Biology subjects

Park, S. E.

Publications and source records attributed to Park, S. E..

8 recordsLinked to original sources

bioRxiv2025

Linoleic acid metabolite, 13-S-hydroxyoctadecadienoic acid, suppresses cancer cell growth by inhibiting mTOR

Mechanistic target of rapamycin (mTOR) is a key protein kinase that integrates various internal and external signals to control biological events including cell growth. Whereas substantial efforts were made to elucidate protein subunits interacting with mTOR, endogenous metabolite-mTOR interactions remain largely unknown. Using affinity protein purification and mass spectrometry, we identified direct binding of mTOR to 13-S-hydroxyoctadecadienoic acid (13-S-HODE) which is an oxygenated metabolite of linoleic acid, a polyunsaturated essential fatty acid. Interaction of 13-S-HODE with the catalytic ATP-binding domain of mTOR prevented its kinase activity in an ATP-competitive manner. Furthermore, either 13-S-HODE treatment or expression of arachidonate 15-lipoxygenase (ALOX15), an enzyme responsible for 13-S-HODE production, reduced mTOR signaling, thereby suppressing the growth of cancer cells as well as tumor xenografts. Our results highlight the importance of 13-S-HODE serving as a tumor suppressive, mTOR-inhibiting metabolite that links polyunsaturated fatty acid metabolism and the mTOR signaling in controlling cancer cell growth.

biochemistry↗

bioRxiv2021

Intestinal epithelial IPMK protects mice from experimental colitis via governing colonic tuft cell development

As a pleiotropic signaling factor, inositol polyphosphate multikinase (IPMK) is involved in key biological events such as growth and innate immunity, acting either enzymatically to mediate the biosynthesis of inositol polyphosphates and phosphatidylinositol 3,4,5-trisphosphates, or noncatalytically to control key signaling target molecules. However, the functional significance of IPMK in regulating gut epithelial homeostasis remains largely unknown. Here we show that intestinal epithelial-specific deletion of IPMK aggravates dextran sulfate sodium (DSS)-induced colitis with higher clinical colitis scores and elevated epithelial barrier permeability. No apparent defects in PI3K-AKT signaling pathway and pro-inflammatory cytokine production were found in IPMK-deficient colons challenged by DSS treatment. RNA-sequencing and FACS analyses further revealed significantly decreased tuft cells in IPMK-deficient colons. Importantly, IPMK deletion in the gut epithelium was found to decrease choline acetyltransferase (ChAT) but not IL-25, suggesting selective loss of cholinergic signaling. Thus, these findings identify IPMK as a physiological determinant of tuft cell differentiation and highlight the critical function of IPMK in the control of gut homeostasis.

physiology↗

bioRxiv2021

IPMK physically binds to the SWI/SNF complex and modulates BRG1 occupancy

Inositol polyphosphate multikinase (IPMK), a key enzyme in the inositol polyphosphate (IP) metabolism, is a pleiotropic signaling factor involved in major biological events including transcriptional control. In yeasts, IPMK and its IP products were known to promote the activity of SWI/SNF chromatin remodeling complex, which plays a critical role in gene expression by regulating chromatin accessibility. However, the direct linkage between IPMK and chromatin remodelers remains unclear, raising a question on how IPMK contributes to the transcriptional regulation in mammals. By employing unbiased screenings and in vivo/in vitro immunoprecipitations, here we demonstrated that IPMK physically associates with native mammalian SWI/SNF complexes by directly binding to SMARCB1, BRG1, and SMARCC1. Furthermore, we identified the specific domains required for the IPMK-SMARCB1 binding. Notably, using CUT&RUN and ATAC-seq assays, we discovered that IPMK co-localizes with BRG1 and regulates BRG1 localization as well as BRG1-mediated chromatin accessibility in a genome-wide manner (including promoter-TSS) in mouse embryonic stem cells. Finally, our mRNA-seq analyses revealed that IPMK and SMARCB1 regulate common gene sets, validating a functional link between IPMK and SWI/SNF complex. Together, these findings establish an importance of IPMK in promoter targeting of the SWI/SNF complex, thereby contributing to SWI/SNF-meditated chromatin accessibility and transcription.

molecular biology↗

bioRxiv2020

The genomic epidemiology of multi-drug resistant nontyphoidal Salmonella causing invasive disease in sub-Saharan Africa

BackgroundInvasive nontyphoidal Salmonella (iNTS) is one of the leading causes of bacteraemia in sub-Saharan Africa. Multi-drug resistance (MDR) and further resistance to third generation cephalosporins and fluoroquinolones have emerged in multiple iNTS serotypes. Molecular epidemiological investigations of nontyphoidal Salmonella are needed to better understand the genetic characteristics and transmission dynamics associated with major MDR iNTS serotypes across the continent. MethodsA total of 166 nontyphoidal Salmonella isolates causing invasive disease were collected from a multi-centre study in eight African countries between 2010 and 2014, and whole-genome sequenced to investigate the geographical distribution, antimicrobial genetic determinants and population structure of iNTS serotypes-genotypes. Phylogeographical reconstruction was further conducted in context of the existing genomic framework of iNTS serotypes Typhimurium and Enteritidis. Population-based incidence of MDR-iNTS disease was also estimated. ResultsSalmonella enterica subsp. Enterica serotype Typhimurium (S. Typhimurium) sequence-type (ST) 313 and Salmonella enterica subsp. Enterica serotype Enteritidis (S. Enteritidis) ST11 were predominant, and both exhibited high frequencies of MDR. Salmonella enterica subsp. Enterica serotype Dublin (S. Dublin) ST10 emerged in West Africa. Mutations in the gyrA gene were identified in S. Enteritidis and S. Typhimurium in Ghana; and ST313 carrying blaCTX-M-15 was found in Kenya. Inter-country transmission of MDR ST313 lineage II and the West African Clade of MDR ST11 between Ghana and neighbouring countries including Mali, Burkina Faso, and Nigeria were evident. The incidence of MDR-iNTS disease exceeded 100/100,000-person years-of-observation (PYO) in children aged <5 years in several West African countries. ConclusionsMultiple MDR iNTS serotypes-sequence types, predominantly S. Typhimurium ST313 and S. Enteritidis ST11, are co-circulating in sub-Saharan Africa with evidence of transmission between West African countries. The development of safe and effective iNTS vaccines coupled with appropriate antimicrobial stewardship and adequate epidemiological monitoring are essential to limit the impact of these pathogens in Africa.

genomics↗

bioRxiv2020

Newly developed silicone airway stent (GINA stent): Mechanical characteristics and performance evaluation in pigs

OBJECTIVESCentral airway obstruction (CAO) is caused by various malignant and benign processes. Surgery is a preferred option for CAO, but if not possible, bronchoscopic treatment could be performed. Recently, bronchoscopic treatments have been improved. Particularly in airway stents, new attempts are being made to overcome the existing shortcomings of stents (migration, mucostasis, and granulation tissue formation). We recently developed a new silicone airway stent (GINA stent). The GINA stent has anti-migration design, dynamic structure enabling reduction of stent cross-sectional area, and radiopaqueness. We sought to evaluate mechanical characteristics and performance of our novel GINA stent in a pig tracheal stenosis model. METHODSAll tests were performed by comparing GINA stent [outer diameter (OD, mm) 14, length (L, mm) 55] with Dumon stent (OD14L50). Mechanical tests were done using digital force gage to determine the anti-migration force, expansion force, and flexibility. Short-term (3 weeks) performance was evaluated after stent implantations [GINA (n = 4) vs. Dumon (n = 3)] in a pig model of tracheal stenosis. RESULTSMechanical properties outcomes for GINA vs. Dumon: anti-migration force [18.4 vs. 12.8 Newton (N)]; expansion force (11.9 vs. 14.5 N); flexibility (3.1 vs. 4.5 N). Short-term (3 weeks) GINA vs. Dumon performances: mucus retention (0/4 vs. 0/3); granulation tissue formation (0/4 vs. 0/3); migration (1/4 vs. 2/3). CONCLUSIONSGINA stent demonstrated better mechanical properties than Dumon stent with a stent performance not inferior to Dumon stent.

physiology↗

bioRxiv2020

Rapid Establishment of Tracheal Stenosis in Pigs Using Endotracheal Tube Cuff Overpressure and Electrocautery

BackgroundCentral airway obstruction can be caused by cancer, tracheal intubation, or tuberculosis, among others. If surgery is contraindicated, bronchoscopic therapy may be performed. Bronchoscopic treatment for airway obstruction is continuously evolving. In particular, attempts to overcome the current shortcomings of airway stents (stent migration, mucostasis, and granulation tissue formation) are currently ongoing. To apply a new airway stent to humans, preclinical studies in an appropriate animal model is needed. Canine and porcine tracheas have been used as animal airway stenosis models. However, existing models take a long time to develop (3-8 weeks) and have a disadvantage that the mechanism of stenosis is different from that in humans. PurposeTo establish a new and fast tracheal stenosis model in pigs using a combination of cuff overpressure intubation and electrocautery. MethodsFourteen pigs were divided into three groups: tracheal cautery (TC) group (n = 3), cuff overpressure intubation (COI) group (n = 3), and COI-TC combination group (n = 8). Cuff overpressure (200/400/500 mmHg) was applied using a 9-mm internal diameter endotracheal tube. Tracheal cautery (40/60 watts) was performed using a rigid bronchoscopic electrocoagulator. After intervention, the pigs were observed for 3 weeks and bronchoscopy was performed every 7 days. When the cross-sectional area decreased by > 50%, it was judged that tracheal stenosis was established. ResultsThe time for tracheal stenosis was 14 days in the TC group and 7 days in the COI-TC combination group. In the COI group, no stenosis occurred. In the COI-TC group, electrocautery (40 watts) immediately after intubation for > 1 hour with a cuff pressure of 200 mmHg or more resulted in sufficient tracheal stenosis within 7 days. Moreover, the degree of tracheal stenosis increased in proportion to the cuff pressure and tracheal intubation time. ConclusionsThe combined use of cuff overpressure and electrocautery helped to establish tracheal stenosis in pigs rapidly. This animal model was technically simple and reproducible, and used a mechanism similar to that in human tracheal stenosis. It is expected to help develop new treatments for airway stenosis

physiology↗

bioRxiv2020

A global resource for genomic predictions of antimicrobial resistance and surveillance of Salmonella Typhi at Pathogenwatch

BackgroundMicrobial whole-genome sequencing (WGS) is now increasingly used to inform public health investigations of infectious disease. This approach has transformed our understanding of the global population structure of Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever. WGS has been particularly informative for understanding the global spread of multi-drug resistant (MDR) typhoid. As WGS capacity becomes more decentralised, there is a growing opportunity for collaboration and sharing of surveillance data within and between countries to inform disease control policies. This requires freely available, community driven tools that reduce the barriers to access genomic data for public health surveillance and that deliver genomic data on a global scale. MethodsHere we present the Pathogenwatch (https://pathogen.watch/styphi) scheme for S. Typhi, a web application enabling the rapid identification of genomic markers of antimicrobial resistance (AMR) and contextualization with public genomic data to identify high-risk clones at a population level. Data are delivered in single genome reports or in collections of genomes combined with geographic and other data using trees, maps and tables. ResultsWe show that the clustering of S. Typhi genomes in Pathogenwatch is comparable to established bioinformatics methods, and that genomic predictions of AMR are largely concordant with phenotypic drug susceptibility data. We demonstrate the public health utility of Pathogenwatch with examples selected from over 4,300 public genomes available in the application. ConclusionsPathogenwatch democratises genomic epidemiology of S. Typhi by providing an intuitive entry point for the analysis of WGS and linked epidemiological data, enabling international public health monitoring of the emergence and spread of high risk clones.

genomics↗

bioRxiv2019

Associations between absolute neutrophil count and lymphocyte-predominant breast cancer

Tumor-infiltrating lymphocytes (TILs) might be associated with host-cell mediated immunity, which could be partly reflected by peripheral blood cell counts. We aimed to investigate whether peripheral blood cell counts are associated with TILs in breast cancer. Between August 2016 and July 2018, we evaluated the percentage of stromal TILs in breast cancer patients who underwent primary surgery, using the standardized methodology proposed by the international TIL Working Group. Lymphocyte-predominant breast cancer (LPBC) was defined as tumors having high TIL levels ([≥] 50%). Peripheral blood cell counts including absolute neutrophil counts (ANC), absolute lymphocyte counts (ALC) and neutrophil-to-lymphocyte ratio (NLR) was obtained from pretreatment laboratory data. Of the 684 patients, 99 (17.2%) had LPBC, and 478 (82.8%) had non-LBPC. In a comparison of 3 markers of peripheral blood counts, LPBC had a significantly lower mean ANC than non-LPBC (3,330 vs. 3,660; P=0.004), but the other means were not different. Decreasing ANC was an independent clinical factor in predicting LPBC (OR: 0.736, 95% CI: 0.591-0.917; P=0.004). Low peripheral ANC might be linked with LPBC, supporting the hypothesis that systemic immune cell counts might be associated with the tumor-immune microenvironment.

immunology↗