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Articles by Y Shi
Total Records ( 27 ) for Y Shi
  B Huang , W Qin , B Zhao , Y Shi , C Yao , J Li , H Xiao and Y. Jin

MicroRNAs (miRNAs), which are a newly identified class of small single-stranded non-coding RNAs, regulate their target genes via post-transcriptional pathway. It has been proved that miRNAs play important roles in many biological processes. To better understand miRNA function on type 2 diabetes, we used an oligonucleotide microarray to monitor miRNA expression profiles of Goto–Kakizaki (GK) and Wistar rats' skeletal muscle. It was found that seven miRNAs were down-expressed and two miRNAs were over-expressed in the muscle of GK rats. Among them, miR-24 showed the most prominent change. p38 MAPK, which is a direct target of miR-24, also showed expression difference. All the data give a clue that miR-24 might be associated with diabetes through down-regulation of p38 MAPK.

  W Qin , B Zhao , Y Shi , C Yao , L Jin and Y. Jin

MicroRNAs (miRNAs) are a type of small non-coding RNAs that regulate cognate mRNA expressions at the post-transcriptional stage. Although several miRNAs are known to be involved in various biological processes, including developmental timing, patterning, embryogenesis, differentiation and organogenesis, growth control, and apoptosis, many target genes and the functions of most miRNAs are still unclear. Since there is only a partial complementarity between miRNAs and their targets in animal cells, it is difficult to identify the specific target genes for a given miRNA and elucidate its function. In this study, we confirmed that bone morphogenetic protein receptor II (BMPRII) is a direct target of miR-21, and also showed that the protein level of BMPRII correlates inversely with the amount of miR-21 in PC3 and Lncap cells. These findings suggest that miR-21 may have a potential role in regulating the malignancy and metastatic abilities of prostate cancer cells and in self-renewal of stem cells by regulating the expression of BMPRII.

  Y Xie , M Wu , R Song , J Ma , Y Shi , W Qin and Y. Jin

Regulatory T (Treg) cells are a subpopulation of T cells that not only prevent autoimmunity, but also control a wide range of T cell-dependent immune responses. Glucocorticoid treatment (dexamethasone, or Dex) has been reported to amplify IL-2-mediated selective in vivo expansion of Treg cells. We simultaneously administered Dex and IL-2 to the donor in a murine allogeneic lymphocyte transplantation model to expand functional suppressive CD4+CD25+FOXP3+ T cells in the graft and to raise the regulatory T cell/effector T cell (Treg/Teff) ratio to prevent graft-versus-host disease (GVHD). After combined treatment of the donor with Dex (5 mg/kg/day) and IL-2 (300,000 IU/mouse/day) for 3 days, grafts were subjected to flow cytometric analysis, and transplantation was carried out from male C57BL/6 mice to female BALB/c mice aged 8–12 weeks. Results showed that short-term simultaneous administration of Dex and IL-2 markedly expanded functional suppressive CD4+CD25+FOXP3+ T cells in the murine spleen. In this murine allogeneic transplantation model, the grafts from donors with Dex and IL-2 pre-treatment led to a longer survival time for the recipients than for the control group (median survival time > 60 day vs. 12 day, P = 0.0002). The ratio of Treg/Teff also increased remarkably (0.43 ± 0.15 vs. 0.14 ± 0.01, P = 0.01). This study demonstrated that co-stimulation with Dex and IL-2 selectively expanded functional CD4+CD25+FOXP3+ T cells in vivo, and that grafts from donors pre-treated with Dex and IL-2 led to longer survival time and greater suppression of GVHD after allogeneic transplantation. Thus, GVHD can be suppressed by the specific expansion of regulatory T cells with Dex and IL-2 in graft donors.

  J Yang , X Liu , J Yu , L Sheng , Y Shi , Z Li , Y Hu , J Xue , L Wu , Y Liang , J Xia and D. Liang

Gene therapy has emerged as a promising approach for the lethal disorder of Duchenne muscular dystrophy (DMD). Using a novel non-viral delivery system, the human ribosomal DNA (hrDNA) targeting vector, we targeted a minidystrophin-GFP fusion gene into the hrDNA locus of HT1080 cells with a high site-specific integrated efficiency of 10–5, in which the transgene could express efficiently and continuously. The minidystrophin-GFP fusion protein was easily found to localize on the plasma membrane of HT1080 cells, indicating its possible physiologic performance. Our findings showed that the hrDNA-targeting vector might be highly useful for DMD gene therapy study.

  A Watanabe , M. A Sohail , D. A Gomes , A Hashmi , J Nagata , F. S Sutterwala , S Mahmood , M. N Jhandier , Y Shi , R. A Flavell and W. Z. Mehal

The inflammasome is a cytoplasmic multiprotein complex that has recently been identified in immune cells as an important sensor of signals released by cellular injury and death. Analogous to immune cells, hepatic stellate cells (HSC) also respond to cellular injury and death. Our aim was to establish whether inflammasome components were present in HSC and could regulate HSC functionality. Monosodium urate (MSU) crystals (100 µg/ml) were used to experimentally induce inflammasome activation in LX-2 and primary mouse HSC. Twenty-four hours later primary mouse HSC were stained with -smooth muscle actin and visualized by confocal microscopy, and TGF-β and collagen1 mRNA expression was quantified. LX-2 cells were further cultured with or without MSU crystals for 24 h in a transwell chemotaxis assay with PDGF as the chemoattractant. We also examined inhibition of calcium (Ca2+) signaling in LX-2 cells treated with or without MSU crystals using caged inositol 1,4,5-triphosphate (IP3). Finally, we confirmed an important role of the inflammasome in experimental liver fibrosis by the injection of carbon tetrachloride (CCl4) or thioacetamide (TAA) in wild-type mice and mice lacking components of the inflammasome. Components of the inflammasome are expressed in LX-2 cells and primary HSC. MSU crystals induced upregulation of TGF-β and collagen1 mRNA and actin reorganization in HSCs from wild-type mice but not mice lacking inflammasome components. MSU crystals inhibited the release of Ca2+ via IP3 in LX-2 cells and also inhibited PDGF-induced chemotaxis. Mice lacking the inflammasome-sensing and adaptor molecules, NLRP3 and apoptosis-associated speck-like protein containing CARD, had reduced CCl4 and TAA-induced liver fibrosis. We concluded that inflammasome components are present in HSC, can regulate a variety of HSC functions, and are required for the development of liver fibrosis.

  R. P Sahu , R Zhang , S Batra , Y Shi and S. K. Srivastava

In our previous studies, we have shown that benzyl isothiocyanate (BITC) inhibits the growth of human pancreatic cancer cells by inducing apoptosis. In the present study, we demonstrate the activation of all the three (MAPK) family members [extracellular signal-regulated protein kinase (ERK), c-jun N-terminal kinase (JNK) and P38] in response to BITC treatment. Exposure of Capan-2 cells with varying concentrations of BITC for 24 h resulted in the phosphorylation (activation) of ERK at Thr202/Tyr204, JNK at Thr183/Tyr185 and P38 at Thr180/Tyr182, leading to the induction of apoptosis. Similar MAPK activation was also observed in MiaPaCa-2 cells in response to BITC treatment. However, normal human pancreatic ductal epithelial cells did not show the activation of MAPK's and remained unaffected by BITC treatment. To confirm the role of ERK, JNK and P38 in BITC-induced G2/M arrest and apoptosis, Capan-2 cells were pre-treated with MAPK-specific inhibitors or MAPK8-short hairpin RNA (shRNA) prior to BITC treatment. Significant protection from BITC-induced G2/M arrest was observed in the cells pre-treated with MAPK kinase (MEK-1) but not JNK or P38 inhibitors. On the other hand, BITC-induced apoptosis was almost completely abrogated in the cells pre-treated with MEK-1, JNK or P38 inhibitors. Similarly, MAPK8-shRNA also offered almost complete protection against BITC-induced G2/M arrest and apoptosis. Furthermore, we observed that BITC treatment leads to the generation of reactive oxygen species (ROS) in Capan-2 and MiaPaCa-2 cells, which in part was orchestrated by depletion of reduced glutathione (GSH) level. Blocking ROS generation with N-acetyl-L-cysteine (NAC) significantly prevented GSH depletion and activation of ERK and JNK but not P38. Further, NAC or tiron prevented G2/M arrest by blocking G2/M regulatory proteins and completely protected the cells from BITC-induced apoptosis. Taken together, our results suggest that BITC-mediated G2/M arrest is mediated through ERK activation, whereas apoptosis is via ERK, JNK and P38.

  R Wakili , Y. H Yeh , X Yan Qi , M Greiser , D Chartier , K Nishida , A Maguy , L. R Villeneuve , P Boknik , N Voigt , J Krysiak , S Kaab , U Ravens , W. A Linke , G. J. M Stienen , Y Shi , J. C Tardif , U Schotten , D Dobrev and S. Nattel

Atrial fibrillation impairs atrial contractility, inducing atrial stunning that promotes thromboembolic stroke. Action potential (AP)-prolonging drugs are reported to normalize atrial hypocontractility caused by atrial tachycardia remodeling (ATR). Here, we addressed the role of AP duration (APD) changes in ATR-induced hypocontractility.

Methods and Results—

ATR (7-day tachypacing) decreased APD (perforated patch recording) by 50%, atrial contractility (echocardiography, cardiomyocyte video edge detection), and [Ca2+]i transients. ATR AP waveforms suppressed [Ca2+]i transients and cell shortening of control cardiomyocytes; whereas control AP waveforms improved [Ca2+]i transients and cell shortening in ATR cells. However, ATR cardiomyocytes clamped with the same control AP waveform had 60% smaller [Ca2+]i transients and cell shortening than control cells. We therefore sought additional mechanisms of contractile impairment. Whole-cell voltage clamp revealed reduced ICaL; ICaL inhibition superimposed on ATR APs further suppressed [Ca2+]i transients in control cells. Confocal microscopy indicated ATR-impaired propagation of the Ca2+ release signal to the cell center in association with loss of t-tubular structures. Myofilament function studies in skinned permeabilized cardiomyocytes showed altered Ca2+ sensitivity and force redevelopment in ATR, possibly due to hypophosphorylation of myosin-binding protein C and myosin light-chain protein 2a (immunoblot). Hypophosphorylation was related to multiple phosphorylation system abnormalities where protein kinase A regulatory subunits were downregulated, whereas autophosphorylation and expression of Ca2+-calmodulin-dependent protein kinase II and protein phosphatase 1 activity were enhanced. Recovery of [Ca2+]i transients and cell shortening occurred in parallel after ATR cessation.


Shortening of APD contributes to hypocontractility induced by 1-week ATR but accounts for it only partially. Additional contractility-suppressing mechanisms include ICaL current reduction, impaired subcellular Ca2+ signal transmission, and altered myofilament function associated with abnormal myosin and myosin-associated protein phosphorylation. The complex mechanistic basis of the atrial hypocontractility associated with AF argues for upstream therapeutic targeting rather than interventions directed toward specific downstream pathophysiological derangements.

  S Honda , Z. A Lewis , M Huarte , L. Y Cho , L. L David , Y Shi and E. U. Selker

Transposable elements are common in genomes and must be controlled. Many organisms use DNA methylation to silence such selfish DNA, but the mechanisms that restrict the methylation to appropriate regions are largely unknown. We identified a JmjC domain protein in Neurospora, DNA METHYLATION MODULATOR-1 (DMM-1), that prevents aberrant spreading of DNA and histone H3K9 methylation from inactivated transposons into nearby genes. Mutation of a conserved residue within the JmjC Fe(II)-binding site abolished dmm-1 function, as did mutations in conserved cysteine-rich domains. Mutants defective only in dmm-1 mutants grow poorly, but growth is restored by reduction or elimination of DNA methylation using the drug 5-azacytosine or by mutation of the DNA methyltransferase gene dim-2. DMM-1 relies on an associated protein, DMM-2, which bears a DNA-binding motif, for localization and proper function. HP1 is required to recruit the DMM complex to the edges of methylated regions.

  Y Shi , R Buffenstein , D. A Pulliam and H. Van Remmen

The oxidative stress theory and its correlate the mitochondrial theory of aging are among the most studied and widely accepted of all hypotheses of the mechanism of aging. To date, most of the supporting evidence for these theories has come from investigations using common model organisms such as Caenorhabditis elegans, Drosophila melanogaster, and laboratory rodents. However, comparative data from a wide range of endotherms provide equivocal support as to whether oxidative stress is merely a correlate, rather than a determinant, of species’ maximum lifespan. The great majority of studies in this area have been devoted to the relationship between reactive oxygen species and maximal longevity in young adult organisms, with little emphasis on mitochondrial respiratory efficiency, age-related alterations in mitochondrial physiology or oxidative damage. The advantage of studying a broader spectrum of species is the broad range of virtually every biological phenotype/trait, such as lifespan, body weight and metabolic rate. Here we summarize the results from a number of comparative studies in an effort to correlate oxidant production and oxidative damage among many species with their maximal lifespan and briefly discuss the pitfalls and limitations. Based on current information, it is not possible to accept or dispute the oxidative stress theory of aging, nor can we exclude the possibility that private mechanisms might offer an explanation for the longevity of exceptionally long-lived animal models. Thus, there is need for more thorough and controlled investigations with more unconventional animal models for a deeper understanding of the role of oxidative stress in longevity.

  Q Niu , Z Huang , Y Shi , L Wang , X Pan and C. Hu

Objectives. To identify novel serum protein biomarkers and establish diagnostic pattern for rheumatoid arthritis (RA) by using proteomic technology. Methods. Serum proteomic spectra were generated by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) combined with weak cationic exchange magnetic beads. A training set of spectra, derived from analyzing sera from 22 patients with RA, 26 patients with other autoimmune diseases and 25 age- and sex-matched healthy volunteers, was used to train and develop a decision tree model with a machine learning algorithm called decision boosting. A blinded testing set, including 21 patients with RA, 24 patients with other autoimmune diseases and 25 healthy people, was used to examine the accuracy of the model. Results. A decision tree model was established, consisting of four potential protein biomarkers whose m/z values were 4966.88, 5065.3, 5636.97 and 7766.87, respectively. In validation test, the decision tree model could differentiate RA from other autoimmune diseases and healthy people with the sensitivity of 85.71% and specificity of 87.76%, respectively. Conclusions. The present data suggested that MALDI-TOF-MS combined with magnetic beads could screen and identify some novel serum protein biomarkers related to RA. The proteomic pattern based on the four candidate biomarkers is of value for laboratory diagnosis of RA.

  Z Huang , Y Shi , B Cai , L Wang , Y Wu , B Ying , L Qin , C Hu and Y. Li

Objectives. To discover novel potential biomarkers and establish a diagnostic pattern for SLE by using proteomic technology.

Methods. Serum proteomic spectra were generated by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) combined with weak cationic exchange magnetic beads. A training set of spectra, derived from analysing sera from 32 patients with SLE, 43 patients with other autoimmune diseases and 43 age- and sex-matched healthy volunteers, was used to train and develop a decision tree model with a machine learning algorithm called decision boosting. A blinded testing set, including 32 patients with SLE, 42 patients with other autoimmune diseases and 40 healthy people, was used to determine the accuracy of the model.

Results. The diagnostic pattern with a panel of four potential protein biomarkers of mass-to-charge (m/z) ratio 4070.09, 7770.45, 28 045.1 and 3376.02 could accurately recognize 25 of 32 patients with SLE, 36 of 42 patients with other autoimmune diseases and 36 of 40 healthy people.

Conclusions. The preliminary data suggested a potential application of MALDI-TOF MS combined with magnetic beads as an effective technology to profile serum proteome, and with pattern analysis, a diagnostic model comprising four potential biomarkers was indicated to differentiate individuals with SLE from RA, SS, SSc and healthy controls rapidly and precisely.

  J Das , G Ren , L Zhang , A. I Roberts , X Zhao , A. L.M Bothwell , L Van Kaer , Y Shi and G. Das

Interleukin (IL)-17–producing T helper (Th17) cells play a critical role in the pathophysiology of several autoimmune disorders. The differentiation of Th17 cells requires the simultaneous presence of an unusual combination of cytokines: IL-6, a proinflammatory cytokine, and transforming growth factor (TGF) β, an antiinflammatory cytokine. However, the molecular mechanisms by which TGF-β exerts its effects on Th17 cell differentiation remain elusive. We report that TGF-β does not directly promote Th17 cell differentiation but instead acts indirectly by blocking expression of the transcription factors signal transducer and activator of transcription (STAT) 4 and GATA-3, thus preventing Th1 and Th2 cell differentiation. In contrast, TGF-β had no effect on the expression of retinoic acid receptor–related orphan nuclear receptor t, a Th17-specific transcription factor. Interestingly, in Stat-6–/–T-bet–/– mice, which are unable to generate Th1 and Th2 cells, IL-6 alone was sufficient to induce robust differentiation of Th17 cells, whereas TGF-β had no effect, suggesting that TGF-β is dispensable for Th17 cell development. Consequently, BALB/c Stat-6–/–T-bet–/– mice, but not wild-type BALB/c mice, were highly susceptible to the development of experimental autoimmune encephalomyelitis, which could be blocked by anti–IL-17 antibodies but not by anti–TGF-β antibodies. Collectively, these data provide evidence that TGF-β is not directly required for the molecular orchestration of Th17 cell differentiation.

  S Zhu , W Pan , P Shi , H Gao , F Zhao , X Song , Y Liu , L Zhao , X Li , Y Shi and Y. Qian

Interleukin 17 (IL-17) plays critical roles in the pathogenesis of various autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE). How the signals triggered by this powerful inflammatory cytokine are controlled to avoid abnormal inflammatory responses is not well understood. In this study, we report that TRAF3 is a receptor proximal negative regulator of IL-17 receptor (IL-17R) signaling. TRAF3 greatly suppressed IL-17–induced NF-B and mitogen-activated protein kinase activation and subsequent production of inflammatory cytokines and chemokines. Mechanistically, the binding of TRAF3 to IL-17R interfered with the formation of the receptor signaling activation complex IL-17R–Act1–TRAF6, resulting in suppression of downstream signaling. TRAF3 markedly inhibited IL-17–induced expression of inflammatory cytokine and chemokine genes in vivo and consequently delayed the onset and greatly reduced the incidence and severity of EAE. Thus, TRAF3 is a negative regulator of IL-17R proximal signaling.

  Y Shi , K Porter , N Parameswaran , H. K Bae and J. J. Pestka

The trichothecene mycotoxin deoxynivalenol (DON) induces systemic expression of the interleukin-6 (IL-6) and other proinflammatory cytokines in the mouse. The purpose of this study was to test the hypothesis that DON triggers an endoplasmic reticulum (ER) stress response in murine macrophages capable of driving IL-6 gene expression. DON at concentrations up 5000 ng/ml. was not cytotoxic to peritoneal cells. However, DON markedly decreased protein levels but not the mRNA levels of glucose-regulated protein (GRP) 78 (BiP), a chaperone known to mediate ER stress. Inhibitor studies suggested that DON-induced GRP78 degradation was cathepsin and calpain dependent but was proteosome-independent. RNAi-mediated knockdown of GRP78 resulted in increased IL-6 gene expression indicating a potential downregulatory role for this chaperone. GRP78 is critical to the regulation of the two transcription factors, X-box binding protein 1 (XBP1) and activating transcription factor 6 (ATF6), which bind to cAMP-response element (CRE) and drive expression of CRE-dependent genes such as IL-6. DON exposure was found to increase IRE1 protein, its modified products spliced XBP1 mRNA and XBP1 protein as well as ATF6. Knockdown of ATF6 but not XBP1 partially inhibited DON-induced IL-6 expression in the macrophages. Three other trichothecenes (satratoxin G, roridin, T-2 toxin) and the ribosome inhibitory protein ricin were also found to induce GRP78 degradation suggesting that other translation inhibitors might evoke ER stress. Taken together, these data suggest that in the macrophage DON induces GRP78 degradation and evokes an ER stress response that could contribute, in part, to DON-induced IL-6 gene expression.

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