• Molecules and Cells
• /
• v.38 no.6
• /
• pp.548-561
• /
• 2015

By combining conventional single cell analysis with flow cytometry and public database searches with bioinformatics tools, we extended the expression profiling of thymic stromal cotransporter (TSCOT), Slc46A2/Ly110, that was shown to be expressed in bipotent precursor and cortical thymic epithelial cells. Genome scale analysis verified TSCOT expression in thymic tissue- and cell type- specific fashion and is also expressed in some other epithelial tissues including skin and lung. Coexpression profiling with genes, Foxn1 and Hoxa3, revealed the role of TSCOT during the organogenesis. TSCOT expression was detected in all thymic epithelial cells (TECs), but not in the $CD31^+$endothelial cell lineage in fetal thymus. In addition, ABC transporter-dependent side population and Sca-$1^+$ fetal TEC populations both contain TSCOT-expressing cells, indicating TEC stem cells express TSCOT. TSCOT expression was identified as early as in differentiating embryonic stem cells. TSCOT expression is not under the control of Foxn1 since TSCOT is present in the thymic rudiment of nude mice. By searching variations in the expression levels, TSCOT is positively associated with Grhl3 and Irf6. Cytokines such as IL1b, IL22 and IL24 are the potential regulators of the TSCOT expression. Surprisingly, we found TSCOT expression in the lung is diminished in lung cancers, suggesting TSCOT may be involved in the suppression of lung tumor development. Based on these results, a model for TEC differentiation from the stem cells was proposed in context of multiple epithelial organ formation.

• Journal of Microbiology and Biotechnology
• /
• v.30 no.11
• /
• pp.1651-1658
• /
• 2020

Since Zika virus (ZIKV) was first detected in Uganda in 1947, serious outbreaks have occurred globally in Yap Island, French Polynesia and Brazil. Even though the number of infections and spread of ZIKV have risen sharply, the pathogenesis and replication mechanisms of ZIKV have not been well studied. ZIKV, a recently highlighted Flavivirus, is a mosquito-borne emerging virus causing microcephaly and the Guillain-Barre syndrome in fetuses and adults, respectively. ZIKV polyprotein consists of three structural proteins named C, prM and E and seven nonstructural proteins named NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5 in an 11-kb single-stranded positive sense RNA genome. The function of individual ZIKV genes on the host innate immune response has barely been studied. In this study, we investigated the modulations of the NF-κB promoter activity induced by the MDA5/RIG-I signaling pathway. According to our results, two nonstructural proteins, NS2A and NS4A, dramatically suppressed the NF-κB promoter activity by inhibiting signaling factors involved in the MDA5/RIG-I signaling pathway. Interestingly, NS2A suppressed all components of MDA5/RIG-I signaling pathway, but NS4A inhibited most signaling molecules, except IKKε and IRF3-5D. In addition, both NS2A and NS4A downregulated MDA5-induced NF-κB promoter activity in a dosedependent manner. Taken together, our results suggest that NS2A and NS4A signifcantly antagonize MDA5/RIG-I-mediated NF-κB production, and these proteins seem to be controlled by different mechanisms. This study could help understand the mechanisms of how ZIKV controls innate immune responses and may also assist in the development of ZIKV-specific therapeutics.

• International Area Studies Review
• /
• v.15 no.1
• /
• pp.107-133
• /
• 2011

This paper aims to analyze the causal relationships between agricultural exports and economic growth in the U.S. economy by 50 states. Using the annual data from 1973 to 2007, the theoretical methodologies based on the export-led growth (ELG) model under the static model, the impulse response function (IRF) and forecast error variation decomposition (FEVD) under the vector autoregressive (VAR) model, and the Granger causality test. The results show the causal relationship between agricultural exports and economic growth at the states' level. Especially, the ELG hypothesis is strongly supported in the case of 16 states (HI, ID, KS, MD, MI, MN, NJ, NC, ND, OK, OR, RI, SD, TX, WA, and WI) and is also weakly supported in the case of 31 states. Therefore, the agricultural exports are important factor of developing in the U.S. economy, and furthermore some states (located in coastal area and breadbasket) indicate the strong evidence for agricultural exports-led growth.

• Nutrition Research and Practice
• /
• v.17 no.5
• /
• pp.827-843
• /
• 2023

BACKGROUND/OBJECTIVES: Mitochondrial DNA leakage leads to inflammatory responses via endosome activation. This study aims to evaluate whether the perennial grass water extract (Pogonatherum panicum) ameliorate mitochondrial DNA (mtDNA) leakage. MATERIALS/METHODS: The major bioactive constituents of P. paniceum (PPW) were investigated by high-performance liquid chromatography, after which their antioxidant activities were assessed. In addition, RAW 264.7 macrophages were stimulated with lipopolysaccharide, resulting in mitochondrial damage. Quantitative polymerase chain reaction and enzyme-linked immunosorbent assay were used to examine the gene expression and cytokines. RESULTS: Our results showed that PPW extract-treated activated cells significantly decrease reactive oxygen species and nitric oxide levels by reducing the p2^phox and iNOS expression and lowering cytokine-encoding genes, including IL-6, TNF-α, IL-1β, PG-E2 and IFN-γ relative to the lipopolysaccharide (LPS)-activated macrophages. Furthermore, we observed that LPS enhanced the mtDNA leaked into the cytoplasm, increasing the transcription of Tlr9 and signaling both MyD88/Irf7-dependent interferon and MyD88/NF-κb p65-dependent inflammatory cytokine mRNA expression but which was alleviated in the presence of PPW extract. CONCLUSIONS: Our data show that PPW extract has antioxidant and anti-inflammatory activities by facilitating mtDNA leakage and lowering the Tlr9 expression and signaling activation.

• IMMUNE NETWORK
• /
• v.21 no.5
• /
• pp.33.1-33.19
• /
• 2021

IL-1β plays critical roles in the priming and effector phases of immune responses such as the differentiation, commitment, and memory formation of T cells. In this context, several reports have suggested that the IL-1β signal is crucial for CTL-mediated immune responses to viral infections and tumors. However, little is known regarding whether IL-1β acts directly on CD8⁺ T cells and what the molecular mechanisms underlying expression of IL-1 receptors (IL-1Rs) on CD8⁺ T cells and features of IL-1R⁺ CD8⁺ T cells are. Here, we provide evidence that the expression of IL-1R type I (IL-1RI), the functional receptor of IL-1β, is preferentially induced by IL-21 on TCR-stimulated CD8⁺ T cells. Further, IL-1β enhances the effector function of CD8⁺ T cells expressing IL-21-induced IL-1RI by increasing cytokine production and release of cytotoxic granules containing granzyme B. The IL-21-IL-1RI-IL-1β axis is involved in an augmented effector function through regulation of transcription factors BATF, Blimp-1, and IRF4. Moreover, this axis confers a unique effector function to CD8⁺ T cells compared to conventional type 1 cytotoxic T cells differentiated with IL-12. Chemical inhibitor and immunoprecipitation assay demonstrated that IL-21 induces a unique pattern of STAT activation with the formation of both STAT1:STAT3 and STAT3:STAT5 heterodimers, which are critical for the induction of IL-1RI on TCR-stimulated CD8⁺ T cells. Taken together, we propose that induction of a novel subset of IL-1RI-expressing CD8⁺ T cells by IL-21 may be beneficial to the protective immune response against viral infections and is therefore important to consider for vaccine design.

• Journal of Life Science
• /
• v.19 no.8
• /
• pp.1159-1163
• /
• 2009

It has been postulated that endoplasmic (ER) stress is involved in the development of several diseases. However, the detailed molecular mechanisms have not been fully understood. Therefore, we characterized a genetic network of genes induced by ER stress using cDNA microarray and gene set expression coherence analysis (GSECA), and identified gene function as well as several transcription regulators associated with ER stress. We analyzed time-dependent gene expression profiles in thapsigargin-treated Sk-Hep1 using an oligonucleotide expression chip, and then selected functional gene sets with significantly high expression coherence which was processed into functional clusters according to the expression similarities. The functions related to sugar binding, lysosome, ribosomal protein, ER lumen, and ER to golgi transport increased, whereas the functions with mRNA processing, DNA replication, DNA repair, cell cycle, electron transport chain and helicase activity decreased. Furthermore, functional clusters were investigated for the enrichment of regulatory motifs using GSECA, and several transcriptional regulators associated with regulation of ER-induced gene expression were found.

• International Journal of Stem Cells
• /
• v.16 no.3
• /
• pp.342-355
• /
• 2023

Background and Objectives: Osteoblasts are derived from bone marrow mesenchymal stem cells (BMMSCs) and play important role in bone remodeling. While our previous studies have investigated the cell subtypes and heterogeneity in osteoblasts and BMMSCs separately, cell-to-cell communications between osteoblasts and BMMSCs in vivo in humans have not been characterized. The aim of this study was to investigate the cellular communication between human primary osteoblasts and bone marrow mesenchymal stem cells. Methods and Results: To investigate the cell-to-cell communications between osteoblasts and BMMSCs and identify new cell subtypes, we performed a systematic integration analysis with our single-cell RNA sequencing (scRNA-seq) transcriptomes data from BMMSCs and osteoblasts. We successfully identified a novel preosteoblasts subtype which highly expressed ATF3, CCL2, CXCL2 and IRF1. Biological functional annotations of the transcriptomes suggested that the novel preosteoblasts subtype may inhibit osteoblasts differentiation, maintain cells to a less differentiated status and recruit osteoclasts. Ligand-receptor interaction analysis showed strong interaction between mature osteoblasts and BMMSCs. Meanwhile, we found FZD1 was highly expressed in BMMSCs of osteogenic differentiation direction. WIF1 and SFRP4, which were highly expressed in mature osteoblasts were reported to inhibit osteogenic differentiation. We speculated that WIF1 and sFRP4 expressed in mature osteoblasts inhibited the binding of FZD1 to Wnt ligand in BMMSCs, thereby further inhibiting osteogenic differentiation of BMMSCs. Conclusions: Our study provided a more systematic and comprehensive understanding of the heterogeneity of osteogenic cells. At the single cell level, this study provided insights into the cell-to-cell communications between BMMSCs and osteoblasts and mature osteoblasts may mediate negative feedback regulation of osteogenesis process.

• Journal of Physiology & Pathology in Korean Medicine
• /
• v.26 no.4
• /
• pp.511-518
• /
• 2012

The mechanisms of Toll-like receptor (TLR) signaling have been the focus of extensive studies because TLRs are the target of therapeutic intervention on multiple diseases. In this study, we investigated the inhibitory potential of Vigna angularis (azuki bean) on the TLR signaling. The effect of Vigna angularis extract (JSD) on TLR activation was investigated by assessing NF-${\kappa}B$ and AP-1 inducible secreted embryonic alkaline phosphatase (SEAP) activity. JSD significantly inhibited SEAP activity induced by poly I:C (TLR3 ligand) and poly I (TLR7 ligand) in a dose-dependent manner at concentration below 100 ${\mu}g/ml$ with no sign of cytotoxicity. Pretreatment of JSD markedly suppressed mRNA expressions of pro-inflammatory cytokines and adhesive molecules such as TNF-${\alpha}$, IL-6, RANTES, MCP-1 and ICAM-1 induced by TLR ligands. It also diminished the phosphorylation of $I{\kappa}B$ kinase and $I{\kappa}B$, and followed by $I{\kappa}B$-mediated nuclear translocation of p50, p65, and phosphorylation of p38, JNK, and IRF signaling pathway. In conclusion, our results suggest that Vigna angularis has inhibitory activity on TLR-3 and -7 signaling and it can be further developed as a remedy in curing TLR-related multiple diseases.

• Journal of Microbiology and Biotechnology
• /
• v.33 no.9
• /
• pp.1213-1227
• /
• 2023

Fetal growth restriction (FGR) is a prevalent obstetric condition. This study aimed to investigate the role of Toll-like receptor 9 (TLR9) in regulating the inflammatory response and gut microbiota structure in FGR. An FGR animal model was established in rats, and ODN1668 and hydroxychloroquine (HCQ) were administered. Changes in gut microbiota structure were assessed using 16S rRNA sequencing, and fecal microbiota transplantation (FMT) was conducted. HTR-8/Svneo cells were treated with ODN1668 and HCQ to evaluate cell growth. Histopathological analysis was performed, and relative factor levels were measured. The results showed that FGR rats exhibited elevated levels of TLR9 and myeloid differentiating primary response gene 88 (MyD88). In vitro experiments demonstrated that TLR9 inhibited trophoblast cell proliferation and invasion. TLR9 upregulated lipopolysaccharide (LPS), LPS-binding protein (LBP), interleukin (IL)-1β and tumor necrosis factor (TNF)-α while downregulating IL-10. TLR9 activated the TARF3-TBK1-IRF3 signaling pathway. In vivo experiments showed HCQ reduced inflammation in FGR rats, and the relative cytokine expression followed a similar trend to that observed in vitro. TLR9 stimulated neutrophil activation. HCQ in FGR rats resulted in changes in the abundance of Eubacterium_coprostanoligenes_group at the family level and the abundance of Eubacterium_coprostanoligenes_group and Bacteroides at the genus level. TLR9 and associated inflammatory factors were correlated with Bacteroides, Prevotella, Streptococcus, and Prevotellaceae_Ga6A1_group. FMT from FGR rats interfered with the therapeutic effects of HCQ. In conclusion, our findings suggest that TLR9 regulates the inflammatory response and gut microbiota structure in FGR, providing new insights into the pathogenesis of FGR and suggesting potential therapeutic interventions.

• Tuberculosis and Respiratory Diseases
• /
• v.49 no.1
• /
• pp.49-59
• /
• 2000

Backgrounds : Recent cytogenetic studies indicated that long of the long arm of chromosome 5 is a frequent event in small cell lung canær (SCLC), suggesting the presence of a tumor suppressor gene in its place. To map the precise tumor-suppressor loci on the chromosome arm for further positional cloning efforts, we tested 15 primary SCLCs. Methods : The DNAs extracted from paraffin-embedded tissue blocks with primary tumor and corresponding control tissue were investigated. Nineteen polymorphic microsatellite markers located in the long arm of chromosome 5 were used in the microsatellite analysis. Results : We found that ten (66.7%) of 15 tumors exhibited LOH in at least one of tested microsatellite markers. Two (13%) of 10 tumors exhibiting LOH lost a larger area in chromosome 5q. LOH was observed in five common deleted regions at 5q. Among those areas, LOH between 5q34-qter and 5q35.2-35.3 was most frequent (75%). LOH was also observed in more than 50% of the tumors at four other regions, between 5q14-15 and 5q23-31, 5q31.1, 5q31.3-33.3, and 5q34-35. Three of 15 tumors exhibited shifted bands in at least one of the tested microsatellite markers. Shifted bands occurred in 2.5% (7 of 285) of the loci tested. Conclusion : Our data demonstrated that at least five tumor-suppressor loci exist in the long arm of chromosome 5 and that they may play an important role in small cell lung cancer tumorigenesis.