232 results on '"Park, JeongMin"'
Search Results
202. Goal graph based performance improvement for self-adaptive modules
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Park, Jeongmin, primary, Lee, Joonhoon, additional, and Lee, Eunseok, additional
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- 2008
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203. A Reconfiguration Framework for Self-Healing Software
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Park, Jeongmin, primary, Yoo, Giljong, additional, and Lee, Eunseok, additional
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- 2008
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204. Root Cause Analysis and Proactive Problem Prediction for Self-Healing
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Piao, Shunshan, primary, Park, Jeongmin, additional, and Lee, Eunseok, additional
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- 2007
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205. Sleeping Beauty transposition in the mouse genome is associated with changes in DNA methylation at the site of insertion
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Park, Chang Won, primary, Park, Jeongmin, additional, Kren, Betsy T., additional, and Steer, Clifford J., additional
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- 2006
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206. Proactive Self-healing System for Application Maintenance in Ubiquitous Computing Environment.
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Gavrilova, Marina, Gervasi, Osvaldo, Kumar, Vipin, Tan, C. J. Kenneth, Taniar, David, Laganà, Antonio, Mun, Youngsong, Choo, Hyunseung, Park, Jeongmin, Yoo, Giljong, Jeong, Chulho, and Lee, Eunseok
- Abstract
With evolving modern IT technology, one desirable characteristic of distributed of applications is self-healing, or the ability to reconfigure themselves "on the fly" to circumvent failure. Thus, the goal is to avoid catastrophic failure through prompt execution of remedial actions. This paper proposes a self-healing system that monitors, diagnoses and heals its own internal problems using self-awareness as contextual information. The proposed system consists of multi agents that analyze the log context, error events and resource status in order to perform self-diagnosis and self-healing. For rapid and efficient self-healing, for developing the proposed system, we use a 6-step process: monitoring, filtering, translation, diagnosis, decision and feedback. Our experiments conducted with a prototype system confirm the effectiveness of the proposed system. [ABSTRACT FROM AUTHOR]
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- 2006
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207. Mit1/Lb9andCopg2, new members of mouse imprinted genes closely linked toPeg1/Mest
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Lee, Young Jae, primary, Park, Chang Won, additional, Hahn, Yoonsoo, additional, Park, Jeongmin, additional, Lee, Jieun, additional, Yun, Ji Hye, additional, Hyun, Byunghwa, additional, and Chung, Jae Hoon, additional
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- 2000
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208. Mit1/Lb9and Copg2, new members of mouse imprinted genes closely linked to Peg1/Mest11The nucleotide sequences reported in this paper have been submitted to the GenBank with accession numbers: mouse Mit1/Lb9, AF217545; mouse Copg2, AF205065.
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Lee, Young Jae, Park, Chang Won, Hahn, Yoonsoo, Park, Jeongmin, Lee, Jieun, Yun, Ji Hye, Hyun, Byunghwa, and Chung, Jae Hoon
- Abstract
Two mouse genes, Mit1/Lb9and Copg2, linked to Peg1/Meston mouse chromosome 6, were identified to be imprinted maternally and paternally, respectively. Mit1/Lb9encoding untranslated transcripts resides within the intron 20 of Copg2. The gene is maternally imprinted in adult mouse brain, partially imprinted in other tissues. Copg2consists of 24 exons within the >40 kb genomic region, being expressed ubiquitously in mouse tissues with a partial imprinting pattern in embryos, neonates, and adult brain in contrast to maternally imprinted human COPG2. In addition, we identified an antisense transcript of Copg2, Copg2AS, which overlaps 3′-UTRs of Copg2and Peg1/Mest. The Copg2AStranscript is maternally imprinted in embryos, neonates, and adult tissues.
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- 2000
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209. Mit1/Lb9 and Copg2, new members of mouse imprinted genes closely linked to Peg1/Mest11The nucleotide sequences reported in this paper have been submitted to the GenBank with accession numbers: mouse Mit1/Lb9, AF217545; mouse Copg2, AF205065
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Lee, Young Jae, Park, Chang Won, Hahn, Yoonsoo, Park, Jeongmin, Lee, Jieun, Yun, Ji Hye, Hyun, Byunghwa, and Chung, Jae Hoon
- Subjects
Peg1/Mest ,Imprinting ,Coatomer protein complex ,Antisense RNA - Abstract
Two mouse genes, Mit1/Lb9 and Copg2, linked to Peg1/Mest on mouse chromosome 6, were identified to be imprinted maternally and paternally, respectively. Mit1/Lb9 encoding untranslated transcripts resides within the intron 20 of Copg2. The gene is maternally imprinted in adult mouse brain, partially imprinted in other tissues. Copg2 consists of 24 exons within the >40 kb genomic region, being expressed ubiquitously in mouse tissues with a partial imprinting pattern in embryos, neonates, and adult brain in contrast to maternally imprinted human COPG2. In addition, we identified an antisense transcript of Copg2, Copg2AS, which overlaps 3′-UTRs of Copg2 and Peg1/Mest. The Copg2AS transcript is maternally imprinted in embryos, neonates, and adult tissues.
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210. Soil Contamination of Heavy Metals in the vicinity of the Shincheon, Dongducheon City
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Park, JeongMin and Kim, SunJoon
- Abstract
ABSTRACTCultivated soil and groundwater samples were collected and analyzed in the vicinity of the Shincheon which flows through industrial area of Dongducheon city to evaluate the pollution status of soil and groundwater and to determine the dispersion pattern of heavy metals in soils. Measurements of heavy metal concentrations in the soil sample were carried out using four pretreatment techniques; total extraction, 0.1N-HCl extraction, aqua-regia extraction and sequential extraction. By 0.1N-HCl extraction, all the samples contained less extent of guideline for soil conservation act in Korea. By aqua-regia extraction, one sample collected around the factory area showed higher concentration of Cr than the indicative value for further investigation and those of Cu and Zn than the reference values of the Netherlands. Concentrations of heavy metals decrease with depths in soils around the factory area and with distances from the stream. In addition, heavy metal contents of soils collected after wet season are much higher than those in dry season. The dominant fractions of Cr and Cu in soil are bound to organic matter/sulphides and residual fraction. Most of Pb and Zn exist in the residual fraction. Samples having higher contents of Cr and Cu than reference values of Netherlands by aqua-regia digestion show much higher proportions of organic matter/sulphides than the others. Except one sample showing slightly high content of Zn, metal contents of groundwater samples were within drinking water standard of Korea. Seasonal variation of metal contents, variations with distances from the stream and with depth, and acceptable groundwater quality indicate that soil contamination in the vicinity of the Shincheon is resulted from the flooding of sediments during rainy season rather than groundwater movement.
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- 1999
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211. Photochemical Reaction Mechanism of Intramolecular H Transfer Reaction of H 2 C 3 O + ⋅ Radical Cation.
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Kim J, Oh D, Park E, Park J, Kim J, and Lim JS
- Abstract
The photochemical reaction mechanism underlying the intramolecular H-transfer of the H
2 C3 O+ ⋅ radical cation to the H2 CCCO+ ⋅ methylene ketene cation was elucidated using time-dependent density functional theory and high-level ab initio methods. Once the D1 state of H2 C3 O+ ⋅ is populated, the reaction proceeds to form an intermediate (IM) in the D1 state (IM4D1 ). The molecular structure of the conical intersection (CI) was optimized using a multiconfigurational ab initio method. The CI is readily accessible because it lies slightly above the IM4D1 in energy. In addition, the gradient difference vector of the CI is almost parallel to the intramolecular H-transfer reaction coordinate. Once the vibration mode of IM4D1 which is parallel to the reaction coordinate is populated, the degeneracy of the CI is readily lifted and H2 CCCO+ ⋅ was formed via a relaxation pathway in the D0 state. Our calculated results clearly describe the photochemical intramolecular H transfer reaction reported in a recent study., (© 2023 Wiley-VCH GmbH.)- Published
- 2023
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212. CD38/ADP-ribose/TRPM2-mediated nuclear Ca 2+ signaling is essential for hepatic gluconeogenesis in fasting and diabetes.
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Rah SY, Joe Y, Park J, Ryter SW, Park C, Chung HT, and Kim UH
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- Humans, Gluconeogenesis physiology, Glucagon, Adenosine Diphosphate Ribose metabolism, Liver metabolism, Glucose metabolism, Hepatocytes metabolism, Fasting, TRPM Cation Channels genetics, TRPM Cation Channels metabolism, Diabetes Mellitus metabolism
- Abstract
Hepatic glucose production by glucagon is crucial for glucose homeostasis during fasting, yet the underlying mechanisms remain incompletely delineated. Although CD38 has been detected in the nucleus, its function in this compartment is unknown. Here, we demonstrate that nuclear CD38 (nCD38) controls glucagon-induced gluconeogenesis in primary hepatocytes and liver in a manner distinct from CD38 occurring in the cytoplasm and lysosomal compartments. We found that the localization of CD38 in the nucleus is required for glucose production by glucagon and that nCD38 activation requires NAD
+ supplied by PKCδ-phosphorylated connexin 43. In fasting and diabetes, nCD38 promotes sustained Ca2+ signals via transient receptor potential melastatin 2 (TRPM2) activation by ADP-ribose, which enhances the transcription of glucose-6 phosphatase and phosphoenolpyruvate carboxykinase 1. These findings shed light on the role of nCD38 in glucagon-induced gluconeogenesis and provide insight into nuclear Ca2+ signals that mediate the transcription of key genes in gluconeogenesis under physiological conditions., (© 2023. The Author(s).)- Published
- 2023
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213. Postures anomaly tracking and prediction learning model over crowd data analytics.
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Aljuaid H, Akhter I, Alsufyani N, Shorfuzzaman M, Alarfaj M, Alnowaiser K, Jalal A, and Park J
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Innovative technology and improvements in intelligent machinery, transportation facilities, emergency systems, and educational services define the modern era. It is difficult to comprehend the scenario, do crowd analysis, and observe persons. For e-learning-based multiobject tracking and predication framework for crowd data via multilayer perceptron, this article recommends an organized method that takes e-learning crowd-based type data as input, based on usual and abnormal actions and activities. After that, super pixel and fuzzy c mean, for features extraction, we used fused dense optical flow and gradient patches, and for multiobject tracking, we applied a compressive tracking algorithm and Taylor series predictive tracking approach. The next step is to find the mean, variance, speed, and frame occupancy utilized for trajectory extraction. To reduce data complexity and optimization, we applied T-distributed stochastic neighbor embedding (t-SNE). For predicting normal and abnormal action in e-learning-based crowd data, we used multilayer perceptron (MLP) to classify numerous classes. We used the three-crowd activity University of California San Diego, Department of Pediatrics (USCD-Ped), Shanghai tech, and Indian Institute of Technology Bombay (IITB) corridor datasets for experimental estimation based on human and nonhuman-based videos. We achieve a mean accuracy of 87.00%, USCD-Ped, Shanghai tech for 85.75%, and IITB corridor of 88.00% datasets., Competing Interests: The authors declare there are no competing interests., (©2023 Aljuaid et al.)
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- 2023
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214. High level ab initio and density functional study of TeF6+ and TeCl6+: Attainability of +7 oxidation state for tellurium.
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Kim J, Park E, Park J, Kim J, Yoon K, Oh D, Lee J, Kim TW, and Kim TK
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Discovery of a new oxidation state for an element expands its chemistry. A high oxidation state, such as +7, is rare for sp-block elements except for halogens. In this study, we determined that Te can attain a +7 oxidation state through the existence of a distorted octahedron (DOH) structure of TeCl6+ based on coupled cluster singles and doubles with perturbative triples calculations. We propose a new type of isomerization that resembles pseudorotation. The octahedron structure of TeF6+ bearing one elongated axial bond isomerizes to a DOH via an associated pseudorotation., (© 2023 Author(s). Published under an exclusive license by AIP Publishing.)
- Published
- 2023
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215. CO-Induced TTP Activation Alleviates Cellular Senescence and Age-Dependent Hepatic Steatosis via Downregulation of PAI-1 .
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Park J, Chen Y, Kim J, Hwang E, Park GH, Yang CH, Ryter SW, Park JW, Chung HT, and Joe Y
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Aging can increase the risk of various hepatic diseases, especially non-alcoholic fatty liver disease (NAFLD). Although the mechanisms underlying the pathogenesis of age-related disorders such as NAFLD remain incompletely understood, recent studies have implicated the accumulation of senescent cells as a contributing factor. Here, we show that tristetraprolin (TTP) deficiency accelerates NAFLD during aging by enhancing the senescence-associated secretory phenotype (SASP) as well as several hallmarks of senescence. The sequestration of plasminogen activator inhibitor (PAI)-1, a mediator of cellular senescence, in stress granules, (SGs) inhibits cellular senescence. In our previous report, we have shown that carbon monoxide (CO), a small gaseous mediator, can induce the assembly of SGs via an integrated stress response. Here, we show that CO treatment promotes the assembly of SGs which can sequester PAI-1, resulting in the inhibition of etoposide (ETO)-induced cellular senescence. Notably, CO-induced TTP activation enhances PAI-1 degradation, leading to protection against ETO-induced cellular senescence. CO-dependent Sirt1 activation promotes the inclusion of TTP into SGs, leading to decreased PAI-1 levels. Therefore, our findings highlight the importance of TTP as a therapeutic target in age-related NAFLD and offer a potential new strategy to reduce the detrimental effects of senescent cells in hepatic disorders., Competing Interests: Conflict of interest The authors declare no competing financial interests., (copyright: © 2022 Park et al.)
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- 2023
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216. Metformin-induced TTP mediates communication between Kupffer cells and hepatocytes to alleviate hepatic steatosis by regulating lipophagy and necroptosis.
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Park J, Rah SY, An HS, Lee JY, Roh GS, Ryter SW, Park JW, Yang CH, Surh YJ, Kim UH, Chung HT, and Joe Y
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- Mice, Animals, Liver metabolism, Kupffer Cells, Necroptosis, Hepatocytes metabolism, Communication, Autophagy, Diet, High-Fat, Mice, Inbred C57BL, Lipid Metabolism, Non-alcoholic Fatty Liver Disease metabolism, Metformin pharmacology
- Abstract
Objective: Emerging evidence suggests that crosstalk between Kupffer cells (KCs) and hepatocytes protects against non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms that lead to the reduction of steatosis in NAFLD remain obscure., Methods: Ttp
+/+ and Ttp-/- mice were fed with a high-fat diet. Hepatic steatosis was analyzed by Nile Red staining and measurement of inflammatory cytokines. Lipid accumulation and cell death were evaluated in co-culture systems with primary hepatocytes and KCs derived from either Ttp+/+ or Ttp-/- mice., Results: Tristetraprolin (TTP), an mRNA binding protein, was essential for the protective effects of metformin in NAFLD. Metformin activated TTP via the AMPK-Sirt1 pathway in hepatocytes and KCs. TTP inhibited TNF-α production in KCs, which in turn decreased hepatocyte necroptosis. Downregulation of Rheb expression by TTP promoted hepatocyte lipophagy via mTORC1 inhibition and increased nuclear translocation of transcription factor-EB (TFEB). Consistently, TTP-deficient NAFLD mice failed to respond to metformin with respect to alleviation of hepatic steatosis, protection of hepatocyte necroptosis, or induction of lipophagy., Conclusions: TTP, which is essential for the protective effects of metformin, may represent a novel primary therapeutic target in NAFLD., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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217. Multimodal Encapsulation to Selectively Permeate Hydrogen and Engineer Channel Conduction for p-Type SnO x Thin-Film Transistor Applications.
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Lee DH, Zhang Y, Chang SJ, Park H, Kim CS, Baek J, Park J, No K, Song HW, Park H, and Lee S
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It has been challenging to synthesize p-type SnO
x (1 < x < 2) and engineer the electrical properties such as carrier density and mobility due to the narrow processing window and the localized oxygen 2p orbitals near the valence band. Herein, we report on the multifunctional encapsulation of p-SnOx to limit the surface adsorption of oxygen and selectively permeate hydrogen into the p-SnOx channel for thin-film transistor (TFT) applications. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) measurements identified that ultrathin SiO2 as a multifunctional encapsulation layer effectively suppressed the oxygen adsorption on the back channel surface of p-SnOx and selectively diffused hydrogen across the entire thickness of the channel. Encapsulated p-SnOx -based TFTs demonstrated much enhanced channel conductance modulation in response to the gate bias applied, featuring higher on-state current and lower off-state current (on/off ratio > 103 ), field effect mobility of 3.41 cm2 /(V s), and threshold voltages of ∼5-10 V. The fabricated devices show minimal deviations as small as ±6% in the TFT performance parameters, which demonstrates good reproducibility of the fabrication process. The relevance between the TFT performance and the effects of hydrogen permeation is discussed in regard to the intrinsic and extrinsic doping mechanisms. Density functional theory calculations reveal that hydrogen-related impurity complexes are in charge of the enhanced channel conductance with gate biases, which further supports the selective permeation of hydrogen through a thin SiO2 encapsulation.- Published
- 2022
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218. Physical human locomotion prediction using manifold regularization.
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Javeed M, Shorfuzzaman M, Alsufyani N, Chelloug SA, Jalal A, and Park J
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Human locomotion is an imperative topic to be conversed among researchers. Predicting the human motion using multiple techniques and algorithms has always been a motivating subject matter. For this, different methods have shown the ability of recognizing simple motion patterns. However, predicting the dynamics for complex locomotion patterns is still immature. Therefore, this article proposes unique methods including the calibration-based filter algorithm and kinematic-static patterns identification for predicting those complex activities from fused signals. Different types of signals are extracted from benchmarked datasets and pre-processed using a novel calibration-based filter for inertial signals along with a Bessel filter for physiological signals. Next, sliding overlapped windows are utilized to get motion patterns defined over time. Then, polynomial probability distribution is suggested to decide the motion patterns natures. For features extraction based kinematic-static patterns, time and probability domain features are extracted over physical action dataset (PAD) and growing old together validation (GOTOV) dataset. Further, the features are optimized using quadratic discriminant analysis and orthogonal fuzzy neighborhood discriminant analysis techniques. Manifold regularization algorithms have also been applied to assess the performance of proposed prediction system. For the physical action dataset, we achieved an accuracy rate of 82.50% for patterned signals. While, the GOTOV dataset, we achieved an accuracy rate of 81.90%. As a result, the proposed system outdid when compared to the other state-of-the-art models in literature., Competing Interests: The authors declare that they have no competing interests., (© 2022 Javeed et al.)
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- 2022
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219. Association between coffee consumption and periodontal diseases: a systematic review and meta-analysis.
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Rhee Y, Choi Y, Park J, Park HR, Kim K, and Kim YH
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- Cohort Studies, Cross-Sectional Studies, Humans, Odds Ratio, Risk Factors, Periodontitis epidemiology
- Abstract
Background: Several studies have demonstrated association between coffee consumption and periodontal diseases. However, no systematic review and meta-analysis was performed. Therefore, we performed a systematic review and meta-analysis to evaluate the association between coffee intake and periodontitis., Methods: We defined PICO statement as "Do coffee drinkers have a higher association of periodontitis or tooth loss than non-coffee drinkers?". We searched for articles using the Embase and Medline databases. The odds ratio was used as an effect measure to evaluate the association between coffee and periodontitis We divided coffee intake doses into three groups: no intake (≤ 0.03 cups/day), low intake (0.03 < x < 1 cups/day), and high intake (≥ 1 cup/day). Cohort and cross-sectional studies were eligible for inclusion in this study. The Newcastle-Ottawa scale was used to qualitatively assess the risk of bias. The degree of heterogeneity between studies was quantified using I
2 statistics., Results: Six articles were analysed, including two cohort studies and four cross-sectional studies. The pooled unadjusted odds ratios of periodontitis were 1.14 (0.93-1.39), 1.05 (0.73-1.52), 1.03 (0.91-1.16) and 1.10 (0.84-1.45) in the 4 meta-analyses (coffee drinker vs. non-coffee drinker, high intake vs. low intake, low intake vs. no intake, high intake vs. no intake), respectively., Conclusion: This is the first meta-analysis to investigate the relationship between coffee consumption and periodontitis. There was no relationship between coffee consumption and periodontitis. Further studies are required to assess whether a relationship between coffee consumption and periodontitis exists or not. PROSPERO registration number: CRD42022301341., (© 2022. The Author(s).)- Published
- 2022
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220. Aspects of Psychiatric Comorbidities in Breast Cancer Patients in Tertiary Hospitals Due to COVID-19 Outbreak in South Korea: A Single Center Longitudinal Cohort Study.
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Park J, Kim S, and Heo J
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- Aged, Cohort Studies, Disease Outbreaks, Female, Humans, Longitudinal Studies, Middle Aged, Pandemics, Quality of Life, Tertiary Care Centers, Breast Neoplasms complications, Breast Neoplasms epidemiology, Breast Neoplasms psychology, COVID-19 epidemiology
- Abstract
Background and Objectives : This study aimed to analyze the prevalence of mental disorders in patients with breast cancer at Ajou University Hospital. In addition, the patterns and prevalence of mental disorders according to the occurrence of coronavirus disease (COVID-19) were analyzed. Materials and Methods : From 1 January 2008 to 30 June 2021, psychiatric disorders were identified in 5174 female patients diagnosed with breast cancer at Ajou University Hospital. Based on the time when COVID-19 occurred, the pattern of onset of mental disorders in patients with breast cancer was analyzed. In addition, the prevalence of mental disorders according to the time of breast cancer diagnosis and age was evaluated. Results : A year before the diagnosis of breast cancer, 371 patients were diagnosed with a mental disorder. Of these, 201 patients were diagnosed with stress and adjustment disorders, and 97 patients had anxiety disorders. The overall frequency of psychiatric disorders after breast cancer diagnosis peaked two months later. Among psychiatric disorders reported before the COVID-19 pandemic, the proportion of stress/adaptation disorders was 52%, and among psychiatric disorders reported after the pandemic, it was significantly higher at 94.7%. Anxiety was found to be high in the elderly group aged ≥ 60 years, and the prevalence of stress and adjustment disorders tended to increase in the non-elderly group. Conclusions : Breast cancer patients showed different patterns of psychiatric disorders according to age, time of breast cancer diagnosis, and the occurrence of COVID-19. Owing to the COVID-19 pandemic, delays in treatment and anxiety about infection have increased the rate of stress and adjustment disorders in cancer patients. Mental health management during the pandemic and after cancer diagnosis can improve the quality of life of patients with cancer.
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- 2022
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221. Potential Role of Heme Oxygenase-1 in the Resolution of Experimentally Induced Colitis through Regulation of Macrophage Polarization.
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Gwak SY, Kim SJ, Park J, Kim SH, Joe Y, Lee HN, Kim W, Muna IA, Na HK, Chung HT, and Surh YJ
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- Animals, Dextran Sulfate, Humans, Lipopolysaccharides adverse effects, Lipopolysaccharides metabolism, Macrophages metabolism, Male, Mice, Mice, Inbred C57BL, Colitis chemically induced, Colitis drug therapy, Heme Oxygenase-1
- Abstract
Background/aims: Heme oxygenase-1 (HO-1) plays a central role in cellular defense against inflammatory insults, and its induction in macrophages potentiates their efferocytic activity. In this study, we explored the potential role of macrophage HO-1 in the resolution of experimentally induced colitis., Methods: To induce colitis, male C57BL/6 mice were treated with 2% dextran sulfate sodium (DSS) in the drinking water for 7 days. To investigate efferocytosis, apoptotic colon epithelial CCD 841 CoN cells were coincubated with bone marrow-derived macrophages (BMDMs)., Results: Administration of the HO-1 inhibitor zinc protoporphyrin IX (ZnPP) blunted the resolution of DSS-induced intestinal inflammation and expression of the proresolving M2 macrophage marker CD206. BMDMs treated with apoptotic colonic epithelial cells showed significantly elevated expression of HO-1 and its regulator Nrf2. Under the same experimental conditions, the proportion of CD206-expressing macrophages was also enhanced. ZnPP treatment abrogated the upregulation of CD206 expression in BMDMs engulfing apoptotic colonic epithelial cells. This result was verified with BMDMs isolated from HO-1-knockout mice. BMDMs, when stimulated with lipopolysaccharide, exhibited increased expression of CD86, a marker of M1 macrophages. Coculture of lipopolysaccharide-stimulated BMDMs with apoptotic colonic epithelial cell debris dampened the expression of CD86 as well as the pro-inflammatory cytokines in an HO-1-dependent manner. Genetic ablation as well as pharmacologic inhibition of HO-1 significantly reduced the proportion of efferocytic BMDMs expressing the scavenger receptor CD36., Conclusions: HO-1 plays a key role in the resolution of experimentally induced colitis by modulating the polarization of macrophages.
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- 2022
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222. PERK activation by SB202190 ameliorates amyloidogenesis via the TFEB-induced autophagy-lysosomal pathway.
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Do M, Park J, Chen Y, Rah SY, Nghiem TT, Gong JH, Ju SA, Kim BS, Yu R, Park JW, Ryter SW, Surh YJ, Kim UH, Joe Y, and Chung HT
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- Autophagy drug effects, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Calcineurin metabolism, Endoplasmic Reticulum Stress, Humans, Lysosomes drug effects, Lysosomes metabolism, Protein Serine-Threonine Kinases, Unfolded Protein Response, Amyloid biosynthesis, Endoribonucleases metabolism, Imidazoles pharmacology, Neuroblastoma metabolism, Pyridines pharmacology, eIF-2 Kinase metabolism
- Abstract
The protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK), a key ER stress sensor of the unfolded protein response (UPR), can confer beneficial effects by facilitating the removal of cytosolic aggregates through the autophagy-lysosome pathway (ALP). In neurodegenerative diseases, the ALP ameliorates the accumulation of intracellular protein aggregates in the brain. Transcription factor-EB (TFEB), a master regulator of the ALP, positively regulates key genes involved in the cellular degradative pathway. However, in neurons, the role of PERK activation in mitigating amyloidogenesis by ALP remains unclear. In this study, we found that SB202190 selectively activates PERK independently of its inhibition of p38 mitogen-activated protein kinase, but not inositol-requiring transmembrane kinase/endoribonuclease-1α (IRE1α) or activating transcription factor 6 (ATF6), in human neuroblastoma cells. PERK activation by SB202190 was dependent on mitochondrial ROS production and promoted Ca
2+ -calcineurin activation. The activation of the PERK-Ca2+ -calcineurin axis by SB202190 positively affects TFEB activity to increase ALP in neuroblastoma cells. Collectively, our study reveals a novel physiological mechanism underlying ALP activation, dependent on PERK activation, for ameliorating amyloidogenesis in neurodegenerative diseases.- Published
- 2022
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223. Chung Hun Wha Dam Tang attenuates atherosclerosis in apolipoprotein E-deficient mice via the NF-κB pathway.
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Joe Y, Uddin MJ, Park J, Ryu J, Cho GJ, Woo Park J, Choi HS, Ho Cha M, Ryter SW, and Chung HT
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- Adipose Tissue drug effects, Animals, Body Weight drug effects, Cytokines genetics, Cytokines metabolism, Dose-Response Relationship, Drug, Drugs, Chinese Herbal administration & dosage, Humans, Inflammation drug therapy, Inflammation metabolism, Male, Mice, Mice, Knockout, ApoE, Oxidative Stress drug effects, RAW 264.7 Cells, Reactive Oxygen Species, U937 Cells, Atherosclerosis prevention & control, Drugs, Chinese Herbal pharmacology, Gene Expression Regulation drug effects, NF-kappa B metabolism
- Abstract
Chung Hun Wha Dam Tang (CHWDT), a traditional Korean herbal formula, has been used for hundreds of years for alleviating dizziness, phlegm, and inflammation. The inhibitory effects of CHWDT on obesity have been reported. However, the effects of CHWDT in atherosclerosis have not yet been explored. Therefore, the aim of the study was to investigate whether CHWDT could confer protection from oxidative stress and inflammation in a high fat diet (HFD)-induced atherosclerosis model. Atherosclerosis was induced by feeding ApoeE
-/- mice with HFD for 6 weeks. To examine the in vivo effects of CHWDT on HFD-induced atherosclerosis, mice on HFD for 6 weeks were orally administrated with CHWDT (400 or 800 mg/kg) every other day for an additional 6 weeks and histological features of aorta were determined by Sudan IV and H&E staining. The mRNA levels of TNF-α, SOD1, SOD2, iNOS or eNOS were determined with RT-PCR analysis or western blot analysis for protein levels. ROS generation was measured by CM-2DCFDA or MitoSox staining using FACS analysis or confocal microscopy. CHWDT decreased the mRNA levels of TNF-α and increased the mRNA levels of SOD1, SOD2 and catalase in both aorta and liver tissues of atherosclerotic mice. CHWDT attenuated TNF-α and iNOS expression in RAW 264.7 cells, U937 cells and HUVECs, and restored eNOS expression in HUVECs. CHWDT decreased H2 O2 -induced cellular ROS generation in RAW 264.7 cells and U937 cells, and also decreased H2 O2 -induced mitochondrial ROS generation in RAW 264.7 cells. Furthermore, SOD1, SOD2 and catalase mRNA levels were increased by pre-treatment with CHWDT in H2 O2 and LPS-stimulated RAW 264.7 cells, as well as in LPS-treated U937 and HUVECs. CHWDT not only decreased LPS-induced NF-κB p65 phosphorylation but also inhibited the translocation of p65 from the cytosol to the nucleus in RAW 264.7 macrophages. These results suggest that CHWDT exerts inhibitory effects on atherosclerosis-induced oxidative stress and inflammation via the NF-κB pathway., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)- Published
- 2019
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224. Synergetic Behavior in 2D Layered Material/Complex Oxide Heterostructures.
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Kang KT, Park J, Suh D, and Choi WS
- Abstract
The marriage between a 2D layered material (2DLM) and a complex transition metal oxide (TMO) results in a variety of physical and chemical phenomena that cannot be achieved in either material alone. Interesting recent discoveries in systems such as graphene/SrTiO
3 , graphene/LaAlO3 /SrTiO3 , graphene/ferroelectric oxide, MoS2 /SrTiO3 , and FeSe/SrTiO3 heterostructures include voltage scaling in field-effect transistors, charge state coupling across an interface, quantum conductance probing of the electrochemical activity, novel memory functions based on charge traps, and greatly enhanced superconductivity. In this context, various properties and functionalities appearing in numerous different 2DLM/TMO heterostructure systems are reviewed. The results imply that the multidimensional heterostructure approach based on the disparate material systems leads to an entirely new platform for the study of condensed matter physics and materials science. The heterostructures are also highly relevant technologically as each constituent material is a promising candidate for next-generation optoelectronic devices., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)- Published
- 2019
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225. Similarities and Distinctions in the Effects of Metformin and Carbon Monoxide in Immunometabolism.
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Park J, Joe Y, Ryter SW, Surh YJ, and Chung HT
- Subjects
- Animals, Endoplasmic Reticulum Stress drug effects, Humans, Metabolic Diseases prevention & control, Mitochondria drug effects, Mitochondria metabolism, Neoplasms prevention & control, Carbon Monoxide pharmacology, Immune System drug effects, Metabolic Networks and Pathways drug effects, Metformin pharmacology
- Abstract
Immunometabolism, defined as the interaction of metabolic pathways with the immune system, influences the pathogenesis of metabolic diseases. Metformin and carbon monoxide (CO) are two pharmacological agents known to ameliorate metabolic disorders. There are notable similarities and differences in the reported effects of metformin and CO on immunometabolism. Metformin, an anti-diabetes drug, has positive effects on metabolism and can exert anti-inflammatory and anti-cancer effects via adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms. CO, an endogenous product of heme oxygenase-1 (HO-1), can exert anti-inflammatory and antioxidant effects at low concentration. CO can confer cytoprotection in metabolic disorders and cancer via selective activation of the protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) pathway. Both metformin and CO can induce mitochondrial stress to produce a mild elevation of mitochondrial ROS (mtROS) by distinct mechanisms. Metformin inhibits complex I of the mitochondrial electron transport chain (ETC), while CO inhibits ETC complex IV. Both metformin and CO can differentially induce several protein factors, including fibroblast growth factor 21 (FGF21) and sestrin2 (SESN2), which maintain metabolic homeostasis; nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of the antioxidant response; and REDD1, which exhibits an anticancer effect. However, metformin and CO regulate these effects via different pathways. Metformin stimulates p53- and AMPK-dependent pathways whereas CO can selectively trigger the PERK-dependent signaling pathway. Although further studies are needed to identify the mechanistic differences between metformin and CO, pharmacological application of these agents may represent useful strategies to ameliorate metabolic diseases associated with altered immunometabolism.
- Published
- 2019
- Full Text
- View/download PDF
226. Highly twisted supercoils for superelastic multi-functional fibres.
- Author
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Son W, Chun S, Lee JM, Lee Y, Park J, Suh D, Lee DW, Jung H, Kim YJ, Kim Y, Jeong SM, Lim SK, and Choi C
- Abstract
Highly deformable and electrically conductive fibres with multiple functionalities may be useful for diverse applications. Here we report on a supercoil structure (i.e. coiling of a coil) of fibres fabricated by inserting a giant twist into spandex-core fibres wrapped in a carbon nanotube sheath. The resulting supercoiled fibres show a highly ordered and compact structure along the fibre direction, which can sustain up to 1,500% elastic deformation. The supercoiled fibre exhibits an increase in resistance of 4.2% for stretching of 1,000% when overcoated by a passivation layer. Moreover, by incorporating pseudocapacitive-active materials, we demonstrate the existence of superelastic supercapacitors with high linear and areal capacitance values of 21.7 mF cm
-1 and 92.1 mF cm-2 , respectively, that can be reversibly stretched by 1,000% without significant capacitance loss. The supercoiled fibre can also function as an electrothermal artificial muscle, contracting 4.2% (percentage of loaded fibre length) when 0.45 V mm-1 is applied.- Published
- 2019
- Full Text
- View/download PDF
227. Carbon monoxide-induced TFEB nuclear translocation enhances mitophagy/mitochondrial biogenesis in hepatocytes and ameliorates inflammatory liver injury.
- Author
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Kim HJ, Joe Y, Rah SY, Kim SK, Park SU, Park J, Kim J, Ryu J, Cho GJ, Surh YJ, Ryter SW, Kim UH, and Chung HT
- Subjects
- Animals, Autophagy drug effects, Autophagy genetics, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Biomarkers metabolism, Calcineurin genetics, Calcineurin metabolism, Chemical and Drug Induced Liver Injury genetics, Chemical and Drug Induced Liver Injury metabolism, Chemical and Drug Induced Liver Injury pathology, Galactosamine administration & dosage, Galactosamine antagonists & inhibitors, Gene Expression Regulation, Hepatocytes drug effects, Hepatocytes metabolism, Hepatocytes pathology, Inflammation, Lipopolysaccharides administration & dosage, Lipopolysaccharides antagonists & inhibitors, Liver drug effects, Liver metabolism, Liver pathology, Lysosomes drug effects, Lysosomes metabolism, Male, Mice, Mice, Inbred C57BL, Mitochondria drug effects, Mitochondria metabolism, Mitophagy drug effects, Mitophagy genetics, Organelle Biogenesis, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Signal Transduction, Tripeptidyl-Peptidase 1, Ubiquitin-Protein Ligases genetics, Ubiquitin-Protein Ligases metabolism, eIF-2 Kinase genetics, eIF-2 Kinase metabolism, Active Transport, Cell Nucleus drug effects, Antimetabolites pharmacology, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, Carbon Monoxide pharmacology, Chemical and Drug Induced Liver Injury prevention & control
- Abstract
Carbon monoxide (CO) can confer protection against cellular stress, whereas the potential involvement of autophagy and lysosomal biogenesis remains incompletely understood. We demonstrate here that the activation of protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK) with CO increased the nuclear translocation of transcription factor EB (TFEB). PERK activation by CO increased intracellular Ca
2+ concentration and the phosphatase activity of calcineurin against TFEB. Moreover, we found that in the deficiency of TFEB, CO not only failed to recruit Parkin to the mitochondria but also failed to increase expression of lysosomal genes such as Lamp1, CathB, and TPP1. Therefore, we suggest that CO increases mitophagy through TFEB nuclear translocation by PERK-calcinuerin activation. In addition, the inhibition of TFEB with siRNA against TFEB abrogated the increase of mtDNA with CO, markers of mitochondrial biogenesis such as PGC1α, NRF1, and TFAM, and the mitochondrial proteins COX II, COX IV, and cytochrome c. To investigate the effects of CO on mitochondrial homeostasis in vivo, mice were treated with lipopolysaccharide (LPS)/D-galactosamine (D-GalN). CO inhalation reduced liver injury after challenge with LPS/GalN. Furthermore, CO inhalation increased TFEB activation, mitophagy and mitochondrial biogenesis in mice treated with LPS/GalN. Our findings describe novel mechanisms underlying CO-dependent cytoprotection in hepatocytes and liver tissue via activation of TFEB-dependent mitophagy and associated induction of both lysosomal and mitochondrial biogenesis.- Published
- 2018
- Full Text
- View/download PDF
228. Nootropic nanocomplex with enhanced blood-brain barrier permeability for treatment of traumatic brain injury-associated neurodegeneration.
- Author
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Park J, Choi E, Shin S, Lim S, Kim D, Baek S, Lee KP, Lee JJ, Lee BH, Kim B, Jeong K, Baik JH, Kim YK, and Kim S
- Subjects
- Animals, Anti-Inflammatory Agents administration & dosage, Anti-Inflammatory Agents pharmacokinetics, Anti-Inflammatory Agents therapeutic use, Blood-Brain Barrier drug effects, Brain Injuries, Traumatic metabolism, Cell Line, Humans, Male, Methylene Blue administration & dosage, Methylene Blue therapeutic use, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Nude, Nanostructures chemistry, Neurodegenerative Diseases etiology, Neurodegenerative Diseases metabolism, Neuroprotective Agents administration & dosage, Neuroprotective Agents pharmacokinetics, Neuroprotective Agents therapeutic use, Nootropic Agents administration & dosage, Nootropic Agents therapeutic use, Permeability, Blood-Brain Barrier metabolism, Brain Injuries, Traumatic complications, Drug Carriers chemistry, Methylene Blue pharmacokinetics, Neurodegenerative Diseases drug therapy, Nootropic Agents pharmacokinetics, Poloxamer chemistry
- Abstract
Traumatic brain injury (TBI) is an intracranial injury which can induce immediate neuroinflammation and long-term neurological deficits. Methylene blue (MB) as a nootropic has a great potential to treat neurodegeneration after TBI because of its anti-inflmmatory and neuroprotective functions. However, its limited accumulation to the brain across the blood-brain barrier (BBB) remains a major hurdle to be overcome. In this paper, we present a polymer surfactant-encapsulated nanocomplex of MB as a delivery system with high BBB permeability for efficacious treatment of TBI-induced neurodegeneration. MB was formulated via electrostatically/hydrophobically directed assembly with fatty acid and Pluronic surfactant (F-127 or F-68) to construct nanocomplexes of two different colloidal sizes (<10 nm and ~108 nm in hydrodynamic diameter for NanoMB-127 and NanoMB-68, respectively). Compared to uncomplexed free MB, formulation into the ultrasmall nanocomplex (NanoMB-127) significantly enhanced the uptake of MB by blood-brain vascular endothelial bEnd3 cells in vitro, and indeed improved its BBB penetration upon systemic administration to normal mice in vivo. However, large-size NanoMB-68 showed negligible BBB crossing despite the efficient bEnd3 cell internalization in vitro, probably due to the unfavorable pharmacokinetic profile associated with its large particle size. By virtue of the efficient BBB penetration and cellular uptake, ultrasmall NanoMB-127 was shown to distinctively reduce the expression level of an inflammatory cytokine with no notable toxicity in vitro and also considerably prevent the neurodegeneration after TBI in mice at much lower doses than free MB. Overall, the Pluronic-supported nanocomplexation method allows efficient brain delivery of MB, offering a novel way of enhancing the efficacy of neurotherapeutics to treat brain diseases., (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
229. Carbon monoxide protects against hepatic steatosis in mice by inducing sestrin-2 via the PERK-eIF2α-ATF4 pathway.
- Author
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Kim HJ, Joe Y, Kim SK, Park SU, Park J, Chen Y, Kim J, Ryu J, Cho GJ, Surh YJ, Ryter SW, Kim UH, and Chung HT
- Subjects
- AMP-Activated Protein Kinases genetics, AMP-Activated Protein Kinases metabolism, Activating Transcription Factor 4 genetics, Activating Transcription Factor 4 metabolism, Animals, Autophagy drug effects, Choline Deficiency genetics, Choline Deficiency metabolism, Choline Deficiency pathology, Disease Models, Animal, Eukaryotic Initiation Factor-2 genetics, Eukaryotic Initiation Factor-2 metabolism, Fatty Liver etiology, Fatty Liver genetics, Fatty Liver pathology, Gene Expression Regulation, Hepatocytes drug effects, Hepatocytes metabolism, Hepatocytes pathology, Liver metabolism, Liver pathology, Male, Mechanistic Target of Rapamycin Complex 1 genetics, Mechanistic Target of Rapamycin Complex 1 metabolism, Methionine adverse effects, Methionine deficiency, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria drug effects, Mitochondria metabolism, Nuclear Proteins agonists, Nuclear Proteins antagonists & inhibitors, Nuclear Proteins metabolism, Organometallic Compounds metabolism, Peroxidases, Primary Cell Culture, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Reactive Oxygen Species metabolism, Signal Transduction, eIF-2 Kinase genetics, eIF-2 Kinase metabolism, Carbon Monoxide pharmacology, Fatty Liver drug therapy, Liver drug effects, Nuclear Proteins genetics, Organometallic Compounds pharmacology, Reactive Oxygen Species agonists
- Abstract
Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, has emerged as one of the most common causes of chronic liver disease in developed countries over the last decade. NAFLD comprises a spectrum of pathological hepatic changes, including steatosis, steatohepatitis, advanced fibrosis, and cirrhosis. Autophagy, a homeostatic process for protein and organelle turnover, is decreased in the liver during the development of NAFLD. Previously, we have shown that carbon monoxide (CO), a reaction product of heme oxygenase (HO) activity, can confer protection in NAFLD, though the molecular mechanisms remain unclear. We therefore investigated the mechanisms underlying the protective effect of CO on methionine/choline-deficient (MCD) diet-induced hepatic steatosis. We found that CO induced sestrin-2 (SESN2) expression through enhanced mitochondrial ROS production and protected against MCD-induced NAFLD progression through activation of autophagy. SESN2 expression was increased by CO or CO-releasing molecule (CORM2), in a manner dependent on signaling through the protein kinase R-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor-2 alpha (eIF2α)/ activating transcription factor-4 (ATF4)-dependent pathway. CO-induced SESN2 upregulation in hepatocytes contributed to autophagy induction through activation of 5'-AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR) complex I (mTORC1). Furthermore, we demonstrate that CO significantly induced the expression of SESN2 and enhanced autophagy in the livers of MCD-fed mice or in MCD-media treated hepatocytes. Conversely, knockdown of SESN2 abrogated autophagy activation and mTOR inhibition in response to CO. We conclude that CO ameliorates hepatic steatosis through the autophagy pathway induced by SESN2 upregulation., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
230. Quantum Conductance Probing of Oxygen Vacancies in SrTiO 3 Epitaxial Thin Film using Graphene.
- Author
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Kang KT, Kang H, Park J, Suh D, and Choi WS
- Abstract
Quantum Hall conductance in monolayer graphene on an epitaxial SrTiO
3 (STO) thin film is studied to understand the role of oxygen vacancies in determining the dielectric properties of STO. As the gate-voltage sweep range is gradually increased in the device, systematic generation and annihilation of oxygen vacancies, evidenced from the hysteretic conductance behavior in the graphene, are observed. Furthermore, based on the experimentally observed linear scaling relation between the effective capacitance and the voltage sweep range, a simple model is constructed to manifest the relationship among the dielectric properties of STO with oxygen vacancies. The inherent quantum Hall conductance in graphene can be considered as a sensitive, robust, and noninvasive probe for understanding the electronic and ionic phenomena in complex transition-metal oxides without impairing the oxide layer underneath., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)- Published
- 2017
- Full Text
- View/download PDF
231. Tristetraprolin mediates the anti-proliferative effects of metformin in breast cancer cells.
- Author
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Pandiri I, Chen Y, Joe Y, Kim HJ, Park J, Chung HT, and Park JW
- Subjects
- Breast Neoplasms genetics, Cell Line, Tumor, Cell Survival drug effects, Down-Regulation, Female, Gene Expression Regulation, Neoplastic, Humans, MCF-7 Cells, Promoter Regions, Genetic, Tumor Suppressor Protein p53 genetics, Breast Neoplasms metabolism, Cytostatic Agents pharmacology, Metformin pharmacology, Proto-Oncogene Proteins c-myc genetics, Tristetraprolin genetics, Tristetraprolin metabolism
- Abstract
Metformin, which is a drug commonly prescribed to treat type 2 diabetes, has anti-proliferative effects in cancer cells; however, the molecular mechanisms underlying this effect remain largely unknown. The aim is to investigate the role of tristetraprolin (TTP), an AU-rich element-binding protein, in anti-proliferative effects of metformin in cancer cells. p53 wild-type and p53 mutant breast cancer cells were treated with metformin, and expression of TTP and c-Myc was analyzed by semi-quantitative RT-PCR, Western blots, and promoter activity assay. Breast cancer cells were transfected with siRNA against TTP to inhibit TTP expression or c-Myc and, after metformin treatment, analyzed for cell proliferation by MTS assay. Metformin induces the expression of tristetraprolin (TTP) in breast cancer cells in a p53-independent manner. Importantly, inhibition of TTP abrogated the anti-proliferation effect of metformin. We observed that metformin decreased c-Myc levels, and ectopic expression of c-Myc blocked the effect of metformin on TTP expression and cell proliferation. Our data indicate that metformin induces TTP expression by reducing the expression of c-Myc, suggesting a new model whereby TTP acts as a mediator of metformin's anti-proliferative activity in cancer cells.
- Published
- 2016
- Full Text
- View/download PDF
232. Cilostazol attenuates murine hepatic ischemia and reperfusion injury via heme oxygenase-dependent activation of mitochondrial biogenesis.
- Author
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Joe Y, Zheng M, Kim HJ, Uddin MJ, Kim SK, Chen Y, Park J, Cho GJ, Ryter SW, and Chung HT
- Subjects
- Animals, Cilostazol, Cytoprotection, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Disease Models, Animal, Gene Expression Regulation, Heme Oxygenase-1 deficiency, Heme Oxygenase-1 genetics, Hep G2 Cells, High Mobility Group Proteins genetics, High Mobility Group Proteins metabolism, Humans, Liver enzymology, Liver pathology, Membrane Proteins deficiency, Membrane Proteins genetics, Mice, Inbred BALB C, Mice, Knockout, Mitochondria, Liver enzymology, Mitochondria, Liver pathology, NF-E2-Related Factor 2 deficiency, NF-E2-Related Factor 2 genetics, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Phosphodiesterase 3 Inhibitors pharmacology, RNA, Messenger metabolism, Reactive Oxygen Species metabolism, Reperfusion Injury enzymology, Reperfusion Injury genetics, Reperfusion Injury pathology, Signal Transduction drug effects, Transcription Factors genetics, Transcription Factors metabolism, Heme Oxygenase-1 metabolism, Liver blood supply, Liver drug effects, Membrane Proteins metabolism, Mitochondria, Liver drug effects, Mitochondrial Turnover drug effects, Protective Agents pharmacology, Reperfusion Injury prevention & control, Tetrazoles pharmacology
- Abstract
Hepatic ischemia-reperfusion (I/R) can cause hepatocellular injury associated with the inflammatory response and mitochondrial dysfunction. We studied the protective effects of the phosphodiesterase inhibitor cilostazol in hepatic I/R and the roles of mitochondria and the Nrf2/heme oxygenase-1 (HO-1) system. Wild-type, Hmox1(-/-), or Nrf2(-/-) mice were subjected to hepatic I/R in the absence or presence of cilostazol followed by measurements of liver injury. Primary hepatocytes were subjected to cilostazol with the HO-1 inhibitor ZnPP, or Nrf2-specific siRNA, followed by assessment of mitochondrial biogenesis. Preconditioning with cilostazol prior to hepatic I/R protected against hepatocellular injury and mitochondrial dysfunction. Cilostazol reduced the serum levels of alanine aminotransferase, TNF-α, and liver myeloperoxidase content relative to control I/R-treated mice. In primary hepatocytes, cilostazol increased the expression of HO-1, and markers of mitochondrial biogenesis, PGC-1α, NRF-1, and TFAM, induced the mitochondrial proteins COX III and COX IV and increased mtDNA and mitochondria content. Pretreatment of primary hepatocytes with ZnPP inhibited cilostazol-induced PGC-1α, NRF-1, and TFAM mRNA expression and reduced mtDNA and mitochondria content. Genetic silencing of Nrf2 prevented the induction of HO-1 and mitochondrial biogenesis by cilostazol in HepG2 cells. Cilostazol induced hepatic HO-1 production and mitochondrial biogenesis in wild-type mice, but not in Hmox1(-/-) or Nrf2(-/-) mice, and failed to protect against liver injury in Nrf2(-/-) mice. These results suggest that I/R injury can impair hepatic mitochondrial function, which can be reversed by cilostazol treatment. These results also suggest that cilostazol-induced mitochondrial biogenesis was mediated by an Nrf-2- and HO-1-dependent pathway., (Copyright © 2015 the American Physiological Society.)
- Published
- 2015
- Full Text
- View/download PDF
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