Publications by authors named "Yi Sa"

52 Publications

Bioengineering Approaches for the Advanced Organoid Research.

Adv Mater 2021 Sep 24:e2007949. Epub 2021 Sep 24.

Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 123 Bevier Road, Piscataway, NJ, 08854, USA.

Recent advances in 3D cell culture technology have enabled scientists to generate stem cell derived organoids that recapitulate the structural and functional characteristics of native organs. Current organoid technologies have been striding toward identifying the essential factors for controlling the processes involved in organoid development, including physical cues and biochemical signaling. There is a growing demand for engineering dynamic niches characterized by conditions that resemble in vivo organogenesis to generate reproducible and reliable organoids for various applications. Innovative biomaterial-based and advanced engineering-based approaches have been incorporated into conventional organoid culture methods to facilitate the development of organoid research. The recent advances in organoid engineering, including extracellular matrices and genetic modulation, are comprehensively summarized to pinpoint the parameters critical for organ-specific patterning. Moreover, perspective trends in developing tunable organoids in response to exogenous and endogenous cues are discussed for next-generation developmental studies, disease modeling, and therapeutics.
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http://dx.doi.org/10.1002/adma.202007949DOI Listing
September 2021

Human WRN is an intrinsic inhibitor of progerin, abnormal splicing product of lamin A.

Sci Rep 2021 04 27;11(1):9122. Epub 2021 Apr 27.

Department of Molecular Biology, Pusan National University, Busan, Republic of Korea.

Werner syndrome (WRN) is a rare progressive genetic disorder, caused by functional defects in WRN protein and RecQ4L DNA helicase. Acceleration of the aging process is initiated at puberty and the expected life span is approximately the late 50 s. However, a Wrn-deficient mouse model does not show premature aging phenotypes or a short life span, implying that aging processes differ greatly between humans and mice. Gene expression analysis of WRN cells reveals very similar results to gene expression analysis of Hutchinson Gilford progeria syndrome (HGPS) cells, suggesting that these human progeroid syndromes share a common pathological mechanism. Here we show that WRN cells also express progerin, an abnormal variant of the lamin A protein. In addition, we reveal that duplicated sequences of human WRN (hWRN) from exon 9 to exon 10, which differ from the sequence of mouse WRN (mWRN), are a natural inhibitor of progerin. Overexpression of hWRN reduced progerin expression and aging features in HGPS cells. Furthermore, the elimination of progerin by siRNA or a progerin-inhibitor (SLC-D011 also called progerinin) can ameliorate senescence phenotypes in WRN fibroblasts and cardiomyocytes, derived from WRN-iPSCs. These results suggest that progerin, which easily accumulates under WRN-deficient conditions, can lead to premature aging in WRN and that this effect can be prevented by SLC-D011.
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http://dx.doi.org/10.1038/s41598-021-88325-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079706PMC
April 2021

Anti-Adipogenic Polyacetylene Glycosides from the Florets of Safflower ().

Biomedicines 2021 Jan 19;9(1). Epub 2021 Jan 19.

School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.

Safflower () is an annual herb belonging to the Compositae family; it has a history of use as a food colorant, dye, and medicine in oriental countries. LC-MS-UV-based chemical analysis of extract of the florets of led to the isolation of two new C-polyacetylene glycosides, (8)-decaene-4,6-diyne-1,10-diol-1---d-glucopyranoside () and (8)-deca-4,6-diyne-1,8-diol-1---d-glucopyranoside (), together with five known analogs (-). The structures of the new compounds were determined by using 1D and 2D NMR spectroscopic data and HR-MS data, as well as chemical transformations. Of compounds -, compounds , , and inhibited the adipogenesis of 3T3-L1 preadipocytes, whereas compounds and promoted adipogenesis. Compounds , , and also prevented lipid accumulation through the suppression of the expression of lipogenic genes and the increase of the expression of lipolytic genes. Moreover, compounds and activated AMPK, which is known to facilitate lipid metabolism. Our findings provide a mechanistic rationale for the use of safflower-derived polyacetylene glycosides as potential therapeutic agents against obesity.
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http://dx.doi.org/10.3390/biomedicines9010091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833391PMC
January 2021

Morolic Acid 3--Caffeate Inhibits Adipogenesis by Regulating Epigenetic Gene Expression.

Molecules 2020 Dec 13;25(24). Epub 2020 Dec 13.

School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.

Obesity causes a wide range of metabolic diseases including diabetes, cardiovascular disease, and kidney disease. Thus, plenty of studies have attempted to discover naturally derived compounds displaying anti-obesity effects. In this study, we evaluated the inhibitory effects of morolic acid 3--caffeate (MAOC), extracted from , on adipogenesis. Treatment of 3T3-L1 cells with MAOC during adipogenesis significantly reduced lipid accumulation and decreased the expression of adiponectin, a marker of mature adipocytes. Moreover, the treatment with MAOC only during the early phase (day 0-2) sufficiently inhibited adipogenesis, comparable with the inhibitory effects observed following MAOC treatment during the whole processes of adipogenesis. In the early phase of adipogenesis, the expression level of which inhibits adipogenesis, increased by MAOC treatment in 3T3-L1 cells. To identify the gene regulatory mechanism, we assessed alterations in histone modifications upon MAOC treatment. Both global and local levels on the promoter region of histone H3 lysine 4 trimethylation, an active transcriptional histone marker, increased markedly by MAOC treatment in 3T3-L1 cells. Our findings identified an epigenetic event associated with inhibition of adipocyte generation by MAOC, suggesting its potential as an efficient therapeutic compound to cure obesity and metabolic diseases.
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http://dx.doi.org/10.3390/molecules25245910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764869PMC
December 2020

Preparations for a European R&D roadmap for an inertial fusion demo reactor.

Philos Trans A Math Phys Eng Sci 2021 Jan 7;379(2189):20200005. Epub 2020 Dec 7.

Los Alamos National Laboratory, Los Alamos, NM, USA.

A European consortium of 15 laboratories across nine nations have worked together under the EUROFusion Enabling Research grants for the past decade with three principle objectives. These are: (a) investigating obstacles to ignition on megaJoule-class laser facilities; (b) investigating novel alternative approaches to ignition, including basic studies for fast ignition (both electron and ion-driven), auxiliary heating, shock ignition, etc.; and (c) developing technologies that will be required in the future for a fusion reactor. A brief overview of these activities, presented here, along with new calculations relates the concept of auxiliary heating of inertial fusion targets, and provides possible future directions of research and development for the updated European Roadmap that is due at the end of 2020. This article is part of a discussion meeting issue 'Prospects for high gain inertial fusion energy (part 2)'.
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http://dx.doi.org/10.1098/rsta.2020.0005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7741006PMC
January 2021

Rosmarinic Acid Methyl Ester Regulates Ovarian Cancer Cell Migration and Reverses Cisplatin Resistance by Inhibiting the Expression of Forkhead Box M1.

Pharmaceuticals (Basel) 2020 Oct 12;13(10). Epub 2020 Oct 12.

School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.

Rosmarinic acid methyl ester (RAME), a derivative of rosmarinic acid (RA), is reported to have several therapeutic effects, including anti-tumor effects against cervical cancer. However, its anti-tumor effects in ovarian cancer is unclear. In this study, we studied the molecular pathways associated with the anti-tumor effects of RAME in ovarian cancer. To identify the effects of RAME in ovarian cancer, RNA sequencing was performed in RAME-treated ovarian cancer cells; we found that RAME treatment downregulated the genes closely involved with the target genes of the transcription factor Forkhead box M1 (FOXM1). It was reported that FOXM1 is overexpressed in a variety of cancer cells and is associated with cell proliferation and tumorigenesis. Therefore, we hypothesized that FOXM1 is a key target of RAME; this could result in its anti-tumor effects. Treatment of ovarian cancer cells with RAME-inhibited cell migration and invasion, as shown by wound healing and transwell migration assays. To examine whether RAME represses the action of FOXM1, we performed quantitative RT-PCR and ChIP-qPCR. Treatment of ovarian cancer cells with RAME decreased the mRNA expression of FOXM1 target genes and the binding of FOXM1 to its target genes. Moreover, FOXM1 expression was increased in cisplatin-resistant ovarian cancer cells, and combination treatment with RAME and cisplatin sensitized the cisplatin-resistant ovarian cancer cells, which was likely due to FOXM1 inhibition. Our research suggests that RAME is a promising option in treating ovarian cancer patients, as it revealed a novel molecular pathway underlying its anti-tumor effects.
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http://dx.doi.org/10.3390/ph13100302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601071PMC
October 2020

Infection of Brain Organoids and 2D Cortical Neurons with SARS-CoV-2 Pseudovirus.

Viruses 2020 09 8;12(9). Epub 2020 Sep 8.

Epigenome Dynamics Control Research Center, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.

Since the global outbreak of SARS-CoV-2 (COVID-19), infections of diverse human organs along with multiple symptoms continue to be reported. However, the susceptibility of the brain to SARS-CoV-2, and the mechanisms underlying neurological infection are still elusive. Here, we utilized human embryonic stem cell-derived brain organoids and monolayer cortical neurons to investigate infection of brain with pseudotyped SARS-CoV-2 viral particles. Spike-containing SARS-CoV-2 pseudovirus infected neural layers within brain organoids. The expression of ACE2, a host cell receptor for SARS-CoV-2, was sustained during the development of brain organoids, especially in the somas of mature neurons, while remaining rare in neural stem cells. However, pseudotyped SARS-CoV-2 was observed in the axon of neurons, which lack ACE2. Neural infectivity of SARS-CoV-2 pseudovirus did not increase in proportion to viral load, but only 10% of neurons were infected. Our findings demonstrate that brain organoids provide a useful model for investigating SARS-CoV-2 entry into the human brain and elucidating the susceptibility of the brain to SARS-CoV-2.
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http://dx.doi.org/10.3390/v12091004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551632PMC
September 2020

HP1γ Sensitizes Cervical Cancer Cells to Cisplatin through the Suppression of UBE2L3.

Int J Mol Sci 2020 Aug 19;21(17). Epub 2020 Aug 19.

College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, Korea.

Cisplatin is the most frequently used agent for chemotherapy against cervical cancer. However, recurrent use of cisplatin induces resistance, representing a major hurdle in the treatment of cervical cancer. Our previous study revealed that HP1γ suppresses UBE2L3, an E2 ubiquitin conjugating enzyme, thereby enhancing the stability of tumor suppressor p53 specifically in cervical cancer cells. As a follow-up study of our previous findings, here we have identified that the pharmacological substances, leptomycin B and doxorubicin, can improve the sensitivity of cervical cancer cells to cisplatin inducing HP1γ-mediated elevation of p53. Leptomycin B, which inhibits the nuclear export of HP1γ, increased cisplatin-dependent apoptosis induction by promoting the activation of p53 signaling. We also found that doxorubicin, which induces the DNA damage response, promotes HP1γ-mediated silencing of UBE2L3 and increases p53 stability. These effects resulted from the nuclear translocation and binding of HP1γ on the UBE2L3 promoter. Doxorubicin sensitized the cisplatin-resistant cervical cancer cells, enhancing their p53 levels and rate of apoptosis when administered together with cisplatin. Our findings reveal a therapeutic strategy to target a specific molecular pathway that contributes to p53 degradation for the treatment of patients with cervical cancer, particularly with cisplatin resistance.
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http://dx.doi.org/10.3390/ijms21175976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503686PMC
August 2020

In vitro modeling for inherited neurological diseases using induced pluripotent stem cells: from 2D to organoid.

Arch Pharm Res 2020 Sep 5;43(9):877-889. Epub 2020 Aug 5.

School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.

Stem cells are characterized by self-renewal and by their ability to differentiate into cells of various organs. With massive progress in 2D and 3D cell culture techniques, in vitro generation of various types of such organoids from patient-derived stem cells is now possible. As in vitro differentiation protocols are usually made to resemble human developmental processes, organogenesis of patient-derived stem cells can provide key information regarding a range of developmental diseases. Human stem cell-based in vitro modeling as opposed to using animal models can particularly benefit the evaluation of neurological diseases because of significant differences in structure and developmental processes between the human and the animal brain. This review focuses on stem cell-based in vitro modeling of neurodevelopmental disorders, more specifically, the fundamentals and technical advancements in monolayer neuron and brain organoid cultures. Furthermore, we discuss the drawbacks of the conventional culture method and explore the advanced, cutting edge 3D organoid models for several neurodevelopmental diseases, including genetic diseases such as Down syndrome, Rett syndrome, and Miller-Dieker syndrome, as well as brain malformations like macrocephaly and microcephaly. Finally, we discuss the limitations of the current organoid techniques and some potential solutions that pave the way for accurate modeling of neurological disorders in a dish.
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http://dx.doi.org/10.1007/s12272-020-01260-zDOI Listing
September 2020

Discovery of Dihydrophaseic Acid Glucosides from the Florets of .

Plants (Basel) 2020 Jul 7;9(7). Epub 2020 Jul 7.

School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.

L. (Compositae; safflower or Hong Hua) has been used in Korean traditional medicine for maintaining the homeostasis of body circulation. Phytochemical investigation was performed on the florets of by liquid chromatography-mass spectrometry (LC/MS), which afforded two dihydrophaseic acid glucosides ( and ). Isolated compounds were structurally confirmed using a combination of spectroscopic methods including 1D and 2D nuclear magnetic resonance and high-resolution electrospray ionization mass spectroscopy. Their absolute configurations were established by quantum chemical electronic circular dichroism calculations and enzymatic hydrolysis. The anti-adipogenesis activity of the isolated compounds was evaluated using 3T3-L1 preadipocytes. Treatment with the dihydrophaseic acid glucoside () during adipocyte differentiation prevented the accumulation of lipid droplets and reduced the expression of adipogenic genes, and . However, compound did not affect adipogenesis. Our study yielded a dihydrophaseic acid glucoside derived from which has potential advantages for treating obesity.
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http://dx.doi.org/10.3390/plants9070858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412175PMC
July 2020

Localized mix-induced radiative cooling in a capsule implosion at the National Ignition Facility.

Phys Rev E 2020 Mar;101(3-1):033205

Lawrence Livermore National Laboratory, Livermore, California 94551, USA.

We present direct measurements of electron temperature variations within an inertially confined deuterium-tritium plasma caused by localized mix of higher-Z materials into the central hot spot. The data are derived from newly developed differentially filtered penumbral imaging of the bremsstrahlung continuum emission. Our analysis reveals distinct localized emitting features in the stagnated hot-spot plasma, and we infer spatial variations in the electron temperature: the mixed region is 660±130eV colder than the surrounding hot-spot plasma at 3.26±0.11keV. Our analysis of the energy flow shows that we measure approximately steady-state conditions where the radiative losses in the mix region are balanced by heat conduction from the surrounding hot deuterium-tritium plasma.
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http://dx.doi.org/10.1103/PhysRevE.101.033205DOI Listing
March 2020

HPV-mediated nuclear export of HP1γ drives cervical tumorigenesis by downregulation of p53.

Cell Death Differ 2020 09 23;27(9):2537-2551. Epub 2020 Mar 23.

College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, 21983, Republic of Korea.

E6 oncoprotein derived from high-risk human papillomavirus (HPV) drives the development of cervical cancer through p53 degradation. Because cervical cancer therapies to inactivate HPV or E6 protein are not available, alternative strategies are required. Here, we show that HPV-mediated nuclear export of human heterochromatin protein 1γ (HP1γ) reduces the stability of p53 through UBE2L3-mediated p53 polyubiquitination during cervical cancer progression. In general, HP1 plays a key role in heterochromatin formation and transcription in the nucleus. However, our immunostaining data showed that the majority of HP1γ is localized in the cytoplasm in HPV-mediated cervical cancer. We found that HPV E6 protein drives unusual nuclear export of HP1γ through the interaction between the NES sequence of HP1γ and exportin-1. The mutation of the NES sequence in HP1γ led to nuclear retention of HP1γ and reduced cervical cancer cell growth and tumor generation. We further discovered that HP1γ directly suppresses the expression of UBE2L3 which drives E6-mediated proteasomal degradation of p53 in cervical cancer. Downregulation of UBE2L3 by overexpression of HP1γ suppressed UBE2L3-dependent p53 degradation-promoting apoptosis of cervical cancer cells. Our findings propose a useful strategy to overcome p53 degradation in cervical cancer through the blockage of nuclear export of HP1γ.
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http://dx.doi.org/10.1038/s41418-020-0520-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429875PMC
September 2020

Fermented ginseng extract, BST204, disturbs adipogenesis of mesenchymal stem cells through inhibition of S6 kinase 1 signaling.

J Ginseng Res 2020 Jan 8;44(1):58-66. Epub 2018 Aug 8.

School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.

Background: The biological and pharmacological effects of BST204, a fermented ginseng extract, have been reported in various disease conditions. However, its molecular action in metabolic disease remains poorly understood. In this study, we identified the antiadipogenic activity of BST204 resulting from its inhibition of the S6 kinase 1 (S6K1) signaling pathway.

Methods: The inhibitory effects of BST204 on S6K1 signaling were investigated by immunoblot, nuclear fractionation, immunoprecipitation analyses. The antiadipogenic effect of BST204 was evaluated by measuring mRNA levels of adipogenic genes and by chromatin immunoprecipitation and quantitative real-time polymerase chain reaction analysis.

Results: Treatment with BST204 inhibited activation and nuclear translocation of S6K1, further decreasing the interaction between S6K1 and histone H2B in 10T1/2 mesenchymal stem cells. Subsequently, phosphorylation of H2B at serine 36 (H2BS36p) by S6K1 was reduced by BST204, inducing an increase in the mRNA expression of , , and , which disturbed adipogenic differentiation and promoted myogenic and early osteogenic gene expression. Consistently, BST204 treatment during adipogenic commitment suppressed the expression of adipogenic marker genes and lipid drop formation.

Conclusion: Our results indicate that BST204 blocks adipogenesis of mesenchymal stem cells through the inhibition of S6K1-mediated histone phosphorylation. This study suggests the potential therapeutic strategy using BST204 to combat obesity and musculoskeletal diseases.
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http://dx.doi.org/10.1016/j.jgr.2018.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033330PMC
January 2020

Ginsenoside Rg3 Induces Browning of 3T3-L1 Adipocytes by Activating AMPK Signaling.

Nutrients 2020 Feb 7;12(2). Epub 2020 Feb 7.

School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.

Ginsenoside Rg3, one of the major components in , has been reported to possess several therapeutic effects including anti-obesity properties. However, its effect on the browning of mature white adipocytes as well as the underlying mechanism remains poorly understood. In this study, we suggested a novel role of Rg3 in the browning of mature 3T3-L1 adipocytes by upregulating browning-related gene expression. The browning effects of Rg3 on differentiated 3T3-L1 adipocytes were evaluated by analyzing browning-related markers using quantitative PCR, immunoblotting, and immunostaining. In addition, the size and sum area of lipid droplets in differentiated 3T3-L1 adipocytes were measured using Oil-Red-O staining. In mature 3T3-L1 adipocytes, Rg3 dose-dependently induced the expression of browning-related genes such as Ucp1, Prdm16, Pgc1α, Cidea, and Dio2. Moreover, Rg3 induced the expression of beige fat-specific genes (CD137 and TMEM26) and lipid metabolism-associated genes (FASN, SREBP1, and MCAD), which indicated the activation of lipid metabolism by Rg3. We also demonstrated that activation of 5' adenosine monophosphate-activated protein kinase (AMPK) is required for Rg3-mediated up-regulation of browning gene expression. Moreover, Rg3 inhibited the accumulation of lipid droplets and reduced the droplet size in mature 3T3-L1 adipocytes. Taken together, this study identifies a novel role of Rg3 in browning of white adipocytes, as well as suggesting a potential mechanism of an anti-obesity effect of .
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http://dx.doi.org/10.3390/nu12020427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071202PMC
February 2020

(±)-Kituramides A and B, pairs of enantiomeric dopamine dimers from the two-spotted cricket Gryllus bimaculatus.

Bioorg Chem 2020 01 24;95:103554. Epub 2019 Dec 24.

School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea. Electronic address:

Two-spotted cricket Gryllus bimaculatus is one of many cricket species, and it is widely used as a food source for insectivorous animals. Moreover, this species is one of the edible insects approved by the Korea Food and Drug Administration (KFDA). (±)-Kituramides A (1) and B (2), which are pairs of novel enantiomeric dopamine dimers possessing a formamide group, were isolated from the two-spotted cricket, together with four other known biosynthetically related compounds (3-6). The chemical structures of 1 and 2 were elucidated using a combination of 1D and 2D NMR spectroscopic experiments and HR-ESIMS data. Compounds 1 and 2 were identified as racemic mixtures; the enantiomers (+)-1/2 and (-)-1/2 were successfully separated by utilizing a chiral HPLC column. The absolute configurations of (±)-1 and (±)-2 were unambiguously delineated by the application of quantum chemical ECD calculations. Further, these insect-derived substances were evaluated to understand their effects on cytokine expression in adipocytes. Treatment with (-)-1, (+)-2, and (-)-2 during adipocyte differentiation significantly promoted the expression of Leptin and IL-6, which resembles the actions of dopamine.
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http://dx.doi.org/10.1016/j.bioorg.2019.103554DOI Listing
January 2020

Vulpinic Acid Controls Stem Cell Fate toward Osteogenesis and Adipogenesis.

Genes (Basel) 2019 12 23;11(1). Epub 2019 Dec 23.

School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.

Vulpinic acid, a naturally occurring methyl ester of pulvinic acid, has been reported to exert anti-fungal, anti-cancer, and anti-oxidative effects. However, its metabolic action has not been implicated yet. Here, we show that vulpinic acid derived from a mushroom, controls the cell fate of mesenchymal stem cells and preadipocytes by inducing the acetylation of histone H3 and α-tubulin, respectively. The treatment of 10T1/2 mesenchymal stem cells with vulpinic acid increased the expression of Wnt6, Wnt10a, and Wnt10b, which led to osteogenesis inhibiting the adipogenic lineage commitment, through the upregulation of H3 acetylation. By contrast, treatment with vulpinic acid promoted the terminal differentiation of 3T3-L1 preadipocytes into mature adipocytes. In this process, the increase in acetylated tubulin was accompanied, while acetylated H3 was not altered. As excessive generation of adipocytes occurs, the accumulation of lipid drops was not concentrated, but dispersed into a number of adipocytes. Consistently, the expressions of lipolytic genes were upregulated and inflammatory factors were downregulated in adipocytes exposed to vulpinic acid during adipogenesis. These findings reveal the multiple actions of vulpinic acid in two stages of differentiation, promoting the osteogenesis of mesenchymal stem cells and decreasing hypertrophic adipocytes, which can provide experimental evidence for the novel metabolic advantages of vulpinic acid.
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http://dx.doi.org/10.3390/genes11010018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017160PMC
December 2019

Anti-adipogenic Effect of β-Carboline Alkaloids from Garlic ().

Foods 2019 Dec 12;8(12). Epub 2019 Dec 12.

School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.

Garlic ( L.) is utilized worldwide for culinary and medicinal use and has diverse health benefits. As part of our ongoing research to identify bioactive components from natural resources, phytochemical analysis of the methanolic extract of garlic led to the isolation and characterization of six compounds: Three eugenol diglycosides (-) and three β-carboline alkaloids (-). In particular, the absolute configurations of β-carboline alkaloids ( and ) were established by gauge-including atomic orbital nuclear magnetic resonance chemical shift calculations, followed by DP4+ analysis. Here, we evaluated the effects of compounds - on 3T3-L1 preadipocyte adipogenesis and lipid metabolism. 3T3-L1 adipocyte differentiation was evaluated using Oil Red O staining; the expression of adipogenic genes was detected using RT-qPCR. Among compounds -, (13)-1-methyl-1,2,3,4-tetrahydro-carboline-3-carboxylic acid () inhibited 3T3-L1 preadipocyte adipogenesis and reduced the expression of adipogenic genes (, , , , and ). Moreover, it markedly decreased the actylation of α-tubulin, which is crucial for cytoskeletal remodeling during adipogenesis. Anti-adipogenic effects were observed upon treatment with compound not only during the entire process, but also on the first two days of adipogenesis. Additionally, treatment with compound regulated the expression of genes involved in adipocyte lipid metabolism, decreasing the lipogenic gene () and increasing lipolytic genes ( and ). We provide experimental evidence of the health benefits of using (13)-1-methyl-1,2,3,4-tetrahydro-carboline-3-carboxylic acid obtained from garlic to prevent excessive adipogenesis in obesity.
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http://dx.doi.org/10.3390/foods8120673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963209PMC
December 2019

Pantheric Acids A-C from a Poisonous Mushroom, , Promote Lipid Accumulation in Adipocytes.

J Nat Prod 2019 12 14;82(12):3489-3493. Epub 2019 Nov 14.

School of Pharmacy , Sungkyunkwan University , Suwon 16419 , Republic of Korea.

is a poisonous mushroom that causes muscle cramps, insanity, and audiovisual disorders. As part of our systematic study on Korean mushrooms, a chemical investigation of fruiting bodies resulted in the isolation and structural identification of three new fatty acid derivatives, pantheric acids A-C (-), and a known compound, 1,10-dimethyl ester-2-decenedioic acid (). Although 1,10-dimethyl ester-2-decenedioic acid () was previously reported as a synthetic product, it was structurally identified from a natural source for the first time. The structures of the new compounds were established by detailed analysis of 1D and 2D (H-H COSY, HSQC, and HMBC) NMR, HRMS, and LC/MS/MS data. The absolute configurations of compounds and were unambiguously determined by a recently developed method using competing enantioselective acylation coupled with LC/MS analysis. The isolated compounds (-) were evaluated for their effects on lipid accumulation during adipocyte maturation. Pantheric acids A-C (-) promoted the enlargement of lipid droplets in 3T3-L1 adipocytes and altered lipid metabolism by inducing lipogenesis and inhibiting lipolysis. Our findings provide experimental evidence suggesting the potential adverse effects of pantheric acids A-C from a poisonous mushroom on lipid metabolism.
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http://dx.doi.org/10.1021/acs.jnatprod.9b00782DOI Listing
December 2019

Identification of a novel S6K1 inhibitor, rosmarinic acid methyl ester, for treating cisplatin-resistant cervical cancer.

BMC Cancer 2019 Aug 6;19(1):773. Epub 2019 Aug 6.

School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.

Background: The mTOR/S6K1 signaling pathway is often activated in cervical cancer, and thus considered a molecular target for cervical cancer therapies. Inhibiting mTOR is cytotoxic to cervical cancer cells and creates a synergistic anti-tumor effect with conventional chemotherapy agents. In this study, we identified a novel S6K1 inhibitor, rosmarinic acid methyl ester (RAME) for the use of therapeutic agent against cervical cancer.

Methods: Combined structure- and ligand-based virtual screening was employed to identify novel S6K1 inhibitors among the in house natural product library. In vitro kinase assay and immunoblot assay was used to examine the effects of RAME on S6K1 signaling pathway. Lipidation of LC3 and mRNA levels of ATG genes were observed to investigate RAME-mediated autophagy. PARP cleavage, mRNA levels of apoptotic genes, and cell survival was measured to examine RAME-mediated apoptosis.

Results: RAME was identified as a novel S6K1 inhibitor through the virtual screening. RAME, not rosmarinic acid, effectively reduced mTOR-mediated S6K1 activation and the kinase activity of S6K1 by blocking the interaction between S6K1 and mTOR. Treatment of cervical cancer cells with RAME promoted autophagy and apoptosis, decreasing cell survival rate. Furthermore, we observed that combination treatment with RAME and cisplatin greatly enhanced the anti-tumor effect in cisplatin-resistant cervical cancer cells, which was likely due to mTOR/S6K1 inhibition-mediated autophagy and apoptosis.

Conclusions: Our findings suggest that inhibition of S6K1 by RAME can induce autophagy and apoptosis in cervical cancer cells, and provide a potential option for cervical cancer treatment, particularly when combined with cisplatin.
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http://dx.doi.org/10.1186/s12885-019-5997-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683399PMC
August 2019

[Current situation analysis and supervision suggestions of traditional Chinese medicine health food claiming to enhance immune function].

Zhongguo Zhong Yao Za Zhi 2019 Mar;44(5):885-890

School of Advanced Medical Science,Shandong University Jinan 250012,China The Second Hospital of Shandong University Jinan 250033,China.

Number of products claiming to enhance immunity function ranks first among all the approved health food products,and number of products whose formula contains Chinese medicine accounts for two thirds of all the products claiming to enhance immunity function. Chinese medicine allowed to be used in health food has a specified range,and the safety of raw materials is generally higher.The usage amount of raw materials shall not exceed the upper limit stipulated in the literature or regulations. The claim of enhancement of immunity function is put forward by western medicine based on modern pharmacology and nutriology. However,immunity is wide in scope and complex in mechanism. The health food that contains Chinese medicine plays an active effect in enhancement of immunity under the guidance of Chinese medicine theory in many ways such as immune organs,immune cells and immune molecules. In this article,the author first analyzed the current use of raw materials for health food,then summarized the approved health food claiming to enhance immunity function,and conducted statistical analysis on the enhancement of immunity for traditional Chinese medicine(TCM)health food,use of raw materials,compatibility of raw materials,conducted in-depth analysis on health food formula,safety,health function,quality control and production process from the perspectives of technical review,supervision and management. Finally,some suggestions on registration and supervision of TCM health food claiming to enhance immunity function were put forward from the perspectives of problems found in the supervision and from the demand of TCM health food in the future.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20190116.005DOI Listing
March 2019

[Some thoughts on health food formulated with traditional Chinese medicine].

Zhongguo Zhong Yao Za Zhi 2019 Mar;44(5):865-869

Institute of Chinese Materia Medica,China Academy of Chinese Medical Sciences Beijing 100700,China.

The health food industry is an important support for the big health industry and the strategy of healthy China. The Chinese medicine prescription health food has exceeded 60% of the total declared health food. However,the main basis for its function evaluation,the Technical Specification for Inspection and Evaluation of Health Food,was abolished in 2018,and 27 of them were based on modern medical and nutritional theories. Quantitative efficacy evaluation methods in western pharmacology are short of function claims and function evaluation methods reflecting the characteristics of traditional Chinese medicine,which could affect the health food industry to a certain extent. Therefore,the establishment of the evaluation mechanism of Chinese medicine prescription health food which conforms to the positioning of health food and the theory of traditional Chinese medicine is helpful for the healthy development of health food industry. In this paper,this problem was explained from five aspects. First,how to differentiate the positioning of Chinese medicine prescription health food from ordinary food and medicine,and how to embody the characteristics of Chinese medicine. Secondly,the relationship between traditional Chinese medicine prescription health food and Chinese patent medicine. Thirdly,how to scientifically and reasonably determine the raw materials of traditional Chinese medicine prescription health food. Fourthly,how to explain the function claim of traditional Chinese medicine prescription health food,and how to evaluate its function scientifically and reasonably. Fifthly,the functional evaluation of Chinese herbal medicine prescription health food is connected with other national scientific and technological strategies. In this paper,a preliminary analysis of the Chinese medicine prescription health food was conducted from the above five aspects,and some personal views and suggestions were put forward,hoping to provide reference for the competent authorities and researchers.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20190116.001DOI Listing
March 2019

Eudesmin impairs adipogenic differentiation via inhibition of S6K1 signaling pathway.

Biochem Biophys Res Commun 2018 11 11;505(4):1148-1153. Epub 2018 Oct 11.

School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea. Electronic address:

Eudesmin has been reported to possess diverse therapeutic effects, including anti-tumor, anti-inflammatory, and anti-bacterial activities. However, its molecular action has not been implicated in metabolic disease. In this study, we show that treatment of mesenchymal stem cells (MSCs) with eudesmin disturbs adipogenesis via suppression of S6K1 signaling pathway. Eudesmin treatment inhibited activation and nuclear translocation of S6K1. Consequently, S6K1-mediated phosphorylation of H2B at serine 36 (H2BS36p) was reduced upon eudesmin treatment, further inducing the expression of Wnt6, Wnt10a, and Wnt10b, which disturbed adipogenic differentiation. Moreover, eudesmin promoted myogenic and osteogenic gene expression in MSCs. Taken together, we found a novel small molecule, eudesmin, to block adipogenesis through down-regulation of S6K1-H2BS36p axis, followed by regulation of cell fate determination genes. This study suggests a promising therapeutic approach with eudesmin to cure obesity and metabolic diseases.
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http://dx.doi.org/10.1016/j.bbrc.2018.09.188DOI Listing
November 2018

Effects of asymmetry and hot-spot shape on ignition capsules.

Phys Rev E 2018 Aug;98(2-1):023203

Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA.

Asymmetric implosion of inertial confinement fusion capsules is known, both experimentally and computationally, to reduce thermonuclear performance. This work shows that low-mode asymmetries degrade performance as a result of a decrease in the hydrodynamic disassembly time of the hot-spot core, which scales with the minimum dimension of the hot spot. The asymmetric shape of a hot spot results in decreased temperatures and areal densities and allows more alpha particles to escape, relative to an ideal spherical implosion, thus reducing alpha-energy deposition in the hot spot. Here, we extend previous ignition theory to include the hot-spot shape and quantify the effects of implosion asymmetry on both the ignition criterion and the capsule performance. The ignition criterion becomes more stringent with increasing deformation of the hot spot. The new theoretical results are validated by comparison with existing experimental data obtained at the National Ignition Facility. The shape effects on thermonuclear performance are relatively more noticeable for capsules having self-heating and high yields. The degradation of thermonuclear burn can be as high as 45% for shots with a yield lower than 2×10^{15} and less than 30% for shots with a higher yield.
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http://dx.doi.org/10.1103/PhysRevE.98.023203DOI Listing
August 2018

Reversine promotes browning of white adipocytes by suppressing miR-133a.

J Cell Physiol 2019 04 21;234(4):3800-3813. Epub 2018 Aug 21.

Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University, Suwon, Korea.

Brown adipocytes are characterized by a high number of uncoupling protein 1 (UCP1)-positive mitochondrial content and increased thermogenic capacity. As UCP1-enriched cells can consume lipids by generating heat, browning of white adipocytes is now highlighted as a promising approach for the prevention of obesity and obesity-associated metabolic diseases. Upon cold exposure or β-adrenergic stimuli, downregulation of microRNA-133 (miR-133) elevates the expression levels of PR domain containing 16 (Prdm16), which has been shown to be a brown adipose determination factor, in brown adipose tissue and subcutaneous white adipose tissues (WAT). Here, we show that treatment of reversine to white adipocytes induces browning via suppression of miR-133a. Reversine treatment promoted the expression of brown adipocyte marker genes, such as Prdm16 and UCP1, increasing the mitochondrial content, while decreasing the levels of miR-133a and white adipocyte marker genes. Ectopic expression of miR-133a mimic reversed the browning effects of the reversine treatment. Moreover, intraperitoneal administration of reversine in mice upregulated thermogenesis and resulted in resistance to high-fat diet-mediated weight gain as well as browning of subcutaneous and epididymal WAT. Taken together, we found a novel way to promote browning of white adipocytes through downregulation of miR-133a followed by activation of Prdm16, with a synthetic chemical, reversine.
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http://dx.doi.org/10.1002/jcp.27148DOI Listing
April 2019

S6K1 controls epigenetic plasticity for the expression of pancreatic α/β cell marker genes.

J Cell Biochem 2018 08 17;119(8):6674-6683. Epub 2018 Apr 17.

School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.

The failure of insulin production by pancreatic β cells is a common hallmark of type 1 diabetes mellitus (T1DM). Because administration of exogenous insulin is associated with diabetes-derived complications, endogenous α to β cell transition can be an attractive alternative. Although decreased β cell size and hypoinsulinaemia have been observed in S6K1-deficient mice, the molecular mechanism underlying the involvement of S6K1 in the transcriptional regulation of insulin remains elusive. Here, we show that the hypoinsulinaemic phenotype of S6K1-deficient mice stems from the dysregulated transcription of a set of genes required for insulin and glucagon production. First, we observed that increased expression of α cell marker genes and decreased expression of β cell marker genes in pancreas tissues from S6K1-deficient mice. Furthermore, S6K1 was highly activated in murine β cell line, βTC6, compared to murine α cell line αTC1. In both α and β cells, active S6K1 promoted the transcription of β cell marker genes, including insulin, whereas S6K1 inhibition increased the transcription of α cell marker genes. Moreover, S6K1 mediated pancreatic gene regulation by modifying two histone marks (activating H3K4me3 and repressing H3K27me3) on gene promoters. These results suggest that S6K1 drives the α to β transition through the epigenetic regulation of cell-specific genes, including insulin and glucagon. This novel role of S6K1 in islet cells provides basic clues to establish therapeutic strategies against T1DM.
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http://dx.doi.org/10.1002/jcb.26853DOI Listing
August 2018

First Liquid Layer Inertial Confinement Fusion Implosions at the National Ignition Facility.

Phys Rev Lett 2016 Dec 7;117(24):245001. Epub 2016 Dec 7.

Los Alamos National Laboratory (LANL), Los Alamos, New Mexico 87185, USA.

The first cryogenic deuterium and deuterium-tritium liquid layer implosions at the National Ignition Facility (NIF) demonstrate D_{2} and DT layer inertial confinement fusion (ICF) implosions that can access a low-to-moderate hot-spot convergence ratio (1230) DT ice layer implosions. Although high CR is desirable in an idealized 1D sense, it amplifies the deleterious effects of asymmetries. To date, these asymmetries prevented the achievement of ignition at the NIF and are the major cause of simulation-experiment disagreement. In the initial liquid layer experiments, high neutron yields were achieved with CRs of 12-17, and the hot-spot formation is well understood, demonstrated by a good agreement between the experimental data and the radiation hydrodynamic simulations. These initial experiments open a new NIF experimental capability that provides an opportunity to explore the relationship between hot-spot convergence ratio and the robustness of hot-spot formation during ICF implosions.
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http://dx.doi.org/10.1103/PhysRevLett.117.245001DOI Listing
December 2016

Glutamate dehydrogenase activator BCH stimulating reductive amination prevents high fat/high fructose diet-induced steatohepatitis and hyperglycemia in C57BL/6J mice.

Sci Rep 2016 11 22;5:37468. Epub 2016 Nov 22.

Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, 443-749, Republic of Korea.

Individuals with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) induced by high calorie western diet are characterized by enhanced lipogenesis and gluconeogenesis in the liver. Stimulation of reductive amination may shift tricarboxylic acid cycle metabolism for lipogenesis and gluconeogenesis toward glutamate synthesis with increase of NAD+/NADH ratio and thus, ameliorate high calorie diet-induced fatty liver and hyperglycemia. Stimulation of reductive amination through glutamate dehydrogenase (GDH) activator 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) reduced both de novo lipogenesis and gluconeogenesis but increased the activities of sirtuins and AMP-activated kinase in primary hepatocytes. Long-term BCH treatment improved most metabolic alterations induced by high fat/high fructose (HF/HFr) diet in C57BL/6J mice. BCH prevented HF/HFr-induced fat accumulation and activation of stress/inflammation signals such as phospho-JNK, phospho-PERK, phospho-p38, and phospho-NFκB in liver tissues. Furthermore, BCH treatment reduced the expression levels of inflammatory cytokines such as TNF-α and IL-1β in HF/HFr-fed mouse liver. BCH also reduced liver collagen and plasma levels of alanine transaminase and aspartate transaminase. On the other hand, BCH significantly improved fasting hyperglycemia and glucose tolerance in HF/HFr-fed mice. In conclusion, stimulation of reductive amination through GDH activation can be used as a strategy to prevent high calorie western diet-induced NAFLD and T2D.
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http://dx.doi.org/10.1038/srep37468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118703PMC
November 2016

Epigenetic role of nuclear S6K1 in early adipogenesis.

BMB Rep 2016 Aug;49(8):401-2

Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.

S6K1 is a key regulator of cell growth, cell size, and metabolism. Although the role of cytosolic S6K1 in cellular processes is well established, the function of S6K1 in the nucleus remains poorly understood. Our recent study has revealed that S6K1 is translocated into the nucleus upon adipogenic stimulus where it directly binds to and phosphorylates H2B at serine 36. Such phosphorylation promotes EZH2 recruitment and subsequent histone H3K27 trimethylation on the promoter of its target genes including Wnt6, Wnt10a, and Wnt10b, leading to repression of their expression. S6K1-mediated suppression of Wnt genes facilitates adipogenic differentiation through the expression of adipogenic transcription factors PPAR and Cebpa. White adipose tissues from S6K1-deficient mice consistently exhibit marked reduction in H2BS36 phosphorylation (H2BS36p) and H3K27 trimethylation (H3K27me3), leading to enhanced expression of Wnt genes. In addition, expression levels of H2BS36p and H3K27me3 are highly elevated in white adipose tissues from mice fed on high-fat diet or from obese humans. These findings describe a novel role of S6K1 as a transcriptional regulator controlling an epigenetic network initiated by phosphorylation of H2B and trimethylation of H3, thus shutting off Wnt gene expression in early adipogenesis. [BMB Reports 2016; 49(8): 401-402].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070725PMC
http://dx.doi.org/10.5483/bmbrep.2016.49.8.116DOI Listing
August 2016

S6K1 Phosphorylation of H2B Mediates EZH2 Trimethylation of H3: A Determinant of Early Adipogenesis.

Mol Cell 2016 05 14;62(3):443-452. Epub 2016 Apr 14.

Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea. Electronic address:

S6K1 has been implicated in a number of key metabolic responses, which contribute to obesity. Critical among these is the control of a transcriptional program required for the commitment of mesenchymal stem cells to the adipocytic lineage. However, in contrast to its role in the cytosol, the functions and targets of nuclear S6K1 are unknown. Here, we show that adipogenic stimuli trigger nuclear translocation of S6K1, leading to H2BS36 phosphorylation and recruitment of EZH2 to H3, which mediates H3K27 trimethylation. This blocks Wnt gene expression, inducing the upregulation of PPARγ and Cebpa and driving increased adipogenesis. Consistent with this finding, white adipose tissue from S6K1-deficient mice exhibits no detectable H2BS36 phosphorylation or H3K27 trimethylation, whereas both responses are highly elevated in obese humans or in mice fed a high-fat diet. These findings define an S6K1-dependent mechanism in early adipogenesis, contributing to the promotion of obesity.
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http://dx.doi.org/10.1016/j.molcel.2016.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325705PMC
May 2016
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