Publications by authors named "Jiyeon Kim"

263 Publications

Immunologic Aspects of Dyslipidemia: a Critical Regulator of Adaptive Immunity and Immune Disorders.

J Lipid Atheroscler 2021 May 11;10(2):184-201. Epub 2021 May 11.

Laboratory of Immune Regulation, Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.

Dyslipidemia is a major cause of cardiovascular diseases which represent a leading cause of death in humans. Diverse immune cells are known to be involved in the pathogenesis of cardiovascular diseases such as atherosclerosis. Conversely, dyslipidemia is known to be tightly associated with immune disorders in humans, as evidenced by a higher incidence of atherosclerosis in patients with autoimmune diseases including psoriasis, rheumatoid arthritis, and systemic lupus erythematosus. Given that the dyslipidemia-related autoimmune diseases are caused by autoreactive T cells and B cells, dyslipidemia seems to directly or indirectly regulate the adaptive immunity. Indeed, accumulating evidence has unveiled that proatherogenic factors can impact the differentiation and function of CD4 T cells, CD8 T cells, and B cells. This review discusses an updated overview on the regulation of adaptive immunity by dyslipidemia and proposes a potential therapeutic strategy for immune disorders by targeting lipid metabolism.
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http://dx.doi.org/10.12997/jla.2021.10.2.184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159760PMC
May 2021

Rapid and simple single-chamber nucleic acid detection system prepared through nature-inspired surface engineering.

Theranostics 2021 3;11(14):6735-6745. Epub 2021 May 3.

Department of Emerging Materials Science, DGIST, Daegu, 42988, Republic of Korea.

Nucleic acid (NA)-based diagnostics enable a rapid response to various diseases, but current techniques often require multiple labor-intensive steps, which is a major obstacle to successful translation to a clinical setting. We report on a surface-engineered single-chamber device for NA extraction and amplification without sample transfer. Our system has two reaction sites: a NA extraction chamber whose surface is patterned with micropillars and a reaction chamber filled with reagents for polymerase-based NA amplification. These two sites are integrated in a single microfluidic device; we applied plastic injection molding for cost-effective, mass-production of the designed device. The micropillars were chemically activated via a nature-inspired silica coating to possess a specific affinity to NA. As a proof-of-concept, a colorimetric pH indicator was coupled to the on-chip analysis of NA for the rapid and convenient detection of pathogens. The NA enrichment efficiency was dependent on the lysate incubation time, as diffusion controls the NA contact with the engineered surface. We could detect down to 1×10 CFU by the naked eye within one hour of the total assay time. We anticipate that the surface engineering technique for NA enrichment could be easily integrated as a part of various types of microfluidic chips for rapid and convenient nucleic acid-based diagnostics.
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http://dx.doi.org/10.7150/thno.57153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171086PMC
May 2021

Type 17 immunity promotes the exhaustion of CD8 T cells in cancer.

J Immunother Cancer 2021 Jun;9(6)

Lab of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea

Background: Multiple types of immune cells producing IL-17 are found in the tumor microenvironment. However, their roles in tumor progression and exhaustion of CD8 tumor-infiltrating lymphocytes (TILs) remain unclear.

Methods: To determine the role of type 17 immunity in tumor, we investigated the growth of B16F10 melanoma and the exhaustion of CD8 TILs in mice, mice, RORγt inhibitor-treated mice, or their respective control mice. Adoptive transfer of tumor-specific IL-17-producing T cells was performed in B16F10-bearing congenic mice. Anti-CD4 or anti-Ly6G antibodies were used to deplete CD4 T cells or CD11bGr-1 myeloid cells , respectively. Correlation between type 17 immunity and T cell exhaustion in human cancer was evaluated by interrogating TCGA dataset.

Results: Depletion of CD4 T cells promotes the exhaustion of CD8 T cells with a concomitant increase in IL-17-producing CD8 T (Tc17) cells in the tumor. Unlike IFN-γ-producing CD8 T (Tc1) cells, tumor-infiltrating Tc17 cells exhibit CD103KLRG1IL-7Rα tissue resident memory-like phenotypes and are poorly cytolytic. Adoptive transfer of IL-17-producing tumor-specific T cells increases, while depletion of IL-17-producing cells decreases, the frequency of PD-1Tim3TOX terminally exhausted CD8 T cells in the tumor. Blockade of IL-17 or RORγt pathway inhibits exhaustion of CD8 T cells and also delays tumor growth . Consistent with these results, human TCGA analyses reveal a strong positive correlation between type 17 and CD8 T cell exhaustion signature gene sets in multiple cancers.

Conclusion: IL-17-producing cells promote terminal exhaustion of CD8 T cells and tumor progression , which can be reversed by blockade of IL-17 or RORγt pathway. These findings unveil a novel role for IL-17-producing cells as tumor-promoting cells facilitating CD8 T cell exhaustion, and propose type 17 immunity as a promising target for cancer immunotherapy.
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http://dx.doi.org/10.1136/jitc-2021-002603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183213PMC
June 2021

Long-term control of diabetes in a nonhuman primate by two separate transplantations of porcine adult islets under immunosuppression.

Am J Transplant 2021 May 31. Epub 2021 May 31.

Xenotransplantation Research Center, Seoul National University, College of Medicine, Seoul, Korea.

Porcine islet transplantation is an alternative to allo-islet transplantation. Retransplantation of islets is a routine clinical practice in islet allotransplantation in immunosuppressed recipients and will most likely be required in islet xenotransplantation in immunosuppressed recipients. We examined whether a second infusion of porcine islets could restore normoglycemia and further evaluated the efficacy of a clinically available immunosuppression regimen including anti-thymocyte globulin for induction; belimumab, sirolimus, and tofacitinib for maintenance; and adalimumab, anakinra, IVIg, and tocilizumab for inflammation control in a pig to non-human primate transplantation setting. Of note, all non-human primates were normoglycemic after the retransplantation of porcine islets without induction therapy. Graft survival was >100 days for all 3 recipients, and 1 of the 3 monkeys showed insulin independence for >237 days. Serious lymphodepletion was not observed, and rhesus cytomegalovirus reactivation was controlled without any serious adverse effects throughout the observation period in all recipients. These results support the clinical applicability of additional infusions of porcine islets. The maintenance immunosuppression regimen we used could protect the reinfused islets from acute rejection.
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http://dx.doi.org/10.1111/ajt.16704DOI Listing
May 2021

Synergistic cycles of protease activity and inflammation via PPARγ degradation in chronic obstructive pulmonary disease.

Exp Mol Med 2021 May 21;53(5):947-955. Epub 2021 May 21.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.

Inflammation, oxidative stress, and protease-antiprotease imbalance have been suggested to be a pathogenic triad in chronic obstructive pulmonary disease (COPD). However, it is not clear how proteases interact with components of inflammatory pathways. Therefore, this study aimed to evaluate the effect of neutrophil elastase (NE) on lipopolysaccharide (LPS)-induced interleukin 8 (IL-8) production and determine the molecular mechanism in human bronchial epithelial cells (HBECs). Immortalized bronchial epithelial cells and primary HBECs were used to investigate the impact of NE on LPS-induced IL-8 production. The molecular mechanism by which NE modulated LPS-induced IL-8 production was confirmed in elastase-treated C57BL/6 mice and primary HBECs obtained from COPD patients and healthy controls. The results showed that NE treatment synergistically augmented LPS-induced IL-8 production in both immortalized bronchial epithelial cells and primary HBECs. NE partially degraded peroxisome proliferator-activated receptor gamma (PPARγ), which is known to regulate IL-8 production in the nucleus. Treatment with a PPARγ agonist and overexpression of PPARγ reversed the NE-induced synergistic increase in LPS-induced IL-8 production. Moreover, PPARγ levels were lower in lung homogenates and lung epithelial cells from elastase-treated mice than in those from saline-treated mice. In accordance with the findings in mice, PPARγ levels were lower in primary HBECs from COPD patients than in those from healthy never-smokers or healthy smokers. In conclusion, a vicious cycle of mutual augmentation of protease activity and inflammation resulting from PPARγ degradation plays a role in the pathogenesis of COPD.
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http://dx.doi.org/10.1038/s12276-021-00626-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178386PMC
May 2021

Hypertriglyceridemia with acute pancreatitis in a 14-year-old girl with diabetic ketoacidosis.

Ann Pediatr Endocrinol Metab 2021 May 14. Epub 2021 May 14.

Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Diabetic ketoacidosis (DKA) is a medically fatal condition in poorly controlled hyperglycemia or newly diagnosed diabetes mellitus. Severe hypertriglyceridemia (HTG) is an uncommon complication of DKA and can be associated with acute pancreatitis (AP). We present the clinical manifestations, laboratory findings, and management of AP associated with HTG in a 14-year-old girl with DKA. The patient with seven-year history of type 2 diabetes presented with epigastric pain, 1 month after stopping insulin injection. DKA, severe HTG, and AP were diagnosed based on the laboratory and imaging tests. She recovered from DKA after conventional treatment for DKA, and her triglyceride (TG) level was reduced from 10,867 mg/dL to normal range after 6 days of admission without anti-lipid medication. Considering not too low C-peptide levels, negative diabetes-related antibodies and high TG level, targeted gene panel sequencing was performed on the genes associated with diabetes and HTG. We identified a heterozygous mutation c.4607C>T (p. Ala1537Val) in ABCC8 related to maturity-onset diabetes of the young (MODY) 12. This is the first reported case of HTG induced AP with DKA in a patient with MODY. In addition, we reviewed the literatures for pediatric cases of HTG with DKA. In patients with DKA, timely awareness of severe HTG related to insulin deficiency is crucial for improving the consequence of AP. We recommend considering AP in all DKA patients presenting with severe HTG to ensure early and proper management.
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http://dx.doi.org/10.6065/apem.2040250.125DOI Listing
May 2021

Cereblon contributes to the development of pulmonary fibrosis via inactivation of adenosine monophosphate-activated protein kinase α1.

Exp Mol Med 2021 May 17;53(5):885-893. Epub 2021 May 17.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.

Pulmonary fibrosis is a progressive and lethal lung disease characterized by the proliferation and differentiation of lung fibroblasts and the accumulation of extracellular matrices. Since pulmonary fibrosis was reported to be associated with adenosine monophosphate-activated protein kinase (AMPK) activation, which is negatively regulated by cereblon (CRBN), we aimed to determine whether CRBN is involved in the development of pulmonary fibrosis. Therefore, we evaluated the role of CRBN in bleomycin (BLM)-induced pulmonary fibrosis in mice and in transforming growth factor-beta 1 (TGF-β1)-induced differentiation of human lung fibroblasts. BLM-induced fibrosis and the mRNA expression of collagen and fibronectin were increased in the lung tissues of wild-type (WT) mice; however, they were significantly suppressed in Crbn knockout (KO) mice. While the concentrations of TGF-β1/2 in bronchoalveolar lavage fluid were increased via BLM treatment, they were similar between BLM-treated WT and Crbn KO mice. Knockdown of CRBN suppressed TGF-β1-induced activation of small mothers against decapentaplegic 3 (SMAD3), and overexpression of CRBN increased it. TGF-β1-induced activation of SMAD3 increased α-smooth muscle actin (α-SMA) and collagen levels. CRBN was found to be colocalized with AMPKα1 in lung fibroblasts. CRBN overexpression inactivated AMPKα1. When cells were treated with metformin (an AMPK activator), the CRBN-induced activation of SMAD3 and upregulation of α-SMA and collagen expression were significantly suppressed, suggesting that increased TGF-β1-induced activation of SMAD3 via CRBN overexpression is associated with AMPKα1 inactivation. Taken together, these data suggest that CRBN is a profibrotic regulator and maybe a potential target for treating lung fibrosis.
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http://dx.doi.org/10.1038/s12276-021-00619-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178361PMC
May 2021

Modulation of Pro-inflammatory and Anti-inflammatory Cytokines in the Fat by an Aloe Gel-based Formula, QDMC, Is Correlated with Altered Gut Microbiota.

Immune Netw 2021 Apr 25;21(2):e15. Epub 2021 Mar 25.

College of Pharmacy, Sahmyook University, Seoul 01795, Korea.

Abnormal inflammatory responses are closely associated with intestinal microbial dysbiosis. Oral administration of Qmatrix-diabetes-mellitus complex (QDMC), an Aloe gel-based formula, has been reported to improve inflammation in type 2 diabetic mice; however, the role of the gut microbiota in ameliorating efficacy of QDMC remains unclear. We investigated the effect of QDMC on the gut microbiota in a type 2 diabetic aged mouse model that was administered a high-fat diet. Proinflammatory (TNF-α and IL-6) and anti-inflammatory (IL-4 and IL-10) cytokine levels in the fat were normalized via oral administration of QDMC, and relative abundances of , , , and were simultaneously significantly increased. The abundance of these bacteria was correlated to the expression levels of cytokines. Our findings suggest that the immunomodulatory activity of QDMC is partly mediated by the altered gut microbiota composition.
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http://dx.doi.org/10.4110/in.2021.21.e15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099612PMC
April 2021

Cyclic RGD Pentapeptide Cilengitide Enhances Efficacy of Gefitinib on TGF-β1-Induced Epithelial-to-Mesenchymal Transition and Invasion in Human Non-Small Cell Lung Cancer Cells.

Front Pharmacol 2021 24;12:639095. Epub 2021 Mar 24.

Department of Medical Laboratory Science, School of Health Science, Dankook University, Cheonan, Korea.

During non-small cell lung cancer (NSCLC) progression, transforming growth factor (TGF)-β mediated epithelial-to-mesenchymal transition (EMT) is an important process leading to high mortality and poor prognosis. The EMT is a fundamental process for morphogenesis characterized by the transformation of cancer cells into invasive forms that can be transferred to other organs during human lung cancer progression. Gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, has shown anti-proliferative effects in EGFR-mutated NSCLC cells and an inhibitory effect on migration and invasion of NSCLC cells to other organs. In this study, we evaluated the combinatorial treatment effect of cilengitide, a cyclic RGD pentapeptide, on TGF-β1-induced EMT phenotype and invasion. Gefitinib suppressed the expression of TGF-β1-induced mesenchymal markers by inhibiting Smad and non-Smad signaling pathways. Cilengitide enhanced the inhibitory effect of gefitinib on TGF-β1-induced expression of mesenchymal markers, phosphorylation of Smad2/3, and invasion of NSCLC A549 cells. We suggested that the use of cilengitide can improve the efficacy of anti-cancer drugs in combination drug-based chemotherapy. These results provide an improved therapeutic strategy for treating and preventing EMT-related disorders, such as NSCLC, lung fibrosis, cancer metastasis, and relapse.
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http://dx.doi.org/10.3389/fphar.2021.639095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104086PMC
March 2021

Inhibitory effects of aprotinin on influenza A and B viruses in vitro and in vivo.

Sci Rep 2021 May 3;11(1):9427. Epub 2021 May 3.

Department of Pharmacy, College of Pharmacy, Korea University, 2511 Sejong-ro, Sejong, 30019, Republic of Korea.

Influenza viruses cause significant morbidity and mortality worldwide. Long-term or frequent use of approved anti-influenza agents has resulted in drug-resistant strains, thereby necessitating the discovery of new drugs. In this study, we found aprotinin, a serine protease inhibitor, as an anti-influenza candidate through screening of compound libraries. Aprotinin has been previously reported to show inhibitory effects on a few influenza A virus (IAV) subtypes (e.g., seasonal H1N1 and H3N2). However, because there were no reports of its inhibitory effects on the other types of influenza viruses, we investigated the inhibitory effects of aprotinin in vitro on a wide range of influenza viruses, including avian and oseltamivir-resistant influenza virus strains. Our cell-based assay showed that aprotinin had inhibitory effects on seasonal human IAVs (H1N1 and H3N2 subtypes), avian IAVs (H5N2, H6N5, and H9N2 subtypes), an oseltamivir-resistant IAV, and a currently circulating influenza B virus. We have also confirmed its activity in mice infected with a lethal dose of influenza virus, showing a significant increase in survival rate. Our findings suggest that aprotinin has the capacity to inhibit a wide range of influenza virus subtypes and should be considered for development as a therapeutic agent against influenza.
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http://dx.doi.org/10.1038/s41598-021-88886-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093218PMC
May 2021

Physical and Psychological Factors Contributing to Incidental Falls in Older Adults Who Perceive Themselves as Unhealthy: A Cross-Sectional Study.

Int J Environ Res Public Health 2021 04 2;18(7). Epub 2021 Apr 2.

Department of Neurology, Gangneung Asan Hospital, University of Ulsan College of Medicine, 38 Bangdong-gil, Sacheon-myeon, Gangneung-si, Gangwon-do 25440, Korea.

Falls have become one of the common causes of morbidity and mortality in the elderly. Advanced age is a strong predictor of falls. Additionally, those who perceive themselves as unhealthy are more likely to suffer from incidental falls in accordance with aging. We aimed to compare individual, physical, and psychological factors between older adults with and without a fall history. Then, we tried to identify physical and psychological variables associated with falls by controlling for individual characteristics. We analyzed public data from the 2017 National Survey of Older Persons in South Korea. Seniors aged 65 years and over who considered themselves in poor health status were eligible. A total of 2765 women and 1280 men ( = 4045) were enrolled, and 940 adults suffered a fall within a year (the average number of falls was 2.5). We applied individual variable-adjusted models and discovered that hearing discomfort (odds ratio (OR) 1.30, 95% confidence interval (CI) 1.09-1.55), limited activities of daily living (ADL) (OR 1.40, 95% CI 1.13-1.74), limited instrumental activities of daily living (IADL) (OR 1.34, 95% CI 1.13-1.61), and depression (OR 1.44, 95% CI 1.23-1.69) significantly increased risk for falls on multivariate logistic regression. Our findings suggest that hearing discomfort, limited ADL/IADL, and depression need to be addressed observantly to prevent falls in the elderly who consider themselves unhealthy.
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http://dx.doi.org/10.3390/ijerph18073738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038270PMC
April 2021

COVID-19 Antiviral and Treatment Candidates: Current Status.

Immune Netw 2021 Feb 15;21(1):e7. Epub 2021 Feb 15.

Department of Pharmacy, Korea University College of Pharmacy, Sejong 30019, Korea.

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 has severely impacted global health and economy. There is currently no effective approved treatment for COVID-19; although vaccines have been granted emergency use authorization in several countries, they are currently only administered to high-risk individuals, thereby leaving a gap in virus control measures. The scientific and clinical communities and drug manufacturers have collaborated to speed up the discovery of potential therapies for COVID-19 by taking advantage of currently approved drugs as well as investigatory agents in clinical trials. In this review, we stratified some of these candidates based on their potential targets in the progression of COVID-19 and discuss some of the results of ongoing clinical evaluations.
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http://dx.doi.org/10.4110/in.2021.21.e7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937511PMC
February 2021

A boy with Coffin-Siris syndrome with a novel frameshift mutation in ARID1B.

Neuro Endocrinol Lett 2021 Jan;41(6):285-289

Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Coffin-Siris syndrome (OMIM #135900) is an autosomal dominant inherited disorder, characterized by dysmorphic features, congenital anomalies, and developmental delay. We report the clinical and molecular findings in a patient with Coffin-Siris syndrome. A 3-year-and-6-month-old boy presented with developmental delay, distinctive facial features, hypertrichosis, partial agenesis of the corpus callosum, fifth digit nail hypoplasia, congenital anomalies, and growth retardation. Targeted gene panel sequencing identified a novel heterozygous frameshift mutation c.2147_2148insAC in ARID1B which was predicted as a premature stop codon p. (Gln717Argfs*29). This is the second report of Coffin-Siris syndrome in Korea. Targeted gene panel sequencing can be used as an effective tool for the diagnosis of rare complex syndromes such as Coffin-Siris syndrome.
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January 2021

Dampening the Fire: A Negative Feedback Loop in Acute Respiratory Distress Syndrome.

Am J Respir Cell Mol Biol 2021 02;64(2):158-160

Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois.

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http://dx.doi.org/10.1165/rcmb.2020-0487EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874398PMC
February 2021

Biobank for multidrug-resistant tuberculosis research: importance of sequential samples.

Pathog Dis 2021 Mar;79(3)

Clinical Research Center, Masan National Tuberculosis Hospital, 215 Gapo-ro, Masanhappo-gu, Changwon-si, Gyeongsangnam-do 51755, Republic of Korea.

Since 2013, Masan National Tuberculosis Hospital has collected standardized specimens from its tuberculosis patients, which include a large number of multidrug-resistant strains. The repository collects matched participants and their bacilli samples, compiling sequential samples from the beginning of treatment. The repository aims to provide resources for in-depth international research.
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http://dx.doi.org/10.1093/femspd/ftab011DOI Listing
March 2021

Short-term therapy with anti-ICAM-1 monoclonal antibody induced long-term liver allograft survival in nonhuman primates.

Am J Transplant 2021 Jan 10. Epub 2021 Jan 10.

Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea.

Tolerance induction remains challenging following liver transplantation and the long-term use of immunosuppressants, especially calcineurin inhibitors, leads to serious complications. We aimed to test an alternative immunosuppressant, a chimeric anti-ICAM-1 monoclonal antibody, MD-3, for improving the outcomes of liver transplantation. We used a rhesus macaque liver transplantation model and monkeys were divided into three groups: no immunosuppression (n = 2), conventional immunosuppression (n = 4), and MD-3 (n = 5). Without immunosuppression, liver allografts failed within a week by acute rejection. Sixteen-week-long conventional immunosuppression that consisted of prednisolone, tacrolimus, and an mTOR inhibitor prolonged liver allograft survival; however, recipients died of acute T cell-mediated rejection (day 52), chronic rejection (days 62 and 66), or adverse effects of mTOR inhibitor (day 32). In contrast, 12-week-long MD-3 therapy with transient conventional immunosuppression in the MD-3 group significantly prolonged the survival of liver allograft recipients (5, 96, 216, 412, 730 days; p = .0483). MD-3 effectively suppressed intragraft inflammatory cell infiltration, anti-donor T cell responses, and donor-specific antibody with intact anti-cytomegalovirus antibody responses. However, this regimen ended in chronic rejection. In conclusion, short-term therapy with MD-3 markedly improved liver allograft survival to 2 years without maintenance of immunosuppressant. MD-3 is therefore a promising immune-modulating agent for liver transplantation.
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http://dx.doi.org/10.1111/ajt.16486DOI Listing
January 2021

Anti-Proliferative Effect of L. Extract in Human T-Cell Acute Lymphocytic Leukemia Cells.

Molecules 2020 Dec 23;26(1). Epub 2020 Dec 23.

Department of Pharmacology, School of Medicine, Eulji University, Daejeon 34824, Korea.

species are well known plants distributed throughout the world, and they contain various bioactive components with different biological activities including anti-cancer effects. In this study, we investigated the inhibitory effect of L. (A.S.) extract on cell survival and IL-2-mediated inflammation in human T cell acute lymphocytic leukemia (T-ALL) Jurkat cells. Our results showed that A.S. extract induced caspase-dependent apoptosis of Jurkat cells with no significant cytotoxicity in the normal peripheral blood mononuclear cells. A.S. extract induced ROS generation through the activation of MAPK p38 phosphorylation. It also inhibited IL-2 mRNA expression and NF-κB signaling mediated by phorbol 12-myristate 13-acetate, and phytohemagglutinin. Combined treatment with A.S. extract and axitinib/dovitinib exerted enhanced inhibitory effects on T-ALL cell growth and IL-2 production. These results provide novel information on the potential use of A.S. extract as a therapeutic herbal agent for the treatment and prevention of T-ALL.
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http://dx.doi.org/10.3390/molecules26010035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795430PMC
December 2020

Highly Efficient Photothermal Therapy with Cell-Penetrating Peptide-Modified Bumpy Au Triangular Nanoprisms using Low Laser Power and Low Probe Dose.

Nano Lett 2021 01 17;21(1):731-739. Epub 2020 Dec 17.

Department of Chemistry, Seoul National University, Seoul 08826, South Korea.

Photothermal therapy (PTT) exploits nanomaterials with optimal heat conversion and cellular penetration using near-infrared (NIR) laser irradiation. However, current PTT agents suffer from inefficient heat conversion, poor intracellular delivery, and a high dose of probes along with excessive laser irradiation, causing limited therapeutic outcomes. Here, bumpy Au triangular nanoprisms (BATrisms) are developed for increasing the surface area, improving cell penetration, shifting the absorption peak to the NIR region, and enhancing the photothermal conversion efficiency (∼86%). Further, leucine (L)- and lysine (K)-rich cell-penetrating peptides (LK peptides) were employed to largely improve their cellular uptake efficiency. Importantly, a significant therapeutic efficacy with LK-BATrisms was demonstrated in a triple-negative breast cancer xenograft mice model. A very small dose of LK-BATrism (2.5 μg Au) was enough to exert antitumor efficacy under very low laser power (808 nm, 0.25 W/cm), causing minimal tissue damages while very efficiently killing cancer cells.
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http://dx.doi.org/10.1021/acs.nanolett.0c04386DOI Listing
January 2021

In Situ Measuring Partition Coefficient at Intact Nanoemulsions: A New Application of Single-Entity Electrochemistry.

Anal Chem 2021 01 8;93(2):1154-1160. Epub 2020 Dec 8.

Department of Chemistry, University of Rhode Island, Kingston, Rhode Island 02881, United States.

We report a new application of the single-entity electrochemistry (SEE) to in situ measure a partition coefficient at intact nanoemulsions (NEs). The partition coefficient at intact NEs is the most crucial physicochemical property to determine the uptake of delivery molecules inside NEs. It, however, has not been unequivocally elucidated by currently existing techniques based on ex situ measurements. Herein, we apply the single-entity electrochemistry (SEE) to directly and quantitatively measure the partition coefficient at NEs in situ. In this work, we use NEs featured with amphiphilic triblock copolymer (Pluronic F-127) as a model system to extract/preconcentrate 2-aminobiphenyl (2-ABP) dissolved in the water and demonstrate a new application of SEE to in situ quantitatively estimate the amounts of 2-ABP distributed into each intact NE. Our SEE measurements reveal that the partitioning is governed by extraction of 2-ABP inside NEs rather than its adsorption on the NE surface, and this extraction is remarkably efficient with up to ∼8 orders of magnitude of the preconcentration factor, thus leading to the unprecedentedly large partition coefficient of 1.9 (±1.4) × 10. This result implies that not only the thermodynamic distribution but also the intermolecular interaction of extracted compounds inside NEs could play a significant role in the apparent partition coefficient ( = 1.9 (±1.4) × 10). The experimentally determined partition coefficient was validated by molecular dynamics (MD) simulations with showing a stabilizing role of intermolecular interaction in the partitioned system. We further verified our methodology with other compounds exhibiting aromatic properties, e.g., ferrocenemethanol. Significantly, our new approach can be readily applicable to investigate practical NEs commercially marketed for drug, food, and cosmetics.
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http://dx.doi.org/10.1021/acs.analchem.0c04205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970832PMC
January 2021

The hexosamine biosynthesis pathway is a targetable liability in KRAS/LKB1 mutant lung cancer.

Nat Metab 2020 12 30;2(12):1401-1412. Epub 2020 Nov 30.

Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, TX, USA.

In non-small-cell lung cancer (NSCLC), concurrent mutations in the oncogene KRAS and the tumour suppressor STK11 (also known as LKB1) encoding the kinase LKB1 result in aggressive tumours prone to metastasis but with liabilities arising from reprogrammed metabolism. We previously demonstrated perturbed nitrogen metabolism and addiction to an unconventional pathway of pyrimidine synthesis in KRAS/LKB1 co-mutant cancer cells. To gain broader insight into metabolic reprogramming in NSCLC, we analysed tumour metabolomes in a series of genetically engineered mouse models with oncogenic KRAS combined with mutations in LKB1 or p53. Metabolomics and gene expression profiling pointed towards activation of the hexosamine biosynthesis pathway (HBP), another nitrogen-related metabolic pathway, in both mouse and human KRAS/LKB1 co-mutant tumours. KRAS/LKB1 co-mutant cells contain high levels of HBP metabolites, higher flux through the HBP pathway and elevated dependence on the HBP enzyme glutamine-fructose-6-phosphate transaminase [isomerizing] 2 (GFPT2). GFPT2 inhibition selectively reduced KRAS/LKB1 co-mutant tumour cell growth in culture, xenografts and genetically modified mice. Our results define a new metabolic vulnerability in KRAS/LKB1 co-mutant tumours and provide a rationale for targeting GFPT2 in this aggressive NSCLC subtype.
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http://dx.doi.org/10.1038/s42255-020-00316-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744327PMC
December 2020

Towards ultralow detection limits of aromatic toxicants in water using pluronic nanoemulsions and single-entity electrochemistry.

Anal Chim Acta 2020 Dec 29;1139:129-137. Epub 2020 Sep 29.

Department of Chemistry, University of Rhode Island, Kingston, RI, 02881, USA. Electronic address:

We demonstrate a new electroanalytical technique using nanoemulsions (NEs) as a nanoextractor combined with single entity electrochemistry (SEE) to separate, preconcentrate analytes from bulk media, and even detect them in situ, enabling ultratrace level analysis. This approach is based on our hypothesis that the custom-designed NEs would enable to effectively scavenge compounds from bulk media. Herein, we use Pluronic F-127 functionalized NEs to extract, preconcentrate target analytes e.g., ferrocene derivatives as a model aromatic toxicant dissolved in the water, and employ SEE to in situ detect and quantitatively estimate analytes extracted in individual NEs. Extraction was markedly efficient to reach ∼8 orders of magnitude of preconcentration factor under the true equilibrium, thereby enabling ultratrace level analysis with a detection limit of ∼0.2 ppb. The key step to attain high sensitivity in our measurements was to modulate the total amount of added NEs respect to the total volume of bulk solution, thereby controlling the extracted amount of analytes in each NE. Our approach is readily applicable to investigate other aromatic toxicants dissolved in the water, thus detecting hazardous carcinogen, 2-aminobiphenyl in the water up to ∼0.1 ppb level. Given the excellent detection performance as well as the broad applicability for ubiquitous aromatic contaminants, the combination of NEs with SEE offers great prospects as a sensor for environmental applications.
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http://dx.doi.org/10.1016/j.aca.2020.09.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962592PMC
December 2020

Impact of growth hormone treatment on scoliosis development and progression: analysis of 1128 patients with idiopathic short stature.

J Pediatr Endocrinol Metab 2021 Feb 13;34(2):243-250. Epub 2020 Nov 13.

Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Objectives: The purpose of this study was to evaluate the impact of recombinant human growth hormone (rhGH) on the development and progression of scoliosis in patients with idiopathic short stature (ISS).

Methods: Patients with ISS who underwent rhGH treatment from 1997 to 2017 and were followed up for scoliosis screening with serial radiographic examination were included. For assessing scoliosis development, patients who did not have scoliosis at the time of rhGH treatment were included and followed up to determine whether scoliosis developed during the treatment. For evaluating scoliosis progression, patients who already had scoliosis were analyzed. Univariate and multivariate Cox regression analyses of demographic and radiographic variables were performed to determine the related factors in the development and progression of scoliosis.

Results: For assessing scoliosis development, 1093 patients were included. The average duration of rhGH treatment was about 2 years. De novo scoliosis developed in 32 patients (3.7%). The analysis revealed that sex (p=0.016) and chronological age (p=0.048) were statistically significant factors associated with scoliosis development. However, no relationship was observed between scoliosis development and rhGH treatment types or duration. Among 67 patients who already had scoliosis at the time of rhGH treatment, 11 (16.4%) showed scoliosis progression. However, the rhGH types and duration also did not affect scoliosis progression.

Conclusions: De novo scoliosis developed in 3.7% and scoliosis progressed in 16.4% of the patients during rhGH treatment. However, scoliosis development or progression was not affected by the types or duration of rhGH treatment in patients with ISS.
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http://dx.doi.org/10.1515/jpem-2020-0393DOI Listing
February 2021

Effect of PTH and corticotomy on implant movement under mechanical force.

BMC Oral Health 2020 11 10;20(1):315. Epub 2020 Nov 10.

Department of Orthodontics, School of Medicine, Ewha Womans University, Anyangcheon-ro 1071, Yangcheon-gu, Seoul, 158-710, South Korea.

Background: Osseointegrated implants are considered as clinically non-movable. Parathyroid hormone (PTH) is known to play a significant role in the regulation of bone remodeling and in intermittent, low doses, result in osteoanabolic effects. This study aimed to investigate the effects of PTH and corticotomy, both under traction force, on osseointegrated implants.

Methods: Four implants-two in each hemimandible-were placed in each of the three study mongrels. Each mongrels were designated as control, normal dose PTH (PTH-1), and high dose PTH (PTH-2) groups, with each groups further subdivided into non-surgery implant and surgery implant. After osseointegration, mechanical force with NiTi closed coil springs (500 g) was applied around each implants. Corticotomy was performed around one of four implants in each mongrels. Parathyroid hormone was administered locally on a weekly basis for 20 weeks. Clinical movement of the implants were evaluated with the superimposed 3D- scanned data, bone- microarchitectural and histologic examinations.

Results: Superimposition analysis showed continuous movement of the non-surgery implant of PTH-1 group. Movement was further justified with lowest bone implant contact (adjusted BIC; 44.77%) in histomorphometric analysis. Upregulation of bone remodeling around the implant was observed in the normal dose PTH group. In the surgery implants, the remarkably higher adjusted BIC compared to the non-surgery implants indicated increased bone formation around the implant surface.

Conclusion: The results indicate that the catabolic and anabolic balance of osseointegrated implants in terms of bone remodeling can be shifted via various interventions including pharmacological, surgical and mechanical force.

Clinical Relevance: Upregulated bone remodeling by PTH and corticotomy under continuous mechanical force showed the possible implications for the movement of osseointegrated dental implant.
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http://dx.doi.org/10.1186/s12903-020-01310-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653691PMC
November 2020

Long-term porcine islet graft survival in diabetic non-human primates treated with clinically available immunosuppressants.

Xenotransplantation 2021 Mar 6;28(2):e12659. Epub 2020 Nov 6.

Xenotransplantation Research Center, College of Medicine, Seoul National University, Seoul, Korea.

Background: Although pancreatic islet transplantation is becoming an effective therapeutic option for patients with type 1 diabetes (T1D) who suffer from a substantially impaired awareness of hypoglycemia, its application is limited due to the lack of donors. Thus, pig-to-human islet xenotransplantation has been regarded as a promising alternative due to the unlimited number of "donor organs." Long-term xenogeneic islet graft survival in pig-to-non-human primate (NHP) models has mainly been achieved by administering the anti-CD154 mAb-based immunosuppressant regimen. Since the anti-CD154 mAb treatment has been associated with unexpected fatal thromboembolic complications in clinical trials, the establishment of a new immunosuppressant regimen that is able to be directly applied in clinical trials is an urgent need.

Methods: We assessed an immunosuppressant regimen composed of clinically available agents at porcine islet transplantation in consecutive diabetic NHPs.

Results: Porcine islet graft survival in consecutive diabetic NHPs (n = 7; >222, >200, 181, 89, 62, 55, and 34 days) without severe adverse events.

Conclusion: We believe that our study could contribute greatly to the initiation of islet xenotransplantation clinical trials.
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http://dx.doi.org/10.1111/xen.12659DOI Listing
March 2021

Effects of a Smartphone-Based Wearable Telerehabilitation System for In-Home Dynamic Weight-Shifting Balance Exercises by Individuals with Parkinson's Disease.

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:5678-5681

This paper describes the effects of a smartphone-based wearable telerehabilitation system (called Smarter Balance System, SBS) intended for in-home dynamic weight-shifting balance exercises (WSBEs) by individuals with Parkinson's disease (PD). Two individuals with idiopathic PD performed in-home dynamic WSBEs in anterior-posterior (A/P) and medial-lateral (M/L) directions, using the SBS 3 days per week for 6 weeks. Exercise performance was quantified by cross-correlation (XCORR) and position error (PE) analyses. Balance and gait performance and level of fear of falling were assessed by limit of stability (LOS), Sensory Organization Test (SOT), Falls Efficacy Scale (FES), Activities-specific Balance Confidence (ABC), and Dynamic Gait Index (DGI) at the pre-(beginning of week 1), post-(end of week 6), and retention-(1 month after week 6) assessments. Regression analyses found that exponential trends of the XCORR and PE described exercise performance more effectively than linear trends. Range of LOS in both A/P and M/L directions improved at the post-assessment compared to the pre-assessment, and was retained at the retention assessment. The preliminary findings emphasize the advantages of wearable balance telerehabilitation technologies when performing in-home balance rehabilitation exercises.
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http://dx.doi.org/10.1109/EMBC44109.2020.9175967DOI Listing
July 2020

Human Cytomegalovirus-Induced Interleukin-10 Production Promotes the Proliferation of in Macrophages.

Front Immunol 2020 10;11:518605. Epub 2020 Sep 10.

Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, South Korea.

Human cytomegalovirus (HCMV) exploits the interleukin-10 (IL-10) pathway as a part of its infection cycle through the manipulation of the host IL-10 signaling cascade. Based on its immunomodulatory nature, HCMV attenuates the host immune response and facilitates the progression of co-infection with other pathogens in an immune-competent host. To investigate the impact of HCMV infection on the burden of non-tuberculous mycobacteria (NTM), whose prevalence is growing rapidly worldwide, macrophages were infected with HCMV and further challenged with . The results showed that HCMV infection significantly increased host IL-10 synthesis and promoted the proliferation of in an IL-10-dependent manner. Transcriptomic analysis revealed that HCMV infection dampened the regulatory pathways of interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin-1 (IL-1), consequently abrogating the immune responses to coinfection in macrophages. These findings provide a mechanistic basis of how HCMV infection may facilitate the development of pathogenic NTM co-infection by upregulating IL-10 expression.
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http://dx.doi.org/10.3389/fimmu.2020.518605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511582PMC
April 2021

Cyclodextrin-Based Synthesis and Host-Guest Chemistry of Plasmonic Nanogap Particles with Strong, Quantitative, and Highly Multiplexable Surface-Enhanced Raman Scattering Signals.

J Phys Chem Lett 2020 Oct 21;11(19):8358-8364. Epub 2020 Sep 21.

Department of Chemistry, Seoul National University, Seoul 08826, South Korea.

We developed a synthetic strategy to form cyclodextrin-based intrananogap particles (CIPs) with a well-defined ∼1 nm interior gap in a high yield (∼97%), and were able to incorporate 10 different Raman dyes inside the gap using the cyclodextrin-based host-guest chemistry, leading to strong, reproducible, and highly multiplexable surface-enhanced Raman scattering (SERS) signals. The average SERS enhancement factor (EF) for CIPs was 3.0 × 10 with a very narrow distribution of the EFs that range from 9.5 × 10 to 9.5 × 10 for ∼95% of the measured particles. Remarkably, 10 different Raman dyes can be loaded within the nanogap of CIPs, and 6 different Raman dye-loaded CIPs with little spectral overlaps were distinctly detected for cancer cell imaging applications with a single excitation source. Our synthetic strategy provides new platforms in precisely forming plasmonic nanogap structures with all key features for widespread use of SERS including strong signal intensity, reliability in quantification of signal and multiplexing capability.
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http://dx.doi.org/10.1021/acs.jpclett.0c02624DOI Listing
October 2020

The Effects of Mobile Texting and Walking Speed on Gait Characteristics of Normal Weight and Obese Adults.

Motor Control 2020 Sep 10;24(4):588-604. Epub 2020 Sep 10.

Texas A&M University-San Antonio.

The aim of this study was to examine how usage of mobile devices while simultaneously walking affects walking characteristics and texting performance of normal weight (NW) and obese (OB) individuals. Thirty-two OB (body mass index [BMI] = 34.4) and NW (BMI = 22.7) adults performed two 60-s walking trials at three-step frequencies along a rectangular walkway in two conditions (No Texting and Texting). Dual-task cost as well as unadjusted spatial and temporal gait characteristics were measured. Dual-task costs for the gait parameters as well as texting performance were not different between the groups, except for the lateral step variability showing a larger variability at the preferred frequency in OB individuals. For the unadjusted variables, OB exhibited longer double support, longer stance time, and lower turn velocity compared with NW. Overall, the results highlight a similar dual-task cost for the OB individuals compared with the NW individuals, in spite of underlying differences in gait mechanics.
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http://dx.doi.org/10.1123/mc.2020-0006DOI Listing
September 2020

Adjuvanticity of Processed gel for Influenza Vaccination in Mice.

Immune Netw 2020 Aug 9;20(4):e31. Epub 2020 Jul 9.

Department of Pharmacy, Korea University College of Pharmacy, Sejong 30019, Korea.

The effectiveness of current influenza vaccines is considered suboptimal, and 1 way to improve the vaccines is using adjuvants. However, the current pool of adjuvants used in influenza vaccination is limited due to safety concerns. , or aloe, has been shown to have immunomodulatory functions and to be safe for oral intake. In this study, we explored the potential of orally administered processed gel (PAG) as an adjuvant for influenza vaccines in C57BL/6 mice. We first evaluated its adjuvanticity with a split-type pandemic H1N1 (pH1N1) Ag by subjecting the mice to lethal homologous influenza challenge. Oral PAG administration with the pH1N1 Ag increased survival rates in mice to levels similar to those of alum and MF59, which are currently used as adjuvants in influenza vaccine formulations. Similarly, oral PAG administration improved the survival of mice immunized with a commercial trivalent influenza vaccine against lethal homologous and heterologous virus challenge. PAG also increased hemagglutination inhibition and virus neutralization Ab titers against homologous and heterologous influenza strains following immunization with the split-type pH1N1 Ag or the commercial trivalent vaccine. Therefore, this study demonstrates that PAG may potentially be used as an adjuvant for influenza vaccines.
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http://dx.doi.org/10.4110/in.2020.20.e31DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458799PMC
August 2020

Oncology Therapeutics Targeting the Metabolism of Amino Acids.

Cells 2020 08 15;9(8). Epub 2020 Aug 15.

Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, IL 60607, USA.

Amino acid metabolism promotes cancer cell proliferation and survival by supporting building block synthesis, producing reducing agents to mitigate oxidative stress, and generating immunosuppressive metabolites for immune evasion. Malignant cells rewire amino acid metabolism to maximize their access to nutrients. Amino acid transporter expression is upregulated to acquire amino acids from the extracellular environment. Under nutrient depleted conditions, macropinocytosis can be activated where proteins from the extracellular environment are engulfed and degraded into the constituent amino acids. The demand for non-essential amino acids (NEAAs) can be met through de novo synthesis pathways. Cancer cells can alter various signaling pathways to boost amino acid usage for the generation of nucleotides, reactive oxygen species (ROS) scavenging molecules, and oncometabolites. The importance of amino acid metabolism in cancer proliferation makes it a potential target for therapeutic intervention, including via small molecules and antibodies. In this review, we will delineate the targets related to amino acid metabolism and promising therapeutic approaches.
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http://dx.doi.org/10.3390/cells9081904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463463PMC
August 2020