In vivo monitoring of dynamic interaction between neutrophil and human umbilical cord blood-derived mesenchymal stem cell in mouse liver during sepsis

BACKGROUND: Sepsis is a global inflammatory disease that causes death. It has been reported that mesenchymal stem cell (MSC) treatment can attenuate inflammatory and septic symptoms. In this study, we investigated how interactions between neutrophils and human umbilical cord blood (hUCB)-MSCs in the liver of septic mice are involved in mitigating sepsis that is mediated by MSCs. Accordingly, we aimed to determine whether hUCB-MSC application could be an appropriate treatment for sepsis. METHODS: To induce septic condition, lipopolysaccharide (LPS) was intraperitoneally (i.p.) injected into mice 24 h after the intravenous (i.v.) injection of saline or hUCB-MSCs. To determine the effect of hUCB-MSCs on the immune response during sepsis, histologic analysis, immunoassays, and two-photon intravital imaging were performed 6 h post-LPS injection. For the survival study, mice were monitored for 6 days after LPS injection. RESULTS: The injection (i.v.) of hUCB-MSCs alleviated the severity of LPS-induced sepsis by increasing IL-10 levels (p < 0.001) and decreasing mortality (p < 0.05) in septic mice. In addition, this significantly reduced the recruitment of neutrophils (p < 0.001) to the liver. In hUCB-MSC-treated condition, we also observed several distinct patterns of dynamic interactions between neutrophils and hUCB-MSCs in the inflamed mouse liver, as well as vigorous interactions between hepatic stellate cells (HSCs or ito cells) and hUCB-MSCs. Interestingly, hUCB-MSCs that originated from humans were not recognized as foreign in the mouse body and consequently did not cause graft rejection. CONCLUSIONS: These distinct interaction patterns between innate immune cells and hUCB-MSCs demonstrated that hUCB-MSCs have beneficial effects against LPS-induced sepsis through associations with neutrophils. In addition, the immunomodulatory properties of hUCB-MSCs might enable immune evasion in the host. Taken together, our results suggest the prospects of hUCB-MSCs as a therapeutic tool to inhibit inflammation and alleviate pathological immune responses such as sepsis.ope

Conserved Noncoding Sequences Boost ADR1 and SP1 Regulated Human Swiprosin-1 Promoter Activity

Swiprosin-1 is expressed in various types of cells or tissues of different species. To investigate the mechanisms underlying Swiprosin-1 expression pattern, we analyzed the promoter activity of 2-kilobase genomic sequences located at 5' flanking region of the Swiprosin-1 gene. The -2000/+41 bp of 5' flanking untranslated promoter region of Swiprosin-1 gene was constitutively transactivated without significant effect of PMA, A23187, or PMA/A23187 stimulation in Jurkat T cells. Further, we identified 5' deletant of proximal promoter region (-100/+41 to -70/+41) plays a pivotal role in activating the Swiprosin-1 gene in Jurkat T cells. Our studies also verified that ADR1 and Sp1 transcription factors were located between -70 and -100 locus of 5' flanking proximal promoter region, which is critical for the Swiprosin-1 promoter activity. ADR1 and Sp1 were shown to bind the regions of -82, -79, -76, -73 and -70 and; -79, -78 and -77, respectively, within the proximal promoter region of Swiprosin-1. Finally conserved noncoding sequences (CNS) -1, -2 and -3 were located between the exon 1 and exon 2 of Swiprosin-1 gene and synergistically transactivated the Swiprosin-1 promoter. In summary, Swiprosin-1 was constitutively expressed in Jurkat T cells by the coordinate action of ADR1 and SP1 transcription factors at the transcriptional level and CNS further boost the proximal region of Swiprosin-1 promoter activity. Our findings provide novel insights that the transcriptional regulation of Swiprosin-1 by targeting ADR1 and Sp1 binding sites may be helpful in exploring novel therapeutic strategies for advanced immune or other disorders.ope

Mitofusin-2 Promotes the Epithelial-Mesenchymal Transition-Induced Cervical Cancer Progression

ope

Anti-helminthic niclosamide inhibits Ras-driven oncogenic transformation via activation of GSK-3

Despite the importance of Ras oncogenes as a therapeutic target in human cancer, their 'undruggable' tertiary structures limit the effectiveness of anti-Ras drugs. Canonical Wnt signaling contributes to Ras activity by glycogen synthase kinase 3 (GSK-3)-dependent phosphorylation at the C-terminus and subsequent degradation. In the accompanying report, we show that the anti-helminthic niclosamide directly binds to GSK-3 and inhibits Axin functions in colon cancer cells, with reversion of Snail-mediated epithelial-mesenchymal transition. In this study, we report that niclosamide effectively suppresses Ras and nuclear NFAT activities regardless of the mutational status of Ras at nM levels. Mechanistically, niclosamide increased endogenous GSK-3 activity, shortening the half-life of mutant Ras. Further, niclosamide activates Raf-1 kinase inhibitory protein, a downstream target of Snail repressor. Niclosamide treatment attenuates Ras-induced oncogenic potential in vitro and in vivo. These findings provide a clinically available repositioned Ras inhibitor as well as a novel strategy for inhibiting the Ras via GSK-3.ope

Niclosamide is a potential therapeutic for familial adenomatosis polyposis by disrupting Axin-GSK3 interaction

The epithelial-mesenchymal transition (EMT) is implicated in tumorigenesis and cancer progression, and canonical Wnt signaling tightly controls Snail, a key transcriptional repressor of EMT. While the suppression of canonical Wnt signaling and EMT comprises an attractive therapeutic strategy, molecular targets for small molecules reverting Wnt and EMT have not been widely studied. Meanwhile, the anti-helminthic niclosamide has been identified as a potent inhibitor of many oncogenic signaling pathways although its molecular targets have not yet been clearly identified. In this study, we show that niclosamide directly targets Axin-GSK3 interaction, at least in part, resulting in suppression of Wnt/Snail-mediated EMT. In vitro and in vivo, disruption of Axin-GSK3 complex by niclosamide induces mesenchymal to epithelial reversion at nM concentrations, accompanied with suppression of the tumorigenic potential of colon cancer. Niclosamide treatment successfully attenuates Snail abundance while increasing E-cadherin abundance in xenograft tumor. Notably, oral administration of niclosamide significantly suppressed adenoma formation in an APC-MIN mice model, indicating that niclosamide is an effective therapeutic for familial adenomatosis polyposis (FAP) patients. In this study, we identified a novel target to control the canonical Wnt pathway and Snail-mediated EMT program, and discovered a repositioned therapeutics for FAP patients.ope

A Study on Improving the Performance of Demand Paging for NAND Flash based Embedded Systems

본 논문은 낸드 플래시 메모리 기반의 디맨드 페이징 시스템에서 페이지 폴트의 처리 성능을 향상시키기 위한 기법에 대해 논의하였다. 특히 원낸드 플래시 메모리를 사용하는 내장형 시스템에서 입출력 아키텍처 개선을 통해 디맨드 페이징 성능을 개선할 수 있는 기법과 압축파일시스템 환경에서 압축해제 오버헤드를 줄임으로써 디맨드 페이징 성능을 향상시킬 수 있는 기법들을 제안한다. 원낸드 플래시 메모리는 기존 낸드 플래시 메모리의 성능을 보완한 퓨전 메모리로 특히 큰 읽기 요청을 빠르게 처리할 수 있다. 하지만 현재 운영체제의 입출력 아키텍처에서는 페이지 폴트로 인해 발생하는 큰 읽기 요청이 입출력 세그먼트 단위로 단편화 되기 때문에 원낸드 플래시 메모리의 성능을 제대로 활용할 수가 없다. 본 논문에서는 이를 해결하기 위해 다음 두 가지 기법을 제안한다. 첫 번째, 가상 입출력 세그먼트 기법은 여러 개의 입출력 세그먼트를 가상 주소 매핑을 통해 하나의 큰 가상 입출력 세그먼트로 처리함으로써 기존 페이지 폴트 처리 시간을 약 48%가량 줄일 수 있었다. 두 번째, 벡터 읽기 기법은 가상 입출력 세그먼트 기법의 단점인 임의 읽기 성능을 향상시키는 기법으로 인터페이스의 변경 및 개선을 통해 디바이스상에서 비연속적인 읽기 요청들을 한번에 원낸드 플래시 메모리에 전달하는 기법이다. 성능평가 결과에 따르면 벡터 읽기 기법을 사용할 경우 페이지 폴트 처리 시간을 56.5%까지 감소시킬 수 있었다. 압축파일시스템의 읽기 성능 개선을 위해서는 다음 두 가지 기법이 제안되었다. 첫 번째는 미리읽기를 고려한 압축파일시스템이다. 미리읽기 기법은 일반적으로 디맨드 페이징 시스템의 성능을 향상시키지만 압축 파일시스템의 경우에는 오히려 불필요한 압축해제 오버헤드를 발생시켜 페이지 폴트 처리 시간을 크게 증가시킨다. 이를 해결하기 위해 본 논문에서는 선택적 압축해제를 통해 불필요한 압축해제 오버헤드를 제거하는 기법을 제안한다. 성능평가에 따르면 제안된 기법은 압축파일시스템의 페이지 폴트 처리 시간을 28%까지 줄일 수 있었다. 두 번째는 가상주소 매핑을 이용해 SquahFS의 읽기성능을 최적화시키는 기법이다. SquashFS는 압축률이 높고 안정성이 뛰어난 압축파일시스템이지만 압축해제 과정이 비효율적이다. 본 논문에서는 가상 주소 매핑을 이용해 반복적인 압축해제함수 호출과 불필요한 복사 오버헤드를 제거해 SquashFS의 압축해제 과정을 최적화 시켰다. 성능평가에 따르면 제안된 최적화 기법은 SquashFS의 읽기 성능을 20%까지 향상시킬 수 있었다.Docto

The Role of MSCs in the Tumor Microenvironment and Tumor Progression

Over the past few decades, longevity without disease has become an important topic worldwide. However, as life expectancy increases, the number of patients with cancer is also increasing. Tumor progression is related to interactions between tumor cells and mesenchymal stem cells (MSCs) in the tumor microenvironment. MSCs are multipotent stromal cells known to be present in a variety of locations in the body, including bones, cartilage, fat, muscles, and dental pulp. MSCs migrate toward inflamed areas during pathological immune responses. MSCs also migrate toward tumor stroma and participate in tumor progression. MSCs can contribute to tumor progression by interacting with tumor cells via paracrine signaling and differentiate into diverse cell types. This also enables MSCs to make direct contact with tumor cells in tumor stroma. Interactions between tumor cells and MSCs enhance tumorigenic and metastatic potential, in addition to stimulating epithelial to mesenchymal transition. Herein, we reviewed the research associated with the tumor-enhancing role of MSCs in tumor progression, from primary tumor growth to distant tumor metastasis.restrictio

Real-time prediction of tokamak plasma using neural networks

Maste

수화제를 대상으로 한 순간희석장치의 개발

학위논문(석사)--서울대학교 대학원 :농공학과 농업기계전공,1999.Maste

폴리염화비닐TiO₂ 나노하이브리드를 이용한 다이옥신 배출 억제에 관한 연구

Thesis(master`s)--서울대학교 대학원 :재료공학부,2005.Maste