applications.
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http://dx.doi.org/10.18632/oncotarget.10813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342693PMC
November 2016