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Effective detection of fetal sex using circulating fetal DNA in first‐trimester maternal plasma
Lim, Ji Hyae,Park, So Yeon,Kim, Shin Young,Kim, Do Jin,Choi, Ji Eun,Kim, Min Hyoung,Choi, Jun Seek,Kim, Moon Young,Yang, Jae Hyug,Ryu, Hyun Mee Federation of American Society for Experimental Bi 2012 The FASEB Journal Vol.26 No.1
<P>The aim of this study was to develop a simple and effective method for noninvasively detecting fetal sex using circulating fetal DNA from first-trimester maternal plasma. A study was conducted with maternal plasma collected from 203 women between 5 and 12 wk of gestation. The presence of circulating fetal DNA was confirmed by a quantitative methylation-specific polymerase chain reaction of the unmethylated-PDE9A gene (U-PDE9A). Multiplex real-time PCR was used to simultaneously quantify the amount of DYS14 and GAPDH in maternal plasma. The results were confirmed by phenotype at birth. Pregnancy outcomes and U-PDE9A concentrations were obtained in all cases, including 99 male-bearing and 104 female-bearing participants. At equivalent specificity (100%), the false-negative rate was 9.1% for DYS14 quantification cycle, 7.1% for DYS14 concentration, and 0.0% for the concentration ratio of DYS14/GAPDH, respectively. In male-bearing participants, DYS14, U-PDE9A, and GAPDH concentrations were significantly lower in the false-negative case than in correct case (P<0.001 in all). Moreover, DYS14, U-PDE9A, and GAPDH concentrations showed significantly positive associations with each other (P0.001 in all). The ratio of DYS14/GAPDH in maternal plasma was an effective biomarker for noninvasive fetal sex detection during the first trimester, indicating that it could be useful for clinical application.</P>
Zheng, Min,Kim, Seul‐,Ki,Joe, Yeonsoo,Back, Sung Hoon,Cho, Hong R.,Kim, Hong Pyo,Ignarro, Louis J.,Chung, Hun‐,Taeg Federation of American Society for Experimental Bi 2012 The FASEB Journal Vol.26 No.6
<P>Endoplasmic reticulum (ER) stress activates the adaptive unfolded protein response, allowing cells to recover folding capacity in the organelle. However, the overwhelming response to severe damage results in apoptotic cell death. Because of the physical proximity between ER and mitochondria, a functional interrelationship between these two organelles, including mitochondrial ATP production and apoptosis, has been suggested. The adaptive response to ER stress includes the maintenance of cellular energetics, which eventually determines cell fate. We previously demonstrated that heme oxygenase-1 (HO-1) activity protects cells against ER stress in a protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dependent pathway. Here, we provide evidence that PERK-mediated induction of HO-1 in murine macrophages, RAW264.7, relays ER stress to mitochondrial DNA (mtDNA) replication and function. ER stress induced by thapsigargin treatments (10-100 nM) resulted in a 2-fold increase in mtDNA contents compared with that in the untreated control. HO-1 activity on ER stress is proven to be critical for mitochondrial integrity because chemical inhibition (zinc protoporphyrin, 5-20 관M) and genetic depletion of HO-1 by small interference RNA transfection suppress the activation of transcription factors for mitochondrial biogenesis. Carbon monoxide (CO), an enzymatic by-product of HO-1 activity is responsible for the function of HO-1. Limited bioavailability of CO by hemoglobin treatment triggers cell death with a concomitant decline in ATP production. Approximately 78.1% of RAW264.7 cells were damaged in the presence of hemoglobin compared with the percentage of injured cells (26.9%) under ER stress alone. Mitochondrial generation of ATP levels significantly declined when CO availability was limited under prolonged ER stress. Taken together, these results suggest that the cellular HO-1/CO system conveys ER stress to cell survival signals from mitochondria via both the activation of transcriptional factors and functional integrity of mtDNA.</P>
Yoon, Dong Suk,Kim, Yun Hee,Lee, Seulgi,Lee, Kyoung‐,Mi,Park, Kwang Hwan,Jang, Yeonsue,Lee, Jin Woo Federation of American Society for Experimental Bi 2014 The FASEB Journal Vol.28 No.7
Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are a heterogeneous population of cells that differ in size and morphology. BM-MSCs become committed to the osteogenic lineage as senescence approaches and lose multipotency. Nevertheless, little is known about the effects of cell-cell interaction between different populations on stemness loss and lineage commitment. The current study aimed to identify mechanisms by which cell-cell interactions between heterogeneous BM-MSCs affect stemness and lineage commitment of multipotent subpopulation. The lineage commitment of primitive multipotent cells was strongly induced in the presence of cytokines secreted by senescent-like cells in a cell culture insert system. Senescent-like cells secreted higher levels of interleukin-6 (IL-6) than primitive multipotent cells in a human cytokine array. IL-6 induced the lineage commitment and stemness loss in multipotent cells by decreasing Sox2 expression. Furthermore, we confirmed that IL-6 decreased the transcriptional activity of Sox2 through up-regulation of Runx2 and Dlx5. We suggest a mechanism by which IL-6 modulates the expression of Sox2, resulting in decreased multipotency and causing primitive multipotent cells to undergo osteogenic lineage commitment. This is the first study to identify mechanisms in which the cell-cell interactions between the different populations play important roles in the stemness loss and lineage commitment of multipotent populations.
Lee, Hee Doo,Koo, Bon‐,Hun,Kim, Yeon Hyang,Jeon, Ok‐,Hee,Kim, Doo‐,Sik Federation of American Society for Experimental Bi 2012 The FASEB Journal Vol.26 No.7
<P>A disintegrin and metalloproteinase 15 (ADAM15), the only ADAM protein containing an Arg-Gly-Asp (RGD) motif in its disintegrin-like domain, is a widely expressed membrane protein that is involved in tumor progression and suppression. However, the underlying mechanism of ADAM15-mediated tumor suppression is not clearly understood. This study demonstrates that ADAM15 is released as an exosomal component, and ADAM15 exosomes exert tumor suppressive activities. We found that exosomal ADAM15 release is stimulated by phorbol 12-myristate 13-acetate, a typical protein kinase C activator, in various tumor cell types, and this results in a corresponding decrease in plasma membrane-associated ADAM15. Exosomes rich in ADAM15 display enhanced binding affinity for integrin 관v관3 in an RGD-dependent manner and suppress vitronectin- and fibronectin-induced cell adhesion, growth, and migration, as well as in vivo tumor growth. Exosomal ADAM15 is released from human macrophages, and macrophage-derived ADAM15 exosomes have tumor inhibitory effects. This work suggests a primary role of ADAM15 for exosome-mediated tumor suppression, as well as functional significance of exosomal ADAM protein in antitumor immunity.</P>
Calsenilin regulates presenilin 1/γ‐secretase‐mediated N‐cadherin ∊‐cleavage and β‐catenin signaling
Jang, Changhwan,Choi, Jin‐,Kyu,Na, Yeo‐,Jung,Jang, Byungki,Wasco, Wilma,Buxbaum, Joseph D.,Kim, Yong‐,Sun,Choi, Eun‐,Kyoung Federation of American Society for Experimental Bi 2011 The FASEB Journal Vol.25 No.12
<P>Presenilin 1 (PS1) is a component of the γ-secretase complex that cleaves a variety of type I membrane proteins, including the β-amyloid precursor protein (β-APP), Notch, and neuronal (N)- and epithelial (E)-cadherins. N-cadherin is an essential adhesion molecule that forms a complex with, and is cleaved by, PS1/γ-secretase and β-catenin in the plasma membrane. The purpose of this study was to determine whether calsenilin, a presenilin-interacting protein, has a functional role in PS1/γ-secretase-mediated N-cadherin ε-cleavage using Western blot analysis, RT-PCR, immunoprecipitation, subcellular fractionation, biotinylation, and a luciferase reporter assay in SH-SY5Y neuroblastoma cells. Here, we demonstrate that the expression of calsenilin leads to a disruption of PS1/γ-secretase-mediated ε-cleavage of N-cadherin, which results in the significant accumulation of N-cadherin C-terminal fragment 1 (Ncad/CTF1), the reduction of cytoplasmic Ncad/CTF2 release, and a deceleration of PS1-CTF delivery to the cell surface. Interestingly, we also found that the expression of calsenilin is associated with the redistribution of β-catenin from the cell surface to a cytoplasmic pool, as well as with the negative regulation of genes that are targets of T-cell factor/β-catenin nuclear signaling. Taken together, our findings suggest that calsenilin is a novel negative regulator of N-cadherin processing that plays an important role in β-catenin signaling.</P>
Acquisition of <i>in vitro</i> and <i>in vivo</i> functionality of Nurr1‐induced dopamine neurons
Park, Chang‐,Hwan,Kang, Jin Sun,Ho Shin, Yeon,Chang, Mi‐,Yoon,Chung, Seungsoo,Koh, Hyun‐,Chul,Zhu, Mei Hong,Bae Oh, Seog,Lee, Yong‐,Sung,Panagiotakos, Georgia,Tabar, Vivian,Stu Federation of American Society for Experimental Bi 2006 The FASEB Journal Vol.20 No.14
<P>Neural precursor cells provide an expandable source of neurons and glia for basic and translational applications. However, little progress has been made in directing naive neural precursors toward specific neuronal fates such as midbrain dopamine (DA) neurons. We have recently demonstrated that transgenic expression of the nuclear orphan receptor Nurr1 is sufficient to drive dopaminergic differentiation of forebrain embryonic rat neural precursors in vitro. However, Nurr1-induced DA neurons exhibit immature neuronal morphologies and functional properties and are unable to induce behavioral recovery in rodent models of Parkinson's disease (PD). Here, we report on the identification of key genetic factors that drive morphological and functional differentiation of Nurr1-derived DA neurons. We show that coexpression of Nurr1, Bcl-XL, and Sonic hedgehog (SHH) or Nurr1 and the proneural bHLH factor Mash1 is sufficient to drive naive rat forebrain precursors into neurons exhibiting the biochemical, electrophysiological, and functional properties of DA neuron in vitro. On transplantation into the striatum of Parkinsonian rats, precursor cells engineered with Nurr1/SHH/Bcl-XL or Nurr1/Mash1 survived in vivo and differentiated into mature DA neurons that can reverse the behavioral deficits in the grafted animals.</P>
Kim, Yoon Seong,Choi, Dong Hee,Block, Michelle L.,Lorenzl, Stefan,Yang, Lichuan,Kim, Youn Jung,Sugama, Shuei,Cho, Byung Pil,Hwang, Onyou,Browne, Susan E.,Kim, Soo Yul,Hong, Jau‐,Shyong,Flint Bea Federation of American Society for Experimental Bi 2007 The FASEB Journal Vol.21 No.1
<P>Recent studies have demonstrated that activated microglia play an important role in dopamine (DA) neuronal degeneration in Parkinson disease (PD) by generating NADPH-oxidase (NADPHO)-derived superoxide. However, the molecular mechanisms that underlie microglial activation in DA cell death are still disputed. We report here that matrix metalloproteinase-3 (MMP-3) was newly induced and activated in stressed DA cells, and the active form of MMP-3 (actMMP-3) was released into the medium. The released actMMP-3, as well as catalytically active recombinant MMP-3 (cMMP-3) led to microglial activation and superoxide generation in microglia and enhanced DA cell death. cMMP-3 caused DA cell death in mesencephalic neuron-glia mixed culture of wild-type (WT) mice, but this was attenuated in the culture of NADPHO subunit null mice (gp91(phox-/-)), suggesting that NADPHO mediated the cMMP-3-induced microglial production of superoxide and DA cell death. Furthermore, in the N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-injected animal model of PD, nigrostriatal DA neuronal degeneration, microglial activation, and superoxide generation were largely attenuated in MMP-3-/- mice. These results indicate that actMMP-3 released from stressed DA neurons is responsible for microglial activation and generation of NADPHO-derived superoxide and eventually enhances nigrostriatal DA neuronal degeneration. Our results could lead to a novel therapeutic approach to PD.</P>
Lee, Ho Won,Singh, Thoudam Debraj,Lee, Sang‐,Woo,Ha, Jeoung‐,Hee,Rehemtulla, Alnawaz,Ahn, Byeong‐,Cheol,Jeon, Young Hyun,Lee, Jaetae Federation of American Society for Experimental Bi 2014 The FASEB Journal Vol.28 No.7
Natural killer (NK) cell-based immunotherapy is a promising strategy for cancer treatment, and caspase-3 is an important effector molecule in NK cell-mediated apoptosis in cancers. Here, we evaluated the antitumor effects of NK cell-based immunotherapy by serial noninvasive imaging of apoptosis using a caspase-3 sensor in mice with human glioma xenografts. Human glioma cells expressing both a caspase-3 sensor as a surrogate marker for caspase-3 activation and Renilla luciferase (Rluc) as a surrogate marker for cell viability were established and referred to as D54-CR cells. Human NK92 cells were used as effector cells. Treatment with NK92 cells resulted in a time-and effector number-dependent increase in bioluminescence imaging (BLI) activity of the caspase-3 sensor in D54-CR cells in vitro. Caspase-3 activation by NK92 treatment was blocked by Z-VAD treatment in D54-CR cells. Transfusion of NK92 cells induced an increase of the BLI signal by caspase-3 activation in a dose-and time-dependent manner in D54-CR tumor-bearing mice but not in PBS-treated mice. Accordingly, sequential BLI with the Rluc reporter gene revealed marked retardation of tumor growth in the NK92-treatment group but not in the PBS-treatment group. These data suggest that noninvasive imaging of apoptosis with a caspase-3 sensor can be used as an effective tool for evaluation of therapeutic efficacy as well as for optimization of NK cell-based immunotherapy.