• Journal of Microbiology and Biotechnology
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• 제29권10호
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• pp.1665-1674
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• 2019

Zika virus (ZIKV) is a mosquito-transmitted, emerging Flavivirus that causes Guillain-$Barr{\acute{e}}$ syndrome and microcephaly in adults and fetuses, respectively. Since ZIKV was first isolated in 1947, severe outbreaks have occurred at various places worldwide, including Yap Island in 2007, French Polynesia in 2013, and Brazil in 2015. Although incidences of ZIKV infection and dissemination have drastically increased, the mechanisms underlying the pathogenesis of ZIKV have not been sufficiently studied. In addition, despite extensive research, the exact roles of individual ZIKV genes in the viral evasion of the host innate immune responses remain elusive. Besides, it is still possible that more than one ZIKV-encoded protein may negatively affect type I interferon (IFN) induction. Hence, in this study, we aimed to determine the modulations of the IFN promoter activity, induced by the MDA5/RIG-I signaling pathway, by over-expressing individual ZIKV genes. Our results show that two nonstructural proteins, NS2A and NS4A, significantly down-regulated the promoter activity of IFN-${\beta}$ by inhibiting multiple signaling molecules involved in the activation of IFN-${\beta}$. Interestingly, while NS2A suppressed both full-length and constitutively active RIG-I, NS4A had inhibitory activity only on full-length RIG-I. In addition, while NS2A inhibited all forms of IRF3 (full-length, regulatory domain-deficient, and constitutively active), NS4A could not inhibit constitutively active IRF3-5D. Taken together, our results showed that NS2A and NS4A play major roles as antagonists of MDA5/RIG-I-mediated IFN-${\beta}$ induction and more importantly, these two viral proteins seem to inhibit induction of the type I IFN responses in differential mechanisms. We believe this study expands our understanding regarding the mechanisms via which ZIKV controls the innate immune responses in cells and may pave the way to development of ZIKV-specific therapeutics.

• 대한임상검사과학회지
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• 제53권4호
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• pp.353-362
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• 2021

암은 전 세계적인 건강문제이다. 암의 종류는 다양하나 암의 발생과정에서의 유사성은 상당히 높다. 모든 암은 유전자의 발현 변화가 있다는 점에서 공통점을 갖는다. 암 발생과정에서 변화되는 유전자의 발현을 이해하는 것은 암치료제나 암백신 개발에 큰 도움을 줄 것이다. 이번 연구에서는 잘 알려진 암발생 물질인 MNNG를 이용하여 정상 위세포에서 암발생 시 변화되는 유전자 발현을 분석하였다. MNNG 처리에 의해 정상 세포와는 다르게 발현되는 유전자인 DEG들을 찾고 이들을 암세포에서 발현되는 DEG들과 비교하였다. 여기에 더해 DEG의 단백질 결과물들의 기능과 단백질들 간의 결합을 분석하여 단순히 유전자의 발현뿐만 아니라 이들 단백질의 신호전달 과정에서의 연관성도 함께 분석하였다. 이 결과 위암 발생과정에서 관여하는 유전자들과 이들 유전자의 단백질 결과물들의 상호 작용을 밝히게 되었다.

• Biomolecules & Therapeutics
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• 제29권3호
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• pp.321-330
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• 2021

Oxidative stress plays a crucial role in the development of neuronal disorders including brain ischemic injury. Thioredoxin 1 (Trx1), a 12 kDa oxidoreductase, has anti-oxidant and anti-apoptotic functions in various cells. It has been highly implicated in brain ischemic injury. However, the protective mechanism of Trx1 against hippocampal neuronal cell death is not identified yet. Using a cell permeable Tat-Trx1 protein, protective mechanism of Trx1 against hydrogen peroxide-induced cell death was examined using HT-22 cells and an ischemic animal model. Transduced Tat-Trx1 markedly inhibited intracellular ROS levels, DNA fragmentation, and cell death in H2O2-treatment HT-22 cells. Tat-Trx1 also significantly inhibited phosphorylation of ASK1 and MAPKs in signaling pathways of HT-22 cells. In addition, Tat-Trx1 regulated expression levels of Akt, NF-κB, and apoptosis related proteins. In an ischemia animal model, Tat-Trx1 markedly protected hippocampal neuronal cell death and reduced astrocytes and microglia activation. These findings indicate that transduced Tat-Trx1 might be a potential therapeutic agent for treating ischemic injury.

• Translational and Clinical Pharmacology
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• 제25권2호
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• pp.67-73
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• 2017

Glimepiride, a third generation sulfonylurea, is an antihyperglycemic agent widely used to treat type 2 diabetes mellitus. In this study, an untargeted urinary metabolomic analysis was performed to identify endogenous metabolites affected by glimepiride administration. Urine samples of twelve healthy male volunteers were collected before and after administration of 2 mg glimepiride. These samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and then subjected to multivariate data analysis including principal component analysis and orthogonal partial least squares discriminant analysis. Through this metabolomic profiling, we identified several endogenous metabolites such as adenosine 3', 5'-cyclic monophosphate (cAMP), quercetin, tyramine, and urocanic acid, which exhibit significant metabolomic changes between pre- and posturine samples. Among these, cAMP, which is known to be related to insulin secretion, was the most significantly altered metabolite following glimepiride administration. In addition, the pathway analysis showed that purine, tyrosine, and histidine metabolism was affected by pharmacological responses to glimepiride. Together, the results suggest that the pharmacometabolomic approach, based on LC-MS/MS, is useful in understanding the alterations in biochemical pathways associated with glimepiride action.

• Biomolecules & Therapeutics
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• 제27권3호
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• pp.327-335
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• 2019

As the elderly population is increasing, Alzheimer's disease (AD) has become a global issue and many clinical trials have been conducted to evaluate treatments for AD. As these clinical trials have been conducted and have failed, the development of new theraphies for AD with fewer adverse effects remains a challenge. In this study, we examined the effects of Theracurmin on cognitive decline using 5XFAD mice, an AD mouse model. Theracurmin is more bioavailable form of curcumin, generated with submicron colloidal dispersion. Mice were treated with Theracurmin (100, 300 and 1,000 mg/kg) for 12 weeks and were subjected to the novel object recognition test and the Barnes maze test. Theracurmin-treated mice showed significant amelioration in recognition and spatial memories compared those of the vehicle-treated controls. In addition, the antioxidant activities of Theracurmin were investigated by measuring the superoxide dismutase (SOD) activity, malondialdehyde (MDA) and glutathione (GSH) levels. The increased MDA level and decreased SOD and GSH levels in the vehicle-treated 5XFAD mice were significantly reversed by the administration of Theracurmin. Moreover, we observed that Theracurmin administration elevated the expression levels of synaptic components, including synaptophysin and post synaptic density protein 95, and decreased the expression levels of ionized calcium-binding adapter molecule 1 (Iba-1), a marker of activated microglia. These results suggest that Theracurmin ameliorates cognitive function by increasing the expression of synaptic components and by preventing neuronal cell damage from oxidative stress or from the activation of microglia. Thus, Theracurmin would be useful for treating the cognitive dysfunctions observed in AD.

• Korean Chemical Engineering Research
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• 제57권4호
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• pp.445-454
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• 2019

Layered double hydroxides (LDHs) 나노입자는 특유의 층상형 결정구조에서 기인된 물리화학적 물성 및 생체친화성을 바탕으로 나노-바이오 분야에서 주목을 받고 있다. 바이오 이미징은 질병의 진단과 치료(테라노스틱스, theranostics=therapy+diagnosis)에 다양하게 활용될 수 있는 핵심적인 분야로 차세대 맞춤의학으로의 새로운 패러다임 실현을 위해서 보다 정확하고 빠른 진단기술이 절실히 요구되고 있다. 이를 실현하기 위한 대안으로 나노기술이 접목된 고감도 분자영상 관련 연구들이 활발히 진행되고 있다. 본 총설에서는 LDH 나노입자를 기반으로 하는 바이오 이미징 시스템의 개발동향에 관하여 소개하고 바이오 이미징에 적합한 나노소재의 구조 및 합성 방법에 대하여 설명하였다. 또한 임상 의학에서 현재 많이 사용되고 있는 형광을 이용한 광학영상, 자기공명영상(MRI), 핵의학영상(PET), 컴퓨터 단층 촬영(CT) 등 다양한 분야에서 어떻게 LDH 나노입자를 이용하여 나노 프로브 개발을 할 수 있는지 연구사례를 기술하면서 나노기술과 첨단영상기술이 융합된 획기적인 고감도 나노 바이오 이미징 시스템 개발 및 그 잠재력에 대하여 전망해 보았다.

• Journal of Gastric Cancer
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• 제19권1호
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• pp.121-131
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• 2019

Purpose: The significance of neuroendocrine differentiation (NED) in gastric carcinoma (GC) is controversial, leading to ambiguous concepts in traditional classifications. This study aimed to determine the prognostic threshold of meaningful NED in GC and clarify its unclear features in existing classifications. Materials and Methods: Immunohistochemical staining for synaptophysin, chromogranin A, and neural cell adhesion molecule was performed for 945 GC specimens. Survival analysis was performed using the log-rank test and univariate/multivariate models with percentages of NED ($P_{NED}$) and demographic and clinicopathological parameters. Results: In total, 275 (29.1%) cases were immunoreactive to at least 1 neuroendocrine (NE) marker. GC-NED was more common in the upper third of the stomach. $P_{NED}$, and Borrmann's classification and tumor, lymph node, metastasis stages were independent prognostic factors. The cutoff $P_{NED}$ was 10%, beyond which patients had significantly worse outcomes, although the risk did not increase with higher $P_{NED}$. Tumors with ${\geq}10%$ NED tended to manifest as Borrmann type III lesion with mixed/diffuse morphology and poorer histological differentiation; the NE components in this population mainly grew in insulae/nests, which differed from the predominant growth pattern (glandular/acinar) in GC with <10% NED. Conclusions: GC with ${\geq}10%$ NED should be classified as a distinct subtype because of its worse prognosis, and more attention should be paid to the necessity of additional therapeutics for NE components.

• 대한상부위장관⦁헬리코박터학회지
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• 제18권3호
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• pp.186-197
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• 2018

Background/Aims: To investigate the predictive factors for improvement of atrophic gastritis (AG) and intestinal metaplasia (IM). Materials and Methods: A total of 778 subjects were prospectively enrolled and followed up for 10 years. Histological analysis of AG and IM was performed by using the updated Sydney system. To find the predictive factors for reversibility of AG and IM, 24 factors including genetic polymorphisms and bacterial and environmental factors were analyzed. Results: In all subjects, the predictive factor by multivariate analysis for improvement of both antral and corpus AG was successful eradication. The predictive factors for improvement of antral IM were age and successful eradication. The predictive factor for improvement of corpus IM was successful eradication. In patients with Helicobacter pylori infection, age and cagA were predictive factors for improvement of AG and IM. In patients with H. pylori eradication, monthly income and cagA were predictive factors for improvement of AG and IM. Conclusions: H. pylori eradication is an important predictive factor of regression of AG and IM and would be beneficial for the prevention of intestinal-type gastric cancer. Young age, high income, and cagA are additional predictive factors for improving AG and IM status. Thus, various factors affect the improvement of AG and IM.

• 한국응용과학기술학회지
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• 제36권2호
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• pp.488-497
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• 2019

본 연구는 감마선을 이용한 육종 차조기 추출물을 통해 항염증 효능을 평가하고자 하였다. RAW 264.7 세포에서 MTT를 통해 세포 생존율을 평가하였으며, LPS로 유도한 RAW 264.7 세포에서 ROS, NO, 염증성 사이토카인, $NF-{\kappa}B$, COX-2 등을 ELISA, Luminex 및 PCR로 측정하였다. 그 결과, 육종 차조기 추출물은 $25{\mu}g/m{\ell}$ 이하에서 세포독성이 없었으며, LPS로 유도된 RAW 264.7 세포에서 ROS, NO, 사이토카인($IL-1{\beta}$, IL-6, $TNF-{\alpha}$)의 생성을 억제하였다. 또한, $NF-{\kappa}B$, COX-2의 발현을 감소시켜 육종 차조기 추출물은 뛰어난 항염증 효과를 보였다. 이와 같은 결과는 염증 매개체로 인해 발생하는 질환을 개선하기 위한 새로운 건강식품 및 치료제의 원료로 개발될 수 있다.

• Biomolecules & Therapeutics
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• 제27권5호
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• pp.474-483
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• 2019

Vascular endothelial growth factor (VEGF) plays a pivotal role in pathologic ocular neovascularization and vascular leakage via activation of VEGF receptor 2 (VEGFR2). This study was undertaken to evaluate the therapeutic mechanisms and effects of the tetrapeptide Arg-Leu-Tyr-Glu (RLYE), a VEGFR2 inhibitor, in the development of vascular permeability and choroidal neovascularization (CNV). In cultured human retinal microvascular endothelial cells (HRMECs), treatment with RLYE blocked VEGF-A-induced phosphorylation of VEGFR2, Akt, ERK, and endothelial nitric oxide synthase (eNOS), leading to suppression of VEGF-A-mediated hyper-production of NO. Treatment with RLYE also inhibited VEGF-A-stimulated angiogenic processes (migration, proliferation, and tube formation) and the hyperpermeability of HRMECs, in addition to attenuating VEGF-A-induced angiogenesis and vascular permeability in mice. The anti-vascular permeability activity of RLYE was correlated with enhanced stability and positioning of the junction proteins VE-cadherin, ${\beta}$-catenin, claudin-5, and ZO-1, critical components of the cortical actin ring structure and retinal endothelial barrier, at the boundary between HRMECs stimulated with VEGF-A. Furthermore, intravitreally injected RLYE bound to retinal microvascular endothelium and inhibited laser-induced CNV in mice. These findings suggest that RLYE has potential as a therapeutic drug for the treatment of CNV by preventing VEGFR2-mediated vascular leakage and angiogenesis.