Papers by Byeong Hwa Jeon
Tissue Engineering Part A, Dec 1, 2013
Sufficient functional restoration of damaged peripheral nerves is a big clinical challenge. In th... more Sufficient functional restoration of damaged peripheral nerves is a big clinical challenge. In this study, a nerve guide conduit (NGC) with selective permeability was prepared by rolling an asymmetrically porous polycaprolactone/Pluronic F127 membrane fabricated using a novel immersion precipitation method. Dual stimulation (nerve growth factor [NGF] as a biological stimulus and low-intensity pulse ultrasound [US] as a physical stimulus) was adapted to enhance nerve regeneration through an NGC. The animal study revealed that each stimulation (NGF or US) has a positive effect to promote the peripheral nerve regeneration through the NGC, however, the US-stimulated NGC group allowed more accelerated nerve regeneration compared with the NGFstimulated group. The NGC group that received dual stimulation (NGF and US) showed more effective nerve regeneration behavior than the groups that received a single stimulation (NGF or US). The asymmetrically porous NGC with dual NGF and US stimulation may be a promising strategy for the clinical treatment of delayed and insufficient functional recovery of a peripheral nerve.
Scientific Reports, Jan 21, 2020
Downregulation of CR6 interacting factor 1 (CRIF1) has been reported to induce mitochondrial dysf... more Downregulation of CR6 interacting factor 1 (CRIF1) has been reported to induce mitochondrial dysfunction, resulting in reduced activity of endothelial nitric oxide synthase (eNOS) and NO production in endothelial cells. Tetrahydrobiopterin (BH4) is an important cofactor in regulating the balance between NO (eNOS coupling) and superoxide production (eNOS uncoupling). However, whether the decreased eNOS and NO production in CRIF1-deficient cells is associated with relative BH4 deficiencyinduced eNOS uncoupling remains completely unknown. Our results showed that CRIF1 deficiency increased eNOS uncoupling and depleted levels of total biopterin and BH4 by reducing the enzymes of BH4 biosynthesis (GCH-1, PTS, SPR, and DHFR) in vivo and vitro, respectively. Supplementation of CRIF1-deficient cells with BH4 significantly increased the recovery of Akt and eNOS phosphorylation and NO synthesis. In addition, scavenging ROS with MitoTEMPO treatment replenished BH4 levels by elevating levels of GCH-1, PTS, and SPR, but with no effect on the level of DHFR. Downregulation of DHFR synthesis regulators p16 or p21 in CRIF1-deficient cells partially recovered the DHFR expression. In summary, CRIF1 deficiency inhibited BH4 biosynthesis and exacerbated eNOS uncoupling. This resulted in reduced NO production and increased oxidative stress, which contributes to endothelial dysfunction and is involved in the pathogenesis of cardiovascular diseases.
Triple-negative breast cancers (TNBCs) are most aggressive type and resistant to standard chemoth... more Triple-negative breast cancers (TNBCs) are most aggressive type and resistant to standard chemotherapy. There is a high demand for developing approaches to treat TNBCs. Recently, some agents inducing post-translational modification (PTM) were suggested to treat therapeutic-resistant cancer cells. We previously discovered that trichostatin A (TSA), histone deacetylase inhibitor (HDACi), - mediated acetylation induced extracellular secretion of the acetylated apurinic apyrimidinic endonuclease 1/redox factor-1 (Ac-APE1/Ref-1). This is the first report showing that the Ac-APE1/Ref-1 is not merely a secreted protein but also a signal molecule that plays a critical role in the apoptotic cell death pathway in TNBC. To study the functional significance of the secreted Ac-APE1/Ref-1, we induced PTM, hyperacetylation of intracellular proteins with co-treatment of acetylsalicylic acid (ASA) and TSA in MDA-MB-231 cells. In response to hyperacetylation, the secretion of Ac-APE1/Ref-1 in a form of exosome-like vesicles was observed in both electron microscopy and confocal image analysis. Accordingly, it was caused a statistically significant inhibition of cell viability and induction of apoptotic DNA fragmentation, leading activation of p38 mitogen-activated protein kinase and apoptotic cell death. Blockade of Ac-APE1/Ref-1 thoroughly recovered from the cell death effects. The hyperacetylation-mediated apoptotic cell death was comparably efficient in treatment of another TNBC cell lines, BT549, and MDA-MB-468. Keeping in view secreted APE1/Ref-1 following acetylation - causing apoptotic cell death we suggest that PTM qualifies as an excellent candidate to be exploited for therapeutic agents to treat TNBCs. For future clinical investigations of TNBCs, this study offers a novel paradigm, which stimulation of apoptotic pathway by action of PTM-induced auto- or paracrine signaling molecules is prior to treatment of standard chemotherapeutic resistant cancer cells. Citation Format: Yu Ran Lee, Ki Mo Kim, Hee Kyoung Joo, Byeong Hwa Jeon, Sunga Choi. Extracellular secreted Ref-1 triggers triple negative breast cancer cells apoptosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4035. doi:10.1158/1538-7445.AM2015-4035
Journal of Biological Chemistry, 2018
The authors declare that they have no conflicts of interest with the contents of this article. Au... more The authors declare that they have no conflicts of interest with the contents of this article. Author's Choice-Final version free via Creative Commons CC-BY license. This article contains Figs. S1 and S2 and Table S1. The atomic coordinates and structure factors (code 5X3S) have been deposited in the Protein Data Bank (http://wwpdb.org/).
International Journal of Molecular Sciences, Aug 12, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
International Journal of Molecular Sciences, Apr 18, 2023
International Journal of Molecular Sciences, Jun 28, 2019
Acetylation of nuclear apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) is associ... more Acetylation of nuclear apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) is associated with its extracellular secretion, despite the lack of an N-terminal protein secretion signal. In this study, we investigated plasma membrane targeting and translocation of APE1/Ref-1 in HEK293T cells with enhanced acetylation. While APE1/Ref-1 targeting was not affected by inhibition of the endoplasmic reticulum/Golgi-dependent secretion, its secretion was reduced by inhibitors of ATP-binding cassette (ABC) transporters, and siRNA-mediated down-regulation of ABC transporter A1. The association between APE1/Ref-1 and ABCA1 transporter was confirmed by proximal ligation assay and immunoprecipitation experiments. An APE1/Ref-1 construct with mutated acetylation sites (K6/K7R) showed reduced co-localization with ABC transporter A1. Exposure of trichostatin A (TSA) induced the acetylation of APE1/Ref-1, which translocated into membrane fraction. Taken together, acetylation of APE1/Ref-1 is considered to be necessary for its extracellular targeting via non-classical secretory pathway using the ABCA1 transporter.
Evidence-Based Complementary and Alternative Medicine
Breast cancer is the most common cancer and the leading cause of cancer-related mortality among f... more Breast cancer is the most common cancer and the leading cause of cancer-related mortality among females worldwide. Triple-negative breast cancer (TNBC) accounts for about 10–15% of all breast cancers and is usually more aggressive and has a poorer prognosis. Sericite has been known to have antitumor and immune-stimulatory effects. Although the chemopreventive potential of sericite has been demonstrated in other cancers, its molecular pathways in TNBC still require investigation. Thus, in the present study, the antitumor mechanism of sericite against MDA-MB231 breast cancer cells was examined in vitro and in an in vivo xenograft mouse model. Sericite treatment reduced cell proliferation and cell proliferation marker proliferating cell nuclear antigen (PCNA) in MDA-MB231 cells. It also decreased the total cell number and arrested cells in the G0/G1 phase of the cell cycle with an increase in the phosphorylation of P53 and upregulation of cell cycle regulatory proteins P21 and P16. In ...
Kidney Research and Clinical Practice
The Korean Journal of Thoracic and Cardiovascular Surgery, 2007
배경: 산화제와 항산화제 사이의 불균형은 폐암의 발생에 중요한 역할을 하는 것으로 생각되는 산화 스트레스를 유발한다. APE/ref-1은 DNA의 복구와 많은 전사인자들의 산... more 배경: 산화제와 항산화제 사이의 불균형은 폐암의 발생에 중요한 역할을 하는 것으로 생각되는 산화 스트레스를 유발한다. APE/ref-1은 DNA의 복구와 많은 전사인자들의 산화환원 조절에 연관된 다 기능성 단백질이다. 그러나 폐암에서 APE/ref-1 발현수준의 변화는 알려져 있지 않다. 대상 및 방법: 49명의 수술적으로 제거한 비소세포성 폐암 환자를 대상으로 하였다. APE/ref-1 항체에 대한 면역조직화학적 염색을 하였고, 특이 항체에 대한 Western blot을 시행해 발현 정도를 분석하였다. 결과: APE/ref-1은 주로 폐암 조직의 비 암세포 부분은 핵에 국한되어 존재하였고, 암세포는 핵과 세포질 모두에 존재하였다. 비소세포성 폐암의 핵과 세포질의 APE/ref-1의 발현은 증가되어 있었고 이는 임상적인 병기와도 상관관계를 보였다. 대표적인 항산화 물질인 catalase는 비소세포성 폐암에서 현격하게 감소되어 있었다. 결론: APE/ref-1, 특히 세포질 내의 APE/ref-1의 증가는 산화스트레스에 보상적으로 일어나는 것으로 생각하며 catalase의 감소는 폐암의 특성을 나타내는 세포 외부의 산화환원과정에 근본적인 역할을 하는 것으로 생각한다. 【Background: An imbalance between oxidants and antioxidants leads to oxidative stress, and this has been proposed to play an important role in the pathogenesis of lung neoplasm. Apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/ref-1) is a multifunctional protein involved in DNA base excision repair and the redox regulation of many transcription factors. However, the alteration of t...
Brain research, Jan 23, 2015
Nafamostat mesilate (NM), a serine protease inhibitor, has a broad range of clinical applications... more Nafamostat mesilate (NM), a serine protease inhibitor, has a broad range of clinical applications that include use as an anticoagulant during hemodialysis in cerebral hemorrhage patients, as a hemoperfusion anticoagulant for patients with intravascular coagulation, hemorrhagic lesions, and hemorrhagic tendencies, and for the improvement of acute pancreatitis. However, the effects of NM on acute cerebral ischemia have yet to be investigated. Thus, the present study utilized a rat model in which transient middle cerebral artery occlusion (MCAO) was used to induce ischemic injury to investigate the effects of NM on infarct volume and histological and biological changes. NM (1mg/kg) was intravenously administered prior to and after the MCAO procedure. Compared to control rats, the administration of NM significantly decreased infarct size and the extent of brain edema after the induction of focal ischemia via MCAO. Additionally, NM treatment attenuated MCAO-induced neuronal degeneration ...
Journal of Neurophysiology, 2015
γ-Aminobutyric acid (GABA) generates persistent tonic inhibitory currents ( Itonic) and conventio... more γ-Aminobutyric acid (GABA) generates persistent tonic inhibitory currents ( Itonic) and conventional inhibitory postsynaptic currents in the hypothalamic paraventricular nucleus (PVN) via activation of GABAA receptors (GABAARs). We investigated the pathophysiological significance of astroglial GABA uptake in the regulation of Itonic in the PVN neurons projecting to the rostral ventrolateral medulla (PVN-RVLM). The Itonic of PVN-RVLM neurons were significantly reduced in heart failure (HF) compared with sham-operated (SHAM) rats. Reduced Itonic sensitivity to THIP argued for the decreased function of GABAAR δ subunits in HF, whereas similar Itonic sensitivity to benzodiazepines argued against the difference of γ2 subunit-containing GABAARs in SHAM and HF rats. HF Itonic attenuation was reversed by a nonselective GABA transporter (GAT) blocker (nipecotic acid, NPA) and a GAT-3 selective blocker, but not by a GAT-1 blocker, suggesting that astroglial GABA clearance increased in HF. Sim...
Cancer Research, 2014
Apurinic/apyrimidinic endonuclease1/redox factor-1 (APE1/Ref-1) is a DNA repair enzyme whose expr... more Apurinic/apyrimidinic endonuclease1/redox factor-1 (APE1/Ref-1) is a DNA repair enzyme whose expression is increased in several forms of cancerous cells. We investigated whether serum APE1/Ref-1 is elevated in patients with bladder cancer. Tumor tissue and serum from patients with bladder cancer who had not received chemotherapy or radiotherapy (n=51) and non-tumor healthy controls (n=55) was used. In immunohistochemistry, and immunoblot analysis, the APE1/Ref-1 protein level of bladder tissues was increased in patients with bladder cancer. The serum APE1/Ref-1 levels were significantly elevated in bladder cancer patients than in those of non-tumor healthy controls and its levels were correlated with tumor staging and grading. The ROC curve of APE1/Ref-1 showed an excellent area under the ROC curve of 0.824. In this study, the optimal combination of sensitivity and specificity were determined as 93% and 59% for a cut-off value of serum APE1/Ref-1 of 2.83 ng/100 μl, respectively. The...
Antioxidants, Feb 27, 2023
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
(A) Western blot analysis with total tissue lysate from WT and CRIF1 EKO mice hearts. α-Tubulin w... more (A) Western blot analysis with total tissue lysate from WT and CRIF1 EKO mice hearts. α-Tubulin was used as the internal control. (B) The expression level of VCAM-1 was quantified by densitometric analysis using image J. (right panel, values are means ± SEM, *p &lt; 0.05). (n=4 per group) <br>
The Korean Journal of Physiology & Pharmacology, 2021
Arterial thrombosis and its associated diseases are considered to constitute a major healthcare p... more Arterial thrombosis and its associated diseases are considered to constitute a major healthcare problem. Arterial thrombosis, defined as blood clot formation in an artery that interrupts blood circulation, is associated with many cardiovascular diseases. Oxidative stress is one of many important factors that aggravates the pathophysiological process of arterial thrombosis. Apurinic/apyrimidinic endonuclease 1/redox factor-1 (Ref-1) has a multifunctional role in cells that includes the regulation of oxidative stress and anti-inflammatory function. The aim of this study was to investigate the therapeutic effect of adenovirus-mediated Ref-1 overexpression on arterial thrombosis induced by 60% FeCl 3 solution in rats. Blood flow was measured to detect the time to occlusion, thrombus formation was detected by hematoxylin and eosin staining, reactive oxygen species (ROS) levels were detected by high-performance liquid chromatography, and the expression of tissue factor and other proteins was detected by Western blot. FeCl 3 aggravated thrombus formation in carotid arteries and reduced the time to artery occlusion. Ref-1 significantly delayed arterial obstruction via the inhibition of thrombus formation, especially by downregulating tissue factor expression through the Akt-GSK3-NF-κB signaling pathway. Ref-1 also reduced the expression of vascular inflammation markers ICAM-1 and VCAM-1, and reduced the level of ROS that contributed to thrombus formation. The results showed that adenovirus-mediated Ref-1 overexpression reduced thrombus formation in the rat carotid artery. In summary, Ref-1 overexpression had anti-thrombotic effects in a carotid artery thrombosis model and could be a target for the treatment of arterial thrombosis.
Cancer Research, 2018
Triple-negative breast cancer (TNBC) represents a relatively small proportion of all BCs but a re... more Triple-negative breast cancer (TNBC) represents a relatively small proportion of all BCs but a relatively large proportion of BC-related death. Thus more effective therapeutic strategies are needed for the management of TNBC. We previously demonstrated that the stimulation of apoptosis by the binding of secreted acetylated-apurinic apyrimidinic endonuclease 1/redox factor-1 (Ac-APE1/Ref-1) to the receptor for advanced glycation end products (RAGE) was essential for the TNBC cell death in response to hyperacetylation. The aim of the present study was to assess the potential therapeutic efficacy of secretory Ac-APE1/Ref-1 in orthotopic TNBC xenografts in vivo. We found that hyperacetylation in xenografts caused secretion of Ac-APE1/Ref-1 into the blood, where the factor bound directly to RAGE in hyperacetylated tumor tissues. Hyperacetylation in the TNBC xenografts induced strong inhibition of tumor growth and development. Hyperacetylation also caused cell death in tumors, accompanied...
Glia, 2019
Tonic extrasynaptic GABAA receptor (GABAAR) activation is under the tight control of tonic GABA r... more Tonic extrasynaptic GABAA receptor (GABAAR) activation is under the tight control of tonic GABA release from astrocytes to maintain the brain's excitation/inhibition (E/I) balance; any slight E/I balance disturbance can cause serious pathological conditions including epileptic seizures. However, the pathophysiological role of tonic GABA release from astrocytes has not been tested in epileptic seizures. Here, we report that pharmacological or genetic intervention of the GABA‐permeable Bestrophin‐1 (Best1) channel prevented the generation of tonic GABA inhibition, disinhibiting CA1 pyramidal neuronal firing and augmenting seizure susceptibility in kainic acid (KA)‐induced epileptic mice. Astrocyte‐specific Best1 over‐expression in KA‐injected Best1 knockout mice fully restored the generation of tonic GABA inhibition and effectively suppressed seizure susceptibility. We demonstrate for the first time that tonic GABA from reactive astrocytes strongly contributes to the compensatory ...
Experimental and Molecular Therapeutics, 2019
In persistent inflammatory state involving the chronic activation of the immune system, the inter... more In persistent inflammatory state involving the chronic activation of the immune system, the interplay between breast cancer and stromal cells is closely associated. We have previously shown that APE1/Ref-1 which could inhibit inflammatory signaling by reductive conformational change of cytokines receptors. In response to hyperacetylation, stimulation by secreted Ac-APE1/Ref-1 binding to RAGE initiated apoptotic cell death in TNBC models, in vitro and in vivo. In the present study, we used Ad-APE1/Ref-1 adenovirus, which can be overexpressed and be secreted into the blood of xenografts. We investigated how the Ad-APE1/Ref-1 influences growth retardation and apoptotic cell death of inflammation associated TNBC in vivo. The Ad-APE1/Ref-1-injection in MDA-MB 231 orthotopic xenografts caused a decrease in the volume and weight of tumors as shown in IVIS images. The treatment of Ad-APE1/Ref-1 also induced an inhibition of tumor growth and development, leading to apoptotic cell death, accompanied by generation of reactive oxygen species. Tumor tissues derived from Ad-APE1/Ref-1 exhibited apoptotic bodies compared with tumors of control or Adβ-galactosidase-injected mice. Moreover, level of inflammatory cytokines was evaluated in plasma of the xenografts; ratio of anti- to pro inflammatory cytokines was comparable with one of normal mice. The PAK1-STAT-3-NFkB axis in inflammatory signaling of tumor tissues derived from AdAPE1/Ref-1 injected mice was significantly inhibited compared to those of control or Adβ-galactosidase-injected mice. These results suggest that regulation of inflammatory signaling with adenoviral mediated APE1/Ref-1 in tumors of MDA-MB-231 xenografts modulates cytokine secretion, thereby inhibiting cancer cell growth. Note: This abstract was not presented at the meeting. Citation Format: Sunga Choi, Yu Ran Lee, Yeon Hyang Kim, Ki Mo Kim, Myoung Soo Park, Byeong Hwa Jeon. Anti-tumor effect of adenovirus encoding APE1/Ref-1 in breast cancer xenografts: anti-inflammation and apoptotic cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4777.
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Papers by Byeong Hwa Jeon