Metabolic Responses to <i>Orientia tsutsugamushi</i> Infection in a Mouse Model

Jung, Jeeyoun,Jung, Youngae,Gill, Byoungchul,Kim, Changhun,Hwang, Kyu-Jam,Ju, Young-Ran,Lee, Hye-Ja,Chu, Hyuk,Hwang, Geum-Sook Public Library of Science 2015 PLoS neglected tropical diseases Vol.9 No.1

<▼1><P>Tsutsugamushi disease is an infectious disease transmitted to humans through the bite of the <I>Orientia tsutsugamushi</I>-infected chigger mite; however, host-pathogen interactions and the precise mechanisms of damage in <I>O. tsutsugamushi</I> infections have not been fully elucidated. Here, we analyzed the global metabolic effects of <I>O. tsutsugamushi</I> infection on the host using <SUP>1</SUP>H-NMR and UPLC-Q-TOF mass spectroscopy coupled with multivariate statistical analysis. In addition, the effect of <I>O. tsutsugamushi</I> infection on metabolite concentrations over time was analyzed by two-way ANOVAs. Orthogonal partial least squares-discriminant analysis (OPLS-DA) showed distinct metabolic patterns between control and <I>O. tsutsugamushi</I>-infected mice in liver, spleen, and serum samples. <I>O. tsutsugamushi</I> infection caused decreased energy production and deficiencies in both remethylation sources and glutathione. In addition, <I>O. tsutsugamushi</I> infection accelerated uncommon energy production pathways (i.e., excess fatty acid and protein oxidation) in host body. Infection resulted in an enlarged spleen with distinct phospholipid and amino acid characteristics. This study suggests that metabolite profiling of multiple organ tissues and serum could provide insight into global metabolic changes and mechanisms of pathology in <I>O. tsutsugamushi</I>-infected hosts.</P></▼1><▼2><P><B>Author Summary</B></P><P>Scrub typhus is an acute febrile illness caused by attacks of <I>Orientia tsutsugamushi</I>-carrying mites, and is the most prevalent febrile illness in the Asia-Pacific region. If not properly treated with antibiotics, patients often develop severe vasculitis that affects multiple organs, and the mortality rate can reach 30%. To explore the pathogenic mechanisms underlying the host-pathogen interaction, we characterized metabolic changes in various organs and the serum of <I>O. tsutsugamushi</I>-infected hosts. After <I>O. tsutsugamushi</I> infection, the host experienced decreased energy production, as well as a severe deficiency in re-methylation sources and glutathione, which impaired purine synthesis, DNA and protein methylation. In addition, abnormal pathways for phosphatidylcholine (PC) biosynthesis and phosphoethanolamine methylation were utilized in the enlarged spleen of <I>O. tsutsugamushi</I>-infected hosts. These results suggested that metabolic profiling could provide insight into global metabolic changes in <I>O. tsutsugamushi</I>-infected hosts, and increase our understanding of the pathogenic mechanisms of <I>O. tsutsugamushi</I>, as well as providing novel therapeutic targets for scrub typhus.</P></▼2>

Characterization of <i>dandelion</i> species using ¹H NMR- and GC-MS-based metabolite profiling

Jung, Youngae,Ahn, Yun Gyong,Kim, Ho Kyoung,Moon, Byeong Cheol,Lee, A Yeong,Ryu, Do Hyun,Hwang, Geum-Sook Royal Society of Chemistry 2011 The Analyst Vol.136 No.20

<P><I>Taraxacum</I>, known as <I>dandelion</I>, is a large genus of plants in the family Asteraceae. Pharmacological studies have shown that these plants display a wide variety of medicinal properties because <I>Taraxacum</I> extracts contain many pharmacologically active metabolites that display anti-inflammatory, antinociceptive, antioxidant, and anticancer activity. Each plant species displays several different natural constituents, the majority of which have not been studied as no global metabolite screen of the diverse <I>Taraxacum</I> species has been performed. In this study, we investigated the metabolite difference in three species of <I>Taraxacum</I> (<I>T. coreanum</I>, <I>T. officinale</I>, and <I>T. platycarpum</I>) by <SUP>1</SUP>H NMR spectroscopy and gas chromatography-mass spectrometry (GC-MS) coupled with multivariate statistical analyses. The aim of this study was to identify the different chemical compositions of the polar and nonpolar extracts in these species. A partial least-squares discriminant analysis showed a significantly higher separation among nonpolar extracts (mainly fatty acids and sterols) compared to polar extracts (mainly amino acids, organic acids, and sugars) between these species. A one-way ANOVA was performed to statistically certify the metabolite differences of these nonpolar extracts. Taken together, these data suggest that a metabolomic approach using combined <SUP>1</SUP>H NMR and GC-MS analysis is an effective analytical method to differentiate biochemical compositions among different species in plants.</P> <P>Graphic Abstract</P><P>Metabolomic studies of three <I>Taraxacum</I> species (<I>T. coreanum</I>, <I>T. officinale</I> and <I>T. platycarpum</I>) were performed for classification between species by complementary use of <SUP>1</SUP>H NMR and GC-MS. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=c1an15403f'> </P>

Metabolite Profiling of the Response of Burdock Roots to Copper Stress

Jung, Youngae,Ha, Miyoung,Lee, Jueun,Ahn, Yun Gyong,Kwak, Jong Hwan,Ryu, Do Hyun,Hwang, Geum-Sook American Chemical Society 2015 Journal of agricultural and food chemistry Vol.63 No.4

<P><I>Arctium lappa</I> L. (Asteraceae), also known as burdock, has a long history of cultivation as a dietary vegetable worldwide. Stress in plants disrupts metabolic homeostasis and requires adjustment of metabolic pathways. Exposure to heavy metals is one of the most prevalent environmental stresses encountered by plants. In this study, metabolite profiling based on <SUP>1</SUP>H NMR and GC–MS was used to obtain a holistic view of the response of burdock roots to copper stress. The principal component analysis model generated from the NMR data showed significant separation between groups. Copper-treated burdock roots were characterized by increased levels of phenols and decreased levels of primary metabolites. These results suggest that copper stress leads to activation of the phenylpropanoid pathway and growth inhibition. GC–MS analyses revealed increased levels of unsaturated fatty acids and decreased levels of sterols in the copper-treated group. Changes in metabolite concentrations were analyzed by UPLC/QTRAP–MS, and the significances were confirmed by two-way analysis of variance and Bonferroni’s test. Interestingly, linoleic acid was increased about 2.7-fold, from 316 ± 64.5 to 855 ± 111 ppm, in the group treated with copper for 6 days. This study demonstrates that metabolomic profiling is an effective analytical approach to understanding the metabolic pathway(s) associated with copper stress in burdock roots.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jafcau/2015/jafcau.2015.63.issue-4/jf503193c/production/images/medium/jf-2014-03193c_0008.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jf503193c'>ACS Electronic Supporting Info</A></P>

Metabolite profiling of <i>Curcuma</i> species grown in different regions using ¹H NMR spectroscopy and multivariate analysis

Jung, Youngae,Lee, Jueun,Kim, Ho Kyoung,Moon, Byeong Cheol,Ji, Yunui,Ryu, Do Hyun,Hwang, Geum-Sook The Royal Society of Chemistry 2012 The Analyst Vol.137 No.23

<P><I>Curcuma</I> is used to treat skin diseases and colic inflammatory disorders, and in insect repellants and antimicrobial and antidiabetic medications. Two <I>Curcuma</I> species (<I>C. aromatica</I> and <I>C. longa</I>) grown in Jeju-do and Jin-do were used in this study. Methanolic extracts were analyzed by <SUP>1</SUP>H NMR spectroscopy, and metabolite profiling coupled with multivariate analysis was applied to characterize the differences between species or origin. PCA analysis showed significantly greater differences between species than origins, and the metabolites responsible for the differences were identified. The concentrations of sugars (glucose, fructose, and sucrose) and essential oils (eucalyptol, curdione, and germacrone) were significantly different between the two species. However, the samples from Jeju-do and Jin-do were different mainly in their concentrations of organic acids (fumarate, succinate, acetate, and formate) and sugars. This study demonstrates that NMR-based metabolomics is an efficient method for fingerprinting and determining differences between <I>Curcuma</I> species or those grown in different regions.</P> <P>Graphic Abstract</P><P>This paper has described metabolite profiling to characterize the differences between <I>Curcuma</I> species grown in different regions by <SUP>1</SUP>H NMR spectroscopy coupled with multivariate analysis. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=c2an35397k'> </P>

Assessment of Peeling of Astragalus Roots Using ¹H NMR- and UPLC-MS-Based Metabolite Profiling

Jung, Jee-Youn,Jung, Youngae,Kim, Jin-Sup,Ryu, Do Hyun,Hwang, Geum-Sook American Chemical Society 2013 Journal of agricultural and food chemistry Vol.61 No.43

<P>A metabolomic analysis was performed to examine the postharvest processing of Astragalus membranaceus roots with a focus on the peeling procedure using <SUP>1</SUP>H NMR and UPLC-MS analyses. Principal component analysis (PCA) score plots from the <SUP>1</SUP>H NMR and UPLC-MS data showed clear separation between peeled and unpeeled <I>Astragalus</I> roots. Peeled roots exhibited significant losses of several primary metabolites, including acetate, alanine, arginine, caprate, fumarate, glutamate, histidine, <I>N</I>-acetylaspartate, malate, proline, sucrose, trigonelline, and valine. In contrast, the peeled roots contained higher levels of asparagine, aspartate, and xylose, which are xylem-related compounds, and formate, which is produced in response to wound stress incurred during postharvest processing. In addition, the levels of isoflavonoids and astragalosides were significantly reduced in peeled <I>Astragalus</I> root. These results demonstrate that metabolite profiling based on a combination of <SUP>1</SUP>H NMR and UPLC-MS analyses can be used to evaluate peeling procedures used in the postharvest processing of herbal medicines.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jafcau/2013/jafcau.2013.61.issue-43/jf4026103/production/images/medium/jf-2013-026103_0008.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jf4026103'>ACS Electronic Supporting Info</A></P>

Noninvasive diagnosis and evaluation of curative surgery for gastric cancer by using NMR-based metabolomic profiling.

Jung, Jeeyoun,Jung, Youngae,Bang, Eun Jung,Cho, Sung-il,Jang, You-Jin,Kwak, Jung-Myun,Ryu, Do Hyun,Park, Sungsoo,Hwang, Geum-Sook Raven Press 2014 Annals of Surgical Oncology Vol.21 No.suppl4

<P>Mass screening for gastric cancer (GC), particularly using endoscopy, may not be the most practical approach as a result of its high cost, lack of acceptance, and poor availability. Thus, novel markers that can be used in cost-effective diagnosis and noninvasive screening for GC are needed.</P>

Intestinal Lin⁻c-Kit⁺NKp46⁻CD4⁻ Population Strongly Produces IL-22 upon IL-1β Stimulation

Lee, Youngae,Kumagai, Yutaro,Jang, Min Seong,Kim, Jung-Hwan,Yang, Bo-Gie,Lee, Eun-Jung,Kim, You-Me,Akira, Shizuo,Jang, Myoung Ho The American Association of Immunologists, Inc. 2013 JOURNAL OF IMMUNOLOGY Vol.190 No.10

<P>Small intestinal innate lymphoid cells (ILCs) regulate intestinal epithelial cell homeostasis and help to prevent pathogenic bacterial infections by producing IL-22. In a global gene-expression analysis comparing small intestinal ILCs (Lin<SUP>−</SUP>c-Kit<SUP>+</SUP>Sca-1<SUP>−</SUP> cells) with non-ILCs (Lin<SUP>−</SUP>c-Kit<SUP>−</SUP>Sca-1<SUP>−</SUP> cells), we found that Lin<SUP>−</SUP>c-Kit<SUP>+</SUP>Sca-1<SUP>−</SUP> cells highly expressed the mRNAs for Il22, antimicrobial peptides, Csf2rb2 (Il3r), mast cell proteases, and Rorc. We then subdivided the Lin<SUP>−</SUP>c-Kit<SUP>+</SUP>Sca-1<SUP>−</SUP> cells into three groups—Lin<SUP>−</SUP>c-Kit<SUP>+</SUP>NKp46<SUP>−</SUP>CD4<SUP>−</SUP>, Lin<SUP>−</SUP>c-Kit<SUP>+</SUP>NKp46<SUP>−</SUP>CD4<SUP>+</SUP> (CD4<SUP>+</SUP> LTi-like cells), and Lin<SUP>−</SUP>c-Kit<SUP>+</SUP>NKp46<SUP>+</SUP> (NKp46<SUP>+</SUP> ILC22 cells)—and showed that the Lin<SUP>−</SUP>c-Kit<SUP>+</SUP>NKp46<SUP>−</SUP>CD4<SUP>−</SUP> cells produced the highest level of IL-22 protein after IL-1β, IL-23, or IL-1β and IL-23 stimulation. In addition, we showed that the majority of the Lin<SUP>−</SUP>c-Kit<SUP>+</SUP>NKp46<SUP>−</SUP>CD4<SUP>−</SUP> population was IL-7Rα<SUP>+</SUP>CD34<SUP>−</SUP>β7<SUP>int</SUP> cells, and IL-7Rα<SUP>−</SUP> cells could be divided into three subsets (CD34<SUP>+</SUP>β7<SUP>int</SUP>, CD34<SUP>−</SUP>β7<SUP>int</SUP>, and CD34<SUP>int</SUP>β7<SUP>hi</SUP> cells). The IL-7Rα<SUP>+</SUP>CD34<SUP>−</SUP>β7<SUP>int</SUP> cells strongly expressed the transcripts for Il17f and Il22 after costimulation with IL-1β and IL-23. The IL-7Rα<SUP>−</SUP>CD34<SUP>+</SUP>β7<SUP>int</SUP> and IL-7Rα<SUP>−</SUP>CD34<SUP>int</SUP>β7<SUP>hi</SUP> cells predominantly expressed the transcripts for mast cell proteases and differentiated almost entirely into mast cells after 1 wk in culture medium supplemented with a cytokine mixture, whereas the IL-7Rα<SUP>−</SUP>CD34<SUP>−</SUP>β7<SUP>int</SUP> cells highly expressed α-defensins and showed no differentiation. Taken together, these findings indicate that the IL-7Rα<SUP>−</SUP>CD34<SUP>+</SUP>β7<SUP>int</SUP> and IL-7Rα<SUP>−</SUP>CD34<SUP>int</SUP>β7<SUP>hi</SUP> populations are mast cell progenitors, and the IL-7Rα<SUP>+</SUP>CD34<SUP>−</SUP>β7<SUP>int</SUP> (CD4<SUP>−</SUP> LTi-like cells) and IL-7Rα<SUP>−</SUP>CD34<SUP>-</SUP>β7<SUP>int</SUP> populations within Lin<SUP>−</SUP>c-Kit<SUP>+</SUP>NKp46<SUP>−</SUP>CD4<SUP>−</SUP> cells may control intestinal homeostasis and provide intestinal protection by producing high levels of IL-22 and α-defensins, respectively.</P>

Urine myo-inositol as a novel prognostic biomarker for diabetic kidney disease: a targeted metabolomics study using nuclear magnetic resonance

( Soie Kwon ),( Jin Seong Hyeon ),( Youngae Jung ),( Lilin Li ),( Jung Nam An ),( Yong Chul Kim ),( Seung Hee Yang ),( Tammy Kim ),( Dong Ki Kim ),( Chun Soo Lim ),( Geum-sook Hwang ),( Jung Pyo Lee ) 대한신장학회 2023 Kidney Research and Clinical Practice Vol.42 No.4

Background: As a leading cause of chronic kidney disease, clinical demand for noninvasive biomarkers of diabetic kidney disease (DKD) beyond proteinuria is increasing. Metabolomics is a popular method to identify mechanisms and biomarkers. We investigated urinary targeted metabolomics in DKD patients. Methods: We conducted a targeted metabolomics study of 26 urinary metabolites in consecutive patients with DKD stage 1 to 5 (n = 208) and healthy controls (n = 26). The relationships between estimated glomerular filtration rate (eGFR) or urine protein-creatinine ratio (UPCR) and metabolites were evaluated. Multivariate Cox analysis was used to estimate relationships between urinary metabolites and the target outcome, end-stage renal disease (ESRD). C statistics and time-dependent receiver operating characteristics (ROC) were used to assess diagnostic validity. Results: During a median 4.5 years of follow-up, 103 patients (44.0%) progressed to ESRD and 65 (27.8%) died. The median fold changes of nine metabolites belonged to monosaccharide and tricarboxylic acid (TCA) cycle metabolites tended to increase with DKD stage. Myo-inositol, choline, and citrates were correlated with eGFR and choline, while mannose and myo-inositol were correlated with UPCR. Elevated urinary monosaccharide and TCA cycle metabolites showed associations with increased morality and ESRD progression. The predictive power of ESRD progression was high, in the order of choline, myo-inositol, and citrate. Although urinary metabolites alone were less predictive than serum creatinine or UPCR, myo-inositol had additive effect with serum creatinine and UPCR. In time-dependent ROC, myo-inositol was more predictive than UPCR of 1-year ESRD progression prediction. Conclusion: Myo-inositol can be used as an additive biomarker of ESRD progression in DKD.

Characteristics and Clinical Significance of De Novo Donor-Specific Anti-HLA Antibodies after Kidney Transplantation

Jung, Hee-Yeon,Kim, Su-Hee,Seo, Min-Young,Cho, Sun-Young,Yang, Youngae,Choi, Ji-Young,Cho, Jang-Hee,Park, Sun-Hee,Kim, Yong-Lim,Kim, Hyung-Kee,Huh, Seung,Won, Dong Il,Kim, Chan-Duck The Korean Academy of Medical Sciences 2018 JOURNAL OF KOREAN MEDICAL SCIENCE Vol.33 No.34

<P><B>Background</B></P><P>The association of de novo donor-specific anti-human leukocyte antigens (HLA) antibodies (DSA) and development of antibody-mediated rejection (AMR) in kidney transplant recipients (KTRs) is still undetermined.</P><P><B>Methods</B></P><P>We prospectively screened de novo DSA in 167 KTRs during 32 months after kidney transplantation (KT). Timing of DSA detection was at 3, 6, and 12 months post-transplant and annually thereafter and when clinically indicated. DSA levels were determined by Luminex assays and expressed as mean fluorescence intensity (MFI). We evaluated the incidence, characteristics of DSA, and association between DSA and tacrolimus trough levels or AMR.</P><P><B>Results</B></P><P>De novo DSA developed in 16 KTRs (9.6%) and acute AMR occurred more commonly in KTRs with de novo DSA compared to KTRs without de novo DSA (18.8% vs. 0%, <I>P</I> < 0.001). All de novo DSA were against class II antigens. The mean number of DSA was 1.8 ± 1.2 and the average MFI of DSA was 7,399 ± 5,470. Tacrolimus trough level during the first 0–2 months after KT was an independent predictor of DSA development (hazard ratio, 0.70; 95% confidence interval, 0.50–0.99; <I>P</I> = 0.043). No differences were found in the number of DSA, average MFI of DSA, and tacrolimus levels during the first year between de novo DSA-positive KTRs with AMR and those without AMR.</P><P><B>Conclusion</B></P><P>The results of our study suggest that monitoring of DSA and maintaining proper tacrolimus levels are essential to prevent AMR during the initial period after KT.</P>

Fucosylation of the epidermal skin by fucosyltransferase 1 plays a role in modulating barrier function through lipids regulation

( Youngae Lee ),( Na Li ),( Jung-hun Seo ),( Jang-hee Oh ),( Dong Hun Lee ),( Jin Ho Chung ) 한국피부장벽학회 2023 한국피부장벽학회지 Vol.25 No.2

Epidermal lipids within the stratum corneum (SC) are pivotal for maintaining the skin barrier function, serving to safeguard against microbial and allergen infiltration, as well as mitigating transcutaneous evaporative water loss (TEWL). In this study, we have demonstrated the novel role of α(1,2)-fucosylation by fucosyltransferase 1 (Fut1) within the granular layer of the skin in modulating epidermal lipids within the SC. Lipidomic analysis revealed diminished levels of epidermal lipid components, including ceramides, fatty acids, and triglycerides, in Fut1-deficient mice in comparison to WT mice. Furthermore, a decrease in the number of lamella bodies, crucial for epidermal lipid secretion, was observed within the granular layer of Fut1-deficient mice compared to WT counterparts. Additionally, we provided evidence of α(1,2)-fucosylation on lysosomal-associated membrane protein 1 (LAMP-1), a structure membrane protein of lamella bodies potentially involved in their biogenesis, as confirmed by immunostaining and immunoprecipitation analyses. Finally, we observed that following tape-stripping, Fut1-deficient mice exhibited heightened TEWL relative to WT mice. These findings underscore the significant role of α(1,2)-fucosylation in the regulation of epidermal lipids, which is essential for maintaining skin barrier functions.