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 Human Immunology. doi:10.1016/j.humimm.2015.09.033. Epub 2015 Sep 30..
 Functional relevance for type 1 diabetes mellitus-associated genetic variants by using integrative analyses 
 
  Abstract
Type 1 diabetes mellitus (type 1 DM) is an autoimmune disease. Although genome-wide association studies (GWAS) and meta-analyses have successfully identified numerous type 1 DM-associated susceptibility loci, the underlying mechanisms for these susceptibility loci are currently largely unclear.
   

  ✔本篇論文使用華聯產品:Mouse OneArray  
 Scientific Reports. 2015, ;5:12061. doi: 10.1038/srep12061.
 Nogo-B protects mice against lipopolysaccharide-induced acute lung injury
 
 
 Wujian Xu, Ying Zhu, Yunye Ning, Yuchao Dong, Haidong Huang, Wei Zhang, Qinying Sun, Qiang Li
  Abstract
Nogo-B, a member of the reticulon 4 protein family, plays a critical role in tissue repair and acute inflammation. Its role in acute lung injury (ALI) remains unclear. Here, we assessed the function of Nogo-B during tissue injury in a lipopolysaccharide (LPS)-induced ALI mouse model. We found that pulmonary Nogo-B was significantly repressed after LPS instillation in C57BL/6 mice. Over-expression of pulmonary Nogo-B using an adenovirus vector carrying the Nogo-B-RFP-3flag gene (Ad-Nogo-B) significantly prolonged the survival of mice challenged with a lethal dose of LPS. The Ad-Nogo-B-treated mice also had less severe lung injury, less alveolar protein exudation, and a higher number of macrophages but less neutrophil infiltration compared with Ad-RFP-treated mice. Interestingly, microarray analysis showed that the Ad-Nogo-B-treated mice had different gene expression profiles compared with the controls and the prominent expression of genes related to wound healing and the humoral immune response after LPS induction. Of the 49 differently expressed genes, we found that the expression of PTX3 was significantly up-regulated following Nogo-B over-expression as observed in lung tissues and RAW264.7 cells. In conclusion, Nogo-B plays a protective role against LPS-induced ALI, and this effect might be exerted through the modulation of alveolar macrophage recruitment and PTX3 production.
   

  ✔本篇論文使用華聯產品:Mouse OneArray  
 Journal of Allergy and Clinical Immunology. 2015, 136(1):59-68.e14. doi: 10.1016/j.jaci.2014.11.037.
 Persistence of asthma requires multiple feedback circuits involving type 2 innate lymphoid cells and IL-33
 
 
 Christianson CA, Goplen NP, Zafar I, Irvin C, Good JT Jr, Rollins DR, Gorentla B, Liu W, Gorska MM, Chu H, Martin RJ, Rafeul Alam
  Abstract
BACKGROUND: Asthma in a mouse model spontaneously resolves after cessation of allergen exposure. We developed a mouse model in which asthma features persisted for 6 months after cessation of allergen exposure. OBJECTIVE: We sought to elucidate factors contributing to the persistence of asthma. METHODS: We used a combination of immunologic, genetic, microarray, and pharmacologic approaches to dissect the mechanism of asthma persistence. RESULTS: Elimination of T cells though antibody-mediated depletion or lethal irradiation and transplantation of recombination-activating gene (Rag1)(-/-) bone marrow in mice with chronic asthma resulted in resolution of airway inflammation but not airway hyperreactivity or remodeling. Elimination of T cells and type 2 innate lymphoid cells (ILC2s) through lethal irradiation and transplantation of Rag2(-/-)£^c(-/-) bone marrow or blockade of IL-33 resulted in resolution of airway inflammation and hyperreactivity. Persistence of asthma required multiple interconnected feedback and feed-forward circuits between ILC2s and epithelial cells. Epithelial IL-33 induced ILC2s, a rich source of IL-13. The latter directly induced epithelial IL-33, establishing a positive feedback circuit. IL-33 autoinduced, generating another feedback circuit. IL-13 upregulated IL-33 receptors and facilitated IL-33 autoinduction, thus establishing a feed-forward circuit. Elimination of any component of these circuits resulted in resolution of chronic asthma. In agreement with the foregoing, IL-33 and ILC2 levels were increased in the airways of asthmatic patients. IL-33 levels correlated with disease severity. CONCLUSIONS: We present a critical network of feedback and feed-forward interactions between epithelial cells and ILC2s involved in maintaining chronic asthma. Although T cells contributed to the severity of chronic asthma, they were redundant in maintaining airway hyperreactivity and remodeling.
   

  ✔本篇論文使用華聯產品:Mouse OneArray  
 OncoImmunology. 2015 Apr 16. doi:10.1080/2162402X.2015.1040215.
 Blockade of TNF-£ signaling benefits cancer therapy by suppressing effector regulatory T cell expansion
 
 
 Li-Yuan Chang, Yung-Chang Lin, Jy-Ming Chiang, Jayashri Mahalingam, Shih-Huan Su, Ching-Tai Huang, Wei-Ting Chen, Chien-Hao Huang, Wen-Juei Jeng, Yi-Cheng Chen, Shi-Ming Lin, I-Shyan Sheen, Chun-Yen Lin
  Abstract
Effector but not naïve regulatory T cells (Treg cells) can accumulate in the peripheral blood as well as the tumor microenvironment, expand during tumor progression and be one of the main suppressors for anti-tumor immunity. However, the underlying mechanisms for effector Treg cell expansion in tumor are still unknown. We demonstrate that effector Treg cell-mediated suppression of anti-tumor CD8+ T cells is tumor non-specific. Furthermore, TNFR2 expression is increased in these Treg cells by Affymetrix chip analysis which was confirmed by monoclonal antibody staining in both hepatocellular carcinoma and colorectal cancer patients and murine models. Correspondingly, increased levels of TNF-£ in both tissue and serum were also demonstrated. Interestingly, TNF-£ could not only expand effector Treg cells through TNFR2 signaling, but also enhanced their suppressive activity against anti-tumor immunity of CD8+ T cells. Furthermore, targeting TNFR2 signaling with a TNF-£ inhibitor could selectively reduce rapid resurgence of effector Treg cells after cyclophosphamide-induced lymphodepletion and markedly inhibit the growth of established tumors. Herein, we propose a novel mechanism in which TNF-£ could promote tumor-associated effector Treg cell expansion and suggest a new cancer immunotherapy strategy using TNF-£ inhibitors to reduce effector Treg cells expansion after cyclophosphamide-induced lymphodepletion.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 Amino Acids. 2015, 47(7):1319-39. doi: 10.1007/s00726-015-1956-7.
 Homocysteine thiolactone and N -homocysteinylated protein induce pro-atherogenic changes in gene expression in human vascular endothelial cells
 
 
 Dorota Gurda, Luiza Handschuh, Weronika Kotkowiak, Hieronim Jakubowski
  Abstract
Genetic or nutritional deficiencies in homocysteine (Hcy) metabolism lead to hyperhomocysteinemia (HHcy) and cause endothelial dysfunction, a hallmark of atherosclerosis. In addition to Hcy, related metabolites accumulate in HHcy but their role in endothelial dysfunction is unknown. Here, we examine how Hcy-thiolactone, N-Hcyprotein, and Hcy affect gene expression and molecular pathways in human umbilical vein endothelial cells. We used microarray technology, real-time quantitative polymerase chain reaction, and bioinformatic analysis with PANTHER, DAVID, and Ingenuity Pathway Analysis (IPA) resources. We identified 47, 113, and 30 mRNAs regulated by N-Hcyprotein, Hcy-thiolactone, and Hcy, respectively, and found that each metabolite induced a unique pattern of gene expression. Top molecular pathways affected by Hcy-thiolactone were chromatin organization, one-carbon metabolism, and lipid-related processes [−log(P value) = 20¡V31]. Top pathways affected by N-Hcy-protein and Hcy were blood coagulation, sulfur amino acid metabolism, and lipid metabolism [−log(P value)] = 4¡V11; also affected by Hcythiolactone, [−log(P value) = 8¡V14]. Top disease related to Hcy-thiolactone, N-Hcy-protein, and Hcy was ¡¥atherosclerosis, coronary heart disease¡¦ [−log(P value) = 9¡V16].Top-scored biological networks affected by Hcy-thiolactone (score = 34¡V40) were cardiovascular disease and function; those affected by N-Hcy-protein (score = 24¡V35) were ¡¥small molecule biochemistry, neurological disease,¡¦ and ¡¥cardiovascular system development and function¡¦; and those affected by Hcy (score = 25¡V37) were ¡¥amino acid metabolism, lipid metabolism,¡¦ ¡¥cellular movement, and cardiovascular and nervous system development and function.¡¦These results indicate that each Hcy metabolite uniquely modulates gene expression in pathways important for vascular homeostasis and identify new genes and pathways that are linked to HHcy-induced endothelial dysfunction and vascular disease.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 The Journal of Immunology. 2015, 194(3):1292-303. doi: 10.4049/jimmunol.1402593.
 The Endoplasmic Reticulum Adaptor Protein ERAdP Initiates NK Cell Activation via the Ubc13-Mediated NF-£eB Pathway
 
 
 Jun Chen, Lu Hao, Chong Li, Buqing Ye, Ying Du, Honglian Zhang, Bo Long, Pingping Zhu, Benyu Liu, Liuliu Yang, Peifeng Li, Yong Tian, Zusen Fan
  Abstract
NK cells play a pivotal role in innate immune responses against pathogenic infections. However, the underlying mechanisms driving defined NK functions remain largely elusive. In this study, we identified a novel endoplasmic reticulum (ER) membrane protein, ER adaptor protein (ERAdP), which is constitutively expressed in human and mouse NK cells. ERAdP is expressed at low levels in peripheral NK cells of hepatitis B virus-associated hepatocellular carcinoma patients. We show that ERAdP initiates NK cell activation through the NF-£eB pathway. Notably, ERAdP interacts with ubiquitin-conjugating enzyme 13 (Ubc13) to potentiate its charging activity. Thus, ERAdP augments Ubc13-mediated NF-£eB essential modulator ubiquitination to trigger the Ubc13-mediated NF-£eB pathway, leading to NK cell activation. Finally, ERAdP transgenic mice display hyperactivated NK cells that are more resistant to pathogenic infections. Therefore, understanding the mechanism of ERAdP-mediated NK cell activation will provide strategies for treatment of infectious diseases.
   

  ✔本篇論文使用華聯產品:Human miRNA OneArray  
 Neurobiology of Aging. 2015, 36(3):1356-68. doi: 10.1016/j.neurobiolaging.2014.11.020.
 The CCAAT/enhancer-binding protein delta/miR135a/thrombospondin 1 axis mediates PGE2-induced angiogenesis in Alzheimer's disease
 
 
 Chiung-Yuan Ko, Yu-Yi Chu, Shuh Narumiya, Jhih-Ying Chi, Tomoyuki Furuyashiki, Tomohiro Aoki, Shao-Ming Wang, Wen-Chang Chang, Ju-Ming Wang
  Abstract
In Alzheimer's disease (AD), large populations of endothelial cells undergo angiogenesis due to brain hypoxia and inflammation. Substantial evidence from epidemiologic, pathologic, and clinical reports suggests that vascular factors are critical for the pathogenesis of AD. However, the precise mechanistic correlation between inflammation and angiogenesis in AD has not been well elucidated. Prostaglandin E2 (PGE2), a key factor of the inflammatory response, has been known to promote angiogenesis. In this study, we demonstrated that PGE2 acts through EP4 receptor and protein kinase A to modulate CCAAT/enhancer-binding protein delta (CEBPD) abundance in astrocytes. Attenuated vessel formation was observed in the brains of AppTg/Cebpd(-/-) mice. We showed that miR135a was responsive to the induction of CEBPD and further negatively regulated thrombospondin 1 (THBS1) transcription by directly targeting its 3'-untranslated region (3'UTR) in astrocytes. Furthermore, conditioned media from astrocytes expressing miR135a promoted Human umbilical vein endothelial cells (HUVECs) tube-like formation, which correlated with the effects of PGE2 on angiogenesis. Our results indicated that CEBPD contributes to the repression of THBS1 transcription by activating the expression of miR135a in astrocytes following PGE2 treatment. We provided new evidence that astrocytic CEBPD increases angiogenesis during AD pathogenesis. This discovery supports the negative influence of CEBPD activation in astrocytes with respect to AD pathogenesis and implies that the CEBPD/miR135a/THBS1 axis could be a therapeutic target of AD.
   

  ✔本篇論文使用華聯產品:Mouse OneArray  
 PLoS One. 2015, 10(4):e0124504. doi: 10.1371/journal.pone.0124504. eCollection 2015.
 Transcriptional Modulation of Intestinal Innate Defense/Inflammation Genes by Preterm Infant Microbiota in a Humanized Gnotobiotic Mouse Model
 
 
 Lei Lu, Yueyue Yu, Yuee Guo, Yunwei Wang, Eugene B. Chang, Erika C. Claud
  Abstract
Background and Aims: It is known that postnatal functional maturation of the small intestine is facilitated by microbial colonization of the gut. Preterm infants exhibit defects in gut maturation, weak innate immunity against intestinal infection and increased susceptibility to inflammatory disorders, all of which may be related to the inappropriate microbial colonization of their immature intestines. The earliest microbes to colonize the preterm infant gut encounter a naïve, immature intestine. Thus this earliest microbiota potentially has the greatest opportunity to fundamentally influence intestinal development and immune function. The aim of this study was to characterize the effect of early microbial colonization on global gene expression in the distal small intestine during postnatal gut development. Methods: Gnotobiotic mouse models with experimental colonization by early (prior to two weeks of life) intestinal microbiota from preterm human infants were utilized. Microarray analysis was used to assess global gene expression in the intestinal epithelium. Results and Conclusion: Multiple intestinal genes involved in metabolism, cell cycle regulation, cell-cell or cell-extracellular matrix communication, and immune function are developmental- and intestinal microbiota- regulated. Using a humanized gnotobiotic mouse model, we demonstrate that certain early preterm infant microbiota from prior to 2 weeks of life specifically induce increased NF-£eB activation and a phenotype of increased inflammation whereas other preterm microbiota specifically induce decreased NF-£eB activation. These fundamental differences correlate with altered clinical outcomes and suggest the existence of optimal early microbial communities to improve health outcomes.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 Evidence-Based Complementary and Alternative Medicine. 2014 Jan 8.
 Gene Expression Profiles Underlying Selective T-Cell-Mediated Immunity Activity of a Chinese Medicine Granule on Mice Infected with Influenza Virus H1N1
 
 
 Na-na Lu, Qi Liu, Shi-jie Ge, JunWu, Qiu Ze-ji, Ze-ji Qiu, Hong-chun Zhang, En-xiang Chao, and Zhuo-nan Yu, Li-gang Gu
  Abstract
A Chinese medicine granule, Shu-Feng-Xuan-Fei (SFXF), is critical for viral clearance in early phase of influenza virus infection. In this study, 72 ICR mice were randomly divided into six groups: normal control group, virus control group, Oseltamivir group, low-dose SFXF, medium-dose SFXF, and high-dose SFXF. Mice were anesthetized and inoculated with 4LD50 of influenza virus A (H1N1) except normal control group. Oseltamivir group received 11.375 mg¡Pkg−1¡Pd−1 Oseltamivir Phosphate. SFXF 3.76, 1.88 and 0.94 g¡Pkg−1¡Pd−1 were administrated to mice in all SFXF groups. Each group was in equal dose of 0.2ml daily for 4 consecutive days. Mice were sacrificed and then total RNA was extracted in lung tissue. Some genes involved in T-cell-mediated immunity were selected by DNA microarray. These candidate genes were verified by Real-Time PCR and western immunoblotting. Compared with virus control group, in Toll-like receptor signaling pathway, 12 virus-altered genes were significantly reduced following medium-dose SFXF treatment. Eighteen antigen processing presentation-associated genes were upregulated by medium-dose SFXF. In the process of T cell receptor signaling pathway, 19 genes were downregulated by medium-dose SFXF treatment. On exploration into effector T cells activation and cytokines, all of altered genes in virus control group were reversed by medium-dose SFXF. Real-time PCR and western immunoblotting showed that the regulation of medium-dose SFXF in IL-4, IFN-, TNF-, IL-1, TLR7, MyD88, p38, and JNK was superior to Oseltamivir and high-dose SFXF group. Therefore, SFXF granules could reduce influenza infected cells and activation of T cells.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 Journal of Diabetes Research. 2013:589451. doi: 10.1155/2013/589451.
 The effect of diabetes-associated autoantigens on cell processes in human PBMCs and their relevance to autoimmune diabetes development.
 
 
 Radek Blatny, Zbynek Halbhuber, Michal Kolar, Ales Neuwirth, Lenka Petruzelkova, Tereza Ulmannova, Stanislava Kolouskova, Zdenek Sumnik, Pavlina Pithova, Maria Krivjanska, Dominik Filipp, Katerina Stechova, Jana Vcelakova
  Abstract
Type 1 Diabetes (T1D) is considered to be a T-helper- (Th-) 1 autoimmune disease; however, T1D pathogenesis likely involves many factors, and sufficient tools for autoreactive T cell detection for the study of this disease are currently lacking. In this study, using gene expression microarrays, we analysed the effect of diabetes-associated autoantigens on peripheral blood mononuclear cells (PBMCs) with the purpose of identifying (pre)diabetes-associated cell processes. Twelve patients with recent onset T1D, 18 first-degree relatives of the TD1 patients (DRL; 9/18 autoantibody positive), and 13 healthy controls (DV) were tested. PBMCs from these individuals were stimulated with a cocktail of diabetes-associated autoantigens (proinsulin, IA-2, and GAD65-derived peptides). After 72 hours, gene expression was evaluated by high-density gene microarray. The greatest number of functional differences was observed between relatives and controls (69 pathways), from which 15% of the pathways belonged to ¡§immune response-related¡¨ processes. In the T1D versus controls comparison, more pathways (24%) were classified as ¡§immune response-related.¡¨ Important pathways that were identified using data from the T1D versus controls comparison were pathways involving antigen presentation by MHCII, the activation of Th17 and Th22 responses, and cytoskeleton rearrangement-related processes. Genes involved in Th17 and TGF-beta cascades may represent novel, promising (pre)diabetes biomarkers.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 Journal of Biological Chemistry . 2013 Dec 23.
 Anthrax Lethal Toxin Inhibits Translation of Hypoxia Inducible Factor 1£ and Causes Decreased Tolerance to Hypoxic Stress
 
 
 Weiming Ouyang, Chikako Torigoe, Hui Fang, Tao Xie, David M. Frucht
  Abstract
Hypoxia is considered to be a contributor to the pathology associated with administration of anthrax lethal toxin (LT). However, we herein report that serum lactate levels in LT-treated mice are reduced, a finding inconsistent with the anaerobic metabolism expected to occur during hypoxia. Reduced lactate levels are also observed in the culture supernatants of LT-treated cells. LT inhibits the accumulation of hypoxia inducible factor (HIF)-1£, a subunit of HIF-1, the master regulator directing cellular responses to hypoxia. The toxin has no effect on the transcription or protein turnover of HIF-1£, but instead acts to inhibit HIF-1£ translation. LT treatment diminishes phosphorylation of eIF4B, eIF4E, and rpS6, critical components of the intracellular machinery required for HIF-1£ translation. Moreover, blockade of MKK1/2-Erk1/2, but not p38 or JNK signaling lowers HIF-1£ protein levels in both normoxic and hypoxic conditions, consistent with a role for MKK1 and MKK2 as the major targets of LT responsible for the inhibition of HIF-1£ translation. The physiological importance of the LT-induced translation blockade is demonstrated by the finding that LT treatment decreases the survival of hepatocyte cell lines grown in hypoxic conditions, an effect that is overcome by pre-induction of HIF-1£. Taken together, these data support a role for LT in dysregulating HIF-1£ and thereby disrupting homeostatic responses to hypoxia, an environmental characteristic of certain tissues at baseline and/or during disseminated infection with Bacillus anthracis.
   

  ✔本篇論文使用華聯產品:Mouse OneArray  
 Cancer Research. 2013 Dec 9.
 Immune chaperone gp96 drives the contributions of macrophages to inflammatory colon tumorigenesis
 
 
 Crystal Morales, Saleh Rachidi, Feng Hong, Shaoli Sun, Xinshou Ouyang, Caroline Wallace, Yongliang Zhang, Elizabeth Garret-Mayer, Jennifer Wu, Bei Liu, Zihai Li
  Abstract
Macrophages are important drivers in the development of inflammation-associated colon cancers, but the mechanistic underpinnings for their contributions are not fully understood. Further, Toll-like receptors (TLR) have been implicated in colon cancer, but their relevant cellular sites of action are obscure. In this study, we show that the endoplasmic reticulum chaperone gp96 is essential in tumor-associated macrophages (TAM) to license their contributions to inflammatory colon tumorigenesis. Mice where gp96 was genetically deleted in a macrophage-specific manner exhibited reduced colitis and inflammation-associated colon tumorigenesis. Attenuation of colon cancer in these mice correlated strikingly with reduced mutation rates of £]-catenin, increased efficiency of the DNA repair machinery and reduced expression of pro-inflammatory cytokines, including IL-17 and IL-23 in the tumor microenvironment. The genotoxic nature of TAM-associated inflammation was evident by increased expression of genes in the DNA repair pathway. Our work deepens understanding of how TAM promote oncogenesis by altering the molecular oncogenic program within epithelial cells, and it identifies gp96 as a lynchpin chaperone needed in TAM to license their function and impact on expression of critical inflammatory cytokines in colon tumorigenesis.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 Evidence-Based Complementary and Alternative Medicine. 2013 Nov 18.
 Gene Expression Profiles Underlying Selective T Cell-mediated Immunity Activity of a Chinese Medicine Granule on Mice Infected with Influenza Virus H1N1
 
 
 Lu Na-na, Liu Qi, Ge Shi-jie, Wu Jun, Qiu Ze-ji, Zhang Hong-chun, Zhao En-xiang, Zhang Yi, Yu Zhuo-nan, Gu Li-gang
  Abstract
Background.Efficacy of a Chinese medicine granule, Shu-Feng-Xuan-Fei (SFXF) has been demonstrated in reducing the duration of fever among patients with influenza. SFXF has also been found efficacious in reducing lung index and pathological lesion and regulating natural killer (NK) cell mediated cytotoxicity in pneumonia mice infected with influenza virus. Yet the effects of SFXF on viral infection in T cell-mediated immunity at the gene transcriptional level have never been reported.Objective.To elucidatethe effectsof SFXF on the major pathways and genes involved in T-cell mediated immunity in the lung of mice subjected toinfluenza virus H1N1 infection. Methods.Seventy-two ICR mice were randomly divided into six groups (n=12): normal control group (N), virus control group (M), Oseltamivirgroup, low-dose SFXF(SL), medium-dose SFXF(SM) and high-dose SFXF(SH). Mice were anesthetized with 2, 2, 2-tribromoethanol in tert-amyl alcohol and inoculated (i.n.) with 4LD50 of virus except normal control group. Oseltamivir groupreceived 11.375 mg•kg-1•d-1Oseltamivir Phosphate. SFXF 3.76, 1.88 and 0.94 g•kg-1•d-1were administrated to mice in all SFXF groups by gastric perfusion. Each group was in equal dose of 0.2ml daily for 4 consecutive days. Mice were sacrificed and then total RNA were extracted in lung tissue. Some genes involved in T cell-mediated immunity were selected by DNA microarray. These candidate genes were verified by Real-Time PCR and western immunoblotting. Results. Compared with virus control group, in Toll-like receptor signaling pathway, 12 virus-altered genes were significantly reduced following the medium-dose SFXF treatment. Eighteen antigen processing presentation-associated genes were up-regulated by medium-dose SFXF, among which 13 genes and 5 genes belong to MHC-I and MHC-II family respectively. In the process of T cell receptor signaling pathway, 19 genes were down-regulated by the medium-dose SFXF treatment. Exploration into effector T cells activation and cytokines, all of altered genes in virus control group were reversed by the medium-dose SFXF. Real-time PCR and western immunoblotting showed the regulation of the medium-dose SFXF in IL-4, IFN-, TNF-, IL-1, TLR7, MyD88, p38 and JNKwas superior to Oseltamivir and high-dose SFXF group. As expected, real-time PCR and western immunoblotting data were consistent with the results of microarray assay. Conclusion. Viral replication was found to have been prevented and the viral infection was eliminated with exposure to SFXF granules. The mechanism could be through the reduction of influenzainfected cells and activationof T cells. This immunomodulation effects could be realized by regulating gene expressions of T cells activation. Thus, SFXF could help to restore a balance of the host immune system, which may be critical for viral clearance in early phase of influenza virus infection.
   

  ✔本篇論文使用華聯產品:Mouse OneArray  
 Cellular Microbiology. 2013 Sep 17. doi: 10.1111/cmi.12216.
 Streptococcal co-infection augments Candida pathogenicity by amplifying the mucosal inflammatory response
 
 
 Xu H, Sobue T, Thompson A, Xie Z, Poon K, Ricker A, Cervantes J, Diaz PI, Dongari-Bagtzoglou A
  Abstract
Mitis-group streptococci are ubiquitous oral commensals that can promote polybacterial biofilm virulence. Using a novel murine oral mucosal co-infection model we sought to determine for the first time whether these organisms promote the virulence of C. albicans mucosal biofilms in oropharyngeal infection and explored mechanisms of pathogenic synergy. We found that Streptococcus oralis colonization of the oral and gastrointestinal tract was augmented in the presence of C. albicans. S. oralis and C. albicans co-infection significantly augmented the frequency and size of oral thrush lesions. Importantly, S. oralis promoted deep organ dissemination of C. albicans. Whole mouse genome tongue microarray analysis showed that when compared with animals infected with one organism, the doubly infected animals had genes in the major categories of neutrophilic response/chemotaxis/inflammation significantly upregulated, indicative of an exaggerated inflammatory response. This response was dependent on TLR2 signalling since oral lesions, transcription of pro-inflammatory genes and neutrophil infiltration, were attenuated in TLR2-/- animals. Furthermore, S. oralis activated neutrophils in a TLR2-dependent manner in vitro. In summary, this study identifies a previously unrecognized pathogenic synergy between oral commensal bacteriaand C. albicans. This is the first report of the ability of mucosal commensal bacteria to modify the virulence of an opportunistic fungal pathogen.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 The Journal of Infectious Diseases. 2013 Sep 16.
 IL-22 inhibits intracellular growth of Mycobacterium tuberculosis by enhancing calgranulin A expression
 
 
 Rohan Dhiman, Sambasivan Venkatasubramanian, Padmaja Paidipally, Peter F. Barnes, Amy Tvinnereim, Ramakrishna Vankayalapati
  Abstract
Previously, we found that IL-22 inhibits intracellular growth of Mycobacterium tuberculosis (M. tb) in human monocyte-derived macrophages (MDMs). In the current study we determined the mechanisms underlying these effects. We found W7, a phagolysosomal fusion inhibitor abrogates IL-22-dependent M. tb growth inhibition in MDMs, suggesting that IL-22 acts through enhanced phagolysosomal fusion. Our microarray analysis indicated that rIL-22 enhances the expression of an intracellular signaling molecule calgranulin A. This was confirmed by real time PCR, western blot and by confocal microscopy. Calgranulin A siRNA abrogated rIL-22-dependent growth inhibition of M. tb in MDMs. IL-22 enhanced Rab7 expression and down regulated Rab14 expression of M. tb-infected MDMs, and these effects were reversed by calgranulin A siRNA. These results suggest that M. tb growth inhibition by IL-22 depends on calgranulin A and enhanced phagolysosomal fusion, which is associated with increased Rab7 and reduced Rab14 expression.
   

  ✔本篇論文使用華聯產品:Mouse&Rat miRNA OneArray  
 Journal of Biomedical Science. 2013, 20(1):64.
 Profiling circulating microRNA expression in a mouse model of nerve allotransplantation
 
 
 Cheng-Shyuan Rau, Johnson Chia-Shen Yang, Shao-Chun Wu, Yi-Chun Chen, Tsu-Hsiang Lu, Ming-Wei Lin, Yi-Chan Wu, Siou-Ling Tzeng, Chia-Jung Wu, Ching-Hua Hsieh
  Abstract
Background: The lack of noninvasive biomarkers of rejection remains a challenge in the accurate monitoring of deeply buried nerve allografts and precludes optimization of therapeutic intervention. This study aimed to establish the expression profile of circulating microRNAs (miRNAs) during nerve allotransplantation with or without immunosuppression. Results: Balb/c mice were randomized into 3 experimental groups, that is, (1) untreated isograft (Balb/c¡÷Balb/c), (2) untreated allograft (C57BL/6¡÷Balb/c), and (3) allograft (C57BL/6¡÷Balb/c) with FK506 immunosuppression. A 1-cm Balb/c or C57BL/6 donor sciatic nerve graft was transplanted into sciatic nerve gaps created in recipient mice. At 1, 3, 7, 10, and 14 d after nerve transplantation, nerve grafts, whole blood, and sera were obtained for miRNA expression analysis with an miRNA array and subsequent validation with quantitative real-time PCR (qRT-PCR). Three circulating miRNAs (miR-320, miR-762, and miR-423-5p) were identified in the whole blood and serum of the mice receiving an allograft with FK506 immunosuppression, within 2 weeks after nerve allotransplantation. However, these 3 circulating miRNAs were not expressed in the nerve grafts. The expression of all these 3 upregulated circulating miRNAs significantly decreased at 2, 4, and 6 d after discontinuation of FK506 immunosuppression. In the nerve graft, miR-125-3b and miR-672 were significantly upregulated in the mice that received an allograft with FK506 only at 7 d after nerve allotransplantation. Conclusions: We identified the circulating miR-320, miR-762, and miR-423-5p as potential biomarkers for monitoring the immunosuppression status of the nerve allograft. However, further research is required to investigate the mechanism behind the dysregulation of these markers and to evaluate their prognostic value in nerve allotransplantation.
   

  ✔本篇論文使用華聯產品:Mouse OneArray  
 Evidence-Based Complementary and Alternative Medicine. 2013 May 8.
 Phytochemical shikonin stimulates epithelial¡Vmesenchymal transition (EMT) in skin wound-healing
 
 
 Shu-Yi Yin, An-Ping Peng, Li-Ting Huang, Ya-Ting Wang, Chun-Wen Lan, Ning-Sun Yang
  Abstract
Although various pharmacological activities of the shikonins have been documented, understanding of the hierarchical regulation of these diverse bio-activities at the genome level is unsubstantiated. In this study, through cross-examination between transcriptome and microRNA array analyses, we predicted that topical treatment of shikonin in vivo affects epithelial¡Vmesenchymal transition (EMT) and the expression of related microRNAs, including 200a, 200b, 200c, 141, 205 and 429 microRNAs, in mouse skin tissues. In situ immunohistological analyses further demonstrated that specific EMT regulatory molecules are enhanced in shikonin-treated epidermal tissues. RT-PCR analyses subsequently confirmed that shikonin treatment downregulated expression of microRNA-205 and other members of the 200 family microRNAs. Further, expression of two RNA targets of the 200 family microRNAs in EMT regulation, Sip1 (Zeb2) and Tcf8 (Zeb1), were consistently upregulated by shikonin treatment. Enhancement of these EMT activities was also detected in shikonin-treated wounds, which repaired faster than controls. These results suggest that topical treatment with shikonin can confer a potent stimulatory effect on EMT and suppress the expression of the associated microRNAs in skin wound-healing. These cellular and molecular evidences support our previous findings on the specific pharmacological effects of shikonin in wound-healing and immune-modulation.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 International Immunology. 2013 Feb 14. doi: 10.1093/intimm/dxs154.
 Transcriptome signature in young children with acute otitis media due to non-typeable Haemophilus influenzae
 
 
 Keyi Liu, Linlin Chen, Ravinder Kaur, Michael E. Pichichero
  Abstract
Non-typeable Haemophilus influenzae (NTHi) causes acute otitis media (AOM) in young children. In our recent paper in Microbes and Infection we described the transcriptome signature elicited from PBMCs at onset of AOM caused by Streptococcus pneumoniae. In the current study we found very different results with NTHi AOM infections; 5.1% of 29 187 genes were differentially regulated by more than 2-fold at the onset of AOM compared with the pre-infection healthy state in the same children. Among the 1487 transcripts, 100 genes associated with the immune defense response were specifically analyzed. About half of the differentially regulated genes associated with antibacterial activity and the cell-mediated immune response were activated and half were suppressed. The important signatures for NTHi in children suggested that the balance of the immune response was toward suppression. Moreover, 90% of the genes associated with a pro-inflammatory cytokine response were down-regulated. The genes associated with the classic complement pathway were down-regulated, although the alternative complement pathway genes were up-regulated. These results provide the first human transcriptome data identifying gene expression in the immune response to be predominantly down-regulated at the onset of AOM due to NTHi.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 Scandinavian Journal of Immunology. 2011 Sep 16. doi: 10.1111/j.1365-3083.2011.02637.x.
 Healthy First-Degree Relatives of Patients with Type 1 Diabetes Exhibit Significant Differences in Basal Gene Expression Pattern of Immunocompetent Cells Compared to Controls: Expression Pattern as Predeterminant of Autoimmune Diabetes
 
 
 M. Kolar, R. Blatny, Z. Halbhuber, J. Vcelakova, M. Hubackova, L. Petruzelkova, Z. Sumnik, B. Obermannova, P. Pithova, V. Stavikova, M. Krivjanska, A. Neuwirth, S. Kolouskova, D. Filipp, K. Stechova
  Abstract
Expression features of genetic landscape which predispose an individual to the type 1 diabetes are poorly understood. We addressed this question by comparing gene expression profile of freshly isolated peripheral blood mononuclear cells isolated from either patients with type 1 diabetes (T1D), or their firstdegree relatives or healthy controls. Our aim was to establish whether a distinct type of ¡¥prodiabetogenic¡¦ gene expression pattern in the group of relatives of patients with T1D could be identified. Whole-genome expression profile of nine patients with T1D, their ten first-degree relatives and ten healthy controls was analysed using the human high-density expression microarray chip. Functional aspects of candidate genes were assessed using the MetaCore software. The highest number of differentially expressed genes (547) was found between the autoantibody-negative healthy relatives and the healthy controls. Some of them represent genes critically involved in the regulation of innate immune responses such as TLR signalling and CCR3 signalling in eosinophiles, humoral immune reactions such as BCR pathway, costimulation and cytokine responses mediated by CD137, CD40 and CD28 signalling and IL-1 proinflammatory pathway. Our data demonstrate that expression profile of healthy relatives of patients with T1D is clearly distinct from the pattern found in the healthy controls. That especially concerns differential activation status of genes and signalling pathways involved in proinflammatory processes and those of innate immunity and humoral reactivity. Thus, we posit that the study of the healthy relative¡¦s gene expression pattern is instrumental for the identification of novel markers associated with the development of diabetes.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 PLOS ONE. 2012, 7(9):e45378. doi: 10.1371/journal.pone.0045378.
 Role of Macrophage CCAAT/Enhancer Binding Protein Delta in the Pathogenesis of Rheumatoid Arthritis in Collagen-Induced Arthritic Mice
 
 
 Ling-Hua Chang, Huei-Sheng Huang, Po-Ting Wu, I-Ming Jou, Min-Hsiung Pan, Wen-Chang Chang, Dennis Ding Hwa Wang, Ju-Ming Wang
  Abstract
BACKGROUND: The up-regulation of CCAAT/enhancer binding protein delta (CEBPD) has frequently been observed in macrophages in age-associated disorders, including rheumatoid arthritis (RA). However, the role of macrophage CEBPD in the pathogenesis of RA is unclear.METHODS: Differentially expressed genes were detected after four hours, one week and twelve weeks of supplementation with either fish oil (FO) or corn oil in normo- and dyslipidemic men using whole genome microarrays.Methodology and Principal Findings: We found that the collagen-induced arthritis (CIA) score and the number of affected paws in Cebpd-/- mice were significantly decreased compared with the wild-type (WT) mice. The histological analysis revealed an attenuated CIA in Cebpd-/- mice, as shown by reduced pannus formation and greater integrity of joint architecture in affected paws of Cebpd-/- mice compared with WT mice. In addition, immunohistochemistry analysis revealed decreased pannus proliferation and angiogenesis in Cebpd-/- mice compared with WT mice. CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions. CCL20, IL23A, CXCL1 and TNFAIP6 contributed to the migration and proliferation of synoviocytes, and the latter two proteins were involved in tube formation of endothelial cells. Finally, two anti-inflammatory chemicals, inotilone and rosmanol, reduced the expression of CEBPD and its downstream targets and mitigated the above phenomena. CONCLUSIONS: Collectively, our findings suggest that CEBPD and its downstream effectors could be biomarkers for the diagnosis of RA and potentially serve as therapeutic targets for RA therapy.
   

  ✔本篇論文使用華聯產品:Mouse OneArray,Rat OneArray  
 Inflammation Research. 2012, 61(12):1395-404. doi: 10.1007/s00011-012-0542-7.
 Mammalian target of rapamycin complex 2 regulates inflammatory response to stress
 
 
 Desmond Mascarenhas, Sheri Routt, Baljit K. Singh
  Abstract
To explore the role of mammalian target of rapamycin 2 (mTORC2) in the activation of inflammatory and oxidative responses in rodent models of acute injury and metabolic stress. The impact of nephrilin, an inhibitor of mTORC2 complex, was assessed in three CD-1 mouse models of acute xenobiotic stress and in a hypertensive Dahl rat model of metabolic stress. Animals received daily subcutaneous bolus injections of saline or 4 mg/kg nephrilin. Tissues were assayed by ELISA, gene arrays and immunohistochemical staining.Nephrilin significantly inhibited elevations in plasma tumor necrosis factor-alpha, kidney substance P, and CX3CR1, and urinary lipocalin-2 [urinary neutrophil gelatinase-associated lipocalin (uNGAL)] in models of acute xenobiotic stress. UCHL1 gene expression levels dropped and plasma HMGB1 levels rose in the rhabdomyolysis model. Both effects were reversed by nephrilin. The inhibitor also blocked diet-induced elevations of uNGAL and albumin-creatinine ratio (UACR) as well as kidney tissue phosphorylation of PKC-beta-2-T641 and p66shc-S36, and reduced dark ring-like staining of nuclei by anti-phos-p66shc-S36 antibody in frozen sections of diseased kidneys from hypertensive Dahl rats fed an 8 % NaCl diet for 4 weeks. Taken together, our results suggest a role for mTORC2 in the inflammatory-oxidative responses to stress.
   

  ✔本篇論文使用華聯產品:Mouse OneArray  
 Virology Journal. 2012, 9:159. doi: 10.1186/1743-422X-9-159.
 Infection with street strain rabies virus induces modulation of the microRNA profile of the mouse brain
 
 
 Pingsen Zhao, Lili Zhao, Kun Zhang, Hao Feng, Hualei Wang, Tiecheng Wang, Tao Xu, Na Feng, Chengyu Wang, Yuwei Gao, Geng Huang, Chuan Qin, Songtao Yang, Xianzhu Xia
  Abstract
Rabies virus (RABV) causes a fatal infection of the central nervous systems (CNS) of warm-blooded animals. Once the clinical symptoms develop, rabies is almost invariably fatal. The mechanism of RABV pathogenesis remains poorly understood. Recent studies have shown that microRNA (miRNA) plays an important role in the pathogenesis of viral infections. Our recent findings have revealed that infection with laboratory-fixed rabies virus strain can induce modulation of the microRNA profile of mouse brains. However, no previous report has evaluated the miRNA expression profile of mouse brains infected with RABV street strain. The results of microarray analysis show that miRNA expression becomes modulated in the brains of mice infected with street RABV. Quantitative real-time PCR assay of the differentially expressed miRNAs confirmed the results of microarray assay. Functional analysis showed the differentially expressed miRNAs to be involved in many immune-related signaling pathways, such as the Jak-STAT signaling pathway, the MAPK signaling pathway, cytokine-cytokine receptor interactions, and Fc gamma R-mediated phagocytosis. The predicted expression levels of the target genes of these modulated miRNAs were found to be correlated with gene expression as measured by DNA microarray and qRT-PCR. RABV causes significant changes in the miRNA expression profiles of infected mouse brains. Predicted target genes of the differentially expression miRNAs are associated with host immune response, which may provide important information for investigation of RABV pathogenesis and therapeutic method.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 BMC Systems Biology. 2012, 6:105. doi: 10.1186/1752-0509-6-105.
 Chemoattraction of macrophages by secretory molecules derived from cells expressing the signal peptide of eosinophil cationic protein
 
 
 Yu-Shu Liu, Pei-Wen Tsai, Yong Wang, Tan-chi Fan, Chia-Hung Hsieh, Margaret Dah-Tsyr Chang, Tun-Wen Pai, Chien-Fu Huang, Chung-Yu Lan, Hao-Teng Chang
  Abstract
Eosinophil cationic protein is a clinical asthma biomarker that would be released into blood, especially gathered in bronchia. The signal peptide of eosinophil cationic protein (ECPsp) plays an important role in translocating ECP to the extracellular space. We previously reported that ECPsp inhibits microbial growth and regulates the expression of mammalian genes encoding tumor growth factor-£ (TGF-£) and epidermal growth factor receptor (EGFR). In the present study, we first generated a DNA microarray dataset, which showed that ECPsp upregulated proinflammatory molecules, including chemokines, interferon-induced molecules, and Toll-like receptors. The levels of mRNAs encoding CCL5, CXCL10, CXCL11, CXCL16, STAT1, and STAT2 were increased in the presence of ECPsp by 2.07-, 4.21-, 7.52-, 2.6-, 3.58-, and 1.67-fold, respectively. We then constructed a functional linkage network by integrating the microarray dataset with the pathway database of Kyoto Encyclopedia of Genes and Genomes (KEGG). Follow-up analysis revealed that STAT1 and STAT2, important transcriptional factors that regulate cytokine expression and release, served as hubs to connect the pathways of cytokine stimulation (TGF-£ and EGFR pathways) and inflammatory responses. Furthermore, integrating TGF-£ and EGFR with the functional linkage network indicated that STAT1 and STAT2 served as hubs that connect two functional clusters, including (1) cell proliferation and survival, and (2) inflammation. Finally, we found that conditioned medium in which cells that express ECPsp had been cultured could chemoattract macrophages. Experimentally, we also demonstrated that the migration of macrophage could be inhibited by the individual treatment of siRNAs of STAT1 or STAT2. Therefore, we hypothesize that ECPsp may function as a regulator for enhancing the migration of macrophages through the upregualtion of the transcriptional factors STAT1 and STAT2. The increased expression and release of various cytokines triggered by ECPsp may attract macrophages to bronchia to purge damaged cells. Our approach, involving experimental and computational systems biology, predicts pathways and potential biological functions for further characterization of this novel function of ECPsp under inflammatory conditions.
   

  ✔本篇論文使用華聯產品:Mouse&Rat miRNA OneArray  
 Journal of Biomedical Science. 2012, 19:69. doi: 10.1186/1423-0127-19-69.
 Whole blood-derived microRNA signatures in mice exposed to lipopolysaccharides
 
 
 Ching-Hua Hsieh, Cheng-Shyuan Rau, Jonathan Chris Jeng, Yi-Chun Chen, Tsu-Hsiang Lu, Chia-Jung Wu, Yi-Chan Wu, Siou-Ling Tzeng, Johnson Chia-Shen Yang
  Abstract
Lipopolysaccharide (LPS) is recognized as the most potent microbial mediator presaging the threat of invasion of Gram-negative bacteria that implicated in the pathogenesis of sepsis and septic shock. This study was designed to examine the microRNA (miRNA) expression in whole blood from mice injected with intraperitoneal LPS. C57BL/6 mice received intraperitoneal injections of varying concentrations (range, 10¡V1000 £gg) of LPS from different bacteria, including Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, Salmonella enterica, and Serratia marcescens and were killed 2, 6, 24, and 72 h after LPS injection. Whole blood samples were obtained and tissues, including lung, brain, liver, and spleen, were harvested for miRNA expression analysis using an miRNA array (Phalanx miRNA OneArrayR 1.0). Upregulated expression of miRNA targets in the whole blood of C57BL/6 and Tlr4?/? mice injected with LPS was quantified using real-time RT-PCR and compared with that in the whole blood of C57BL/6 mice injected with lipoteichoic acid (LTA) from Staphylococcus aureus. Following LPS injection, a significant increase of 15 miRNAs was observed in the whole blood. Among them, only 3 miRNAs showed up-regulated expression in the lung, but no miRNAs showed a high expression level in the other examined tissues. Upregulated expression of the miRNA targets (let-7d, miR-15b, miR-16, miR-25, miR-92a, miR-103, miR-107 and miR-451) following LPS injection on real-time RT-PCR was dose- and time-dependent. miRNA induction occurred after 2 h and persisted for at least 6 h. Exposure to LPS from different bacteria did not induce significantly different expression of these miRNA targets. Additionally, significantly lower expression levels of let-7d, miR-25, miR-92a, miR-103, and miR-107 were observed in whole blood of Tlr4?/? mice. In contrast, LTA exposure induced moderate expression of miR-451 but not of the other 7 miRNA targets. We identified a specific whole blood¡Vderived miRNA signature in mice exposed to LPS, but not to LTA, from different gram-negative bacteria. These whole blood-derived miRNAs are promising as biomarkers for LPS exposure.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 Experimental Hematology. 2012, 40(11):899-905.e5. doi: 10.1016/j.exphem.2012.06.011.
 Gene Expression Profiling of Acute Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation
 
 
 Jan Verner, Jitka Kabathova, Alexandra Tomancova, Sarka Pavlova, Boris Tichy, Marek Mraz, Yvona Brychtova, Marta Krejci, Zbynek Zdrahal, Martin Trbusek, Jana Volejnikova, Petr Sedlacek, Michael Doubek, Jiri Mayer, Sarka Pospisilova
  Abstract
Acute graft-vs-host disease (aGVHD) is a frequent, life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Despite that, there are no reliable molecular markers reflecting the onset or clinical course of aGVHD. We performed a pilot study on gene expression profiling in peripheral blood mononuclear cells taken from 15 patients with hematological malignancies who underwent allo-HSCT and developed aGVHD. Based on survival rates after aGVHD, patients were divided into two groups-favorable (all patients alive; median follow-up 40 months) vs unfavorable group (all patients died; median survival 2 months). Two-hundred and eighty genes differentially expressed between these two groups were identified; among them, genes responsible for cytokine signaling, inflammatory response, and regulation of cell cycle were over-represented; interleukin-8, G0S2, ANXA3, and NR4A2 were upregulated in the unfavorable group, CDKN1C was downregulated in the same group. Interestingly, the same genes were also described as overexpressed in connection with autoimmune diseases. This indicates an involvement of similar immune regulatory pathways also in aGVHD. Our data support use of gene expression profiling at aGVHD onset for a prediction of its outcomes.
   

  ✔本篇論文使用華聯產品:Mouse OneArray  
 Food and Chemical Toxicology. 2012, 50(9):2978-86. doi: 10.1016/j.fct.2012.05.054.
 Genipin inhibits lipopolysaccharide-induced acute systemic inflammation in mice as evidenced by nuclear factor-£eB bioluminescent imaging-guided transcriptomic analysis
 
 
 Chia-Cheng Li, Chien-Yun Hsiang, Hsin-Yi Lo, Fu-Tzu Pai, Shih-Lu Wu, Tin-Yun Ho
  Abstract
Genipin is a natural blue colorant in food industry. Inflammation is correlated with human disorders, and nuclear factor-£eB (NF-£eB) is the critical molecule involved in inflammation. In this study, the anti-inflammatory effect of genipin on the lipopolysaccharide (LPS)-induced acute systemic inflammation in mice was evaluated by NF-£eB bioluminescence-guided transcriptomic analysis. Transgenic mice carrying the NF-£eB-driven luciferase genes were administered intraperitoneally with LPS and various amounts of genipin. Bioluminescent imaging showed that genipin significantly suppressed LPS-induced NF-£eB-dependent luminescence in vivo. The suppression of LPS-induced acute inflammation by genipin was further evidenced by the reductions of cytokine levels in sera and organs. Microarray analysis of these organs showed that the transcripts of 79 genes were differentially expressed in both LPS and LPS/genipin groups, and one third of these genes belonged to chemokine ligand, chemokine receptor, and interferon (IFN)-induced protein genes. Moreover, network analysis showed that NF-£eB played a critical role in the regulation of genipin-affected gene expression. In conclusion, we newly identified that genipin exhibited anti-inflammatory effects in a model of LPS-induced acute systemic inflammation via downregulation of chemokine ligand, chemokine receptor, and IFN-induced protein productions.
   

  ✔本篇論文使用華聯產品:Mouse OneArray  
 PLoS ONE. 2012, 7(3):e31808. doi: 10.1371/journal.pone.0031808.
 5-Fluorouracil Induced Intestinal Mucositis via Nuclear Factor-£eB Activation by Transcriptomic Analysis and In Vivo Bioluminescence Imaging
 
 
 Chung-Ta Chang, Tin-Yun Ho, Ho Lin, Ji-An Liang, Hui-Chi Huang, Chia-Cheng Li, Hsin-Yi Lo, Shih-Lu Wu, Yi-Fang Huang, Chien-Yun Hsiang
  Abstract
5-Fluorouracil (5-FU) is a commonly used drug for the treatment of malignant cancers. However, approximately 80% of patients undergoing 5-FU treatment suffer from gastrointestinal mucositis. The aim of this report was to identify the drug target for the 5-FU-induced intestinal mucositis. 5-FU-induced intestinal mucositis was established by intraperitoneally administering mice with 100 mg/kg 5-FU. Network analysis of gene expression profile and bioluminescent imaging were applied to identify the critical molecule associated with 5-FU-induced mucositis. Our data showed that 5-FU induced inflammation in the small intestine, characterized by the increased intestinal wall thickness and crypt length, the decreased villus height, and the increased myeloperoxidase activity in tissues and proinflammatory cytokine production in sera. Network analysis of 5-FU-affected genes by transcriptomic tool showed that the expression of genes was regulated by nuclear factor-£eB (NF-£eB), and NF-£eB was the central molecule in the 5-FU-regulated biological network. NF-£eB activity was activated by 5-FU in the intestine, which was judged by in vivo bioluminescence imaging and immunohistochemical staining. However, 5-aminosalicylic acid (5-ASA) inhibited 5-FU-induced NF-£eB activation and proinflammatory cytokine production. Moreover, 5-FU-induced histological changes were improved by 5-ASA. In conclusion, our findings suggested that NF-£eB was the critical molecule associated with the pathogenesis of 5-FU-induced mucositis, and inhibition of NF-£eB activity ameliorated the mucosal damage caused by 5-FU.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 Microbes and Infection. 2012, 14(7-8):600-9. doi: 10.1016/j.micinf.2012.01.006.
 Transcriptome signature in young children with acute otitis media due to Streptococcus pneumoniae
 
 
 Keyi Liu, Linlin Chen, Ravinder Kaur, Michael Pichichero
  Abstract
Streptococcus pneumoniae (Spn) is the predominant causative organism of acute otitis media in children. To better understand the genes that are regulated at the onset of AOM caused by Spn infection in the middle ear, the transcriptome profile of peripheral blood mononuclear cells isolated from children prior to and during an AOM event was evaluated by microarray. We found that 1903 (6.2%) of 29,187 genes were differentially regulated greater than 2-fold at the onset of AOM compared to the pre-infection stage of the same children. The ontology of differentially regulated genes was dominated by those involved with the immune response. At onset of infection, genes associated with bacterial defenses were significantly up-regulated, including beta-defensin123, S100 protein A12, Toll-like receptor 5, IL-10, and those involved in the classical and alternative complement pathways. Genes associated with inhibition of bacterial entry through clathrin-dependent endocytosis were also up-regulated. In contrast, genes associated with cell-mediated immune responses were broadly down-regulated. The results provide the first human transcriptome data identifying genes differentially regulated at the onset of AOM in children.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 Journal of Inflammation Research. 2011, 4: 127-138. doi: 10.2147/JIR.S19461.
 Inflammatory cytokines regulate endothelial cell survival and tissue repair functions via NF-£eB signaling
 
 
 Nobuhiro Kanaji, Tadashi Sato, Amy Nelson, Xingqi Wang, YingJi Li, Miok Kim, Masanori Nakanishi, Hesham Basma, Joel Michalski, Maha Farid, Michael Chandler, William Pease, Amol Patil, Stephen I Rennard, Xiangde Liu
  Abstract
Inflammation contributes to the development of fibrotic and malignant diseases. We assessed the ability of inflammatory cytokines to modulate endothelial cell survival and functions related to tissue repair/remodeling. Treatment with interleukin (IL)-1£] or tumor necrosis factor (TNF)-£ (2 ng/mL) led to human pulmonary artery endothelial cells becoming spindle-shaped fibroblast-like cells. However, immunoblot and DNA microarray showed no change in most endothelial and mesenchymal markers. In the presence of IL-1£] or TNF-£, cells were resistant to apoptosis induced by deprivation of serum and growth factor, and were more migratory. In addition, cells treated with IL-1£] or TNF-£ contracted collagen gels more robustly. In contrast, transforming growth factor-£]1 did not induce these responses. RNA interference targeting nuclear factor (NF)-£eB p65 blocked the effects of IL-1£] or TNF-£ on cell morphologic change, survival, migration, and collagen gel contraction. These results suggest that endothelial cells may contribute to tissue repair/remodeling via the NF-£eB signaling in a milieu of airway inflammation.
   

  ✔本篇論文使用華聯產品:Mouse OneArray  
 The Journal of Immunology. 2011, 187(9):4426-30. doi: 10.4049/jimmunol.1101034.
 Cutting edge: IRF8 regulates Bax transcription in vivo in primary myeloid cells
 
 
 Jine Yang, Xiaolin Hu, Mary Zimmerman, Christina M. Torres, Dafeng Yang, Sylvia B. Smith, Kebin Liu
  Abstract
A prominent phenotype of IRF8 knockout (KO) mice is the uncontrolled expansion of immature myeloid cells. The molecular mechanism underlying this myeloproliferative syndrome is still elusive. In this study, we observed that Bax expression level is low in bone marrow preginitor cells and increases dramatically in primary myeloid cells in wt mice. In contrast, Bax expression level remained at a low level in primarymyeloid cells in IRF8 KO mice. However, in vitro IRF8 KO bone marrow-differentiated myeloid cells expressed Bax at a level as high as that in wild type myeloid cells. Furthermore, we demonstrated that IRF8 specifically binds to the Bax promoter region in primary myeloid cells. Functional analysis indicated that IRF8 deficiency results in increased resistance of the primary myeloid cells to Fas-mediated apoptosis. Our findings show that IRF8 directly regulates Bax transcription in vivo, but not in vitro during myeloid cell lineage differentiation.
   

  ✔本篇論文使用華聯產品:Mouse OneArray  
 Biomed Pharmacother.. 2011, 65(8):547-54. doi: 10.1016/j.biopha.2011.03.008.
 CXCL9 attenuated chemotherapy-induced intestinal mucositis by inhibiting proliferation and reducing apoptosis.
 
 
 Han X, Wu Z, Di J, Pan Y, Zhang H, Du Y, Cheng Z, Jin Z, Wang Z, Zheng Q, Zhang P, Wang Y.
  Abstract
Mucositis arising from cancer chemotherapy is a common problem for which there is no definitive treatment. 5-fluorouracil (5-FU) is a common cytotoxic agent used to treat solid tumors. A global gene expression array was performed to identify genetic signals involved in the pathogenesis of mucositis. The chemokine (C-X-C motif) ligand 9 (CXCL9) was one of the candidates identified that presented a characteristic gene expression profile; its temporal expression pattern was correlated with the damage and regeneration phases of the small intestine upon 5-FU chemotherapy. We found that prophylactic CXCL9 administration was able to attenuate the severity of mucositis, weight loss and diarrhea caused by chemotherapy. CXCL9 also increased the tolerance of the mice to lethal-dose chemotherapy. Moreover, we demonstrated that CXCL9 was able to promote the proliferation and regeneration of intestinal cells by inhibiting the proliferation of normal intestinal mucosal cells prior to chemotherapy and by reducing the 5-FU-induced apoptosis in intestinal crypts. Thus, pretreatment with CXCL9 is a new and promising strategy for the alleviation of chemotherapy-induced intestinal mucositis in clinical settings.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 J. Virol. 2011, 85(18):9268-75. doi: 10.1128/JVI.00772-11.
 GFP Reporter System with Transcriptional Sequence Heterogeneity for Monitoring Interferon Response
 
 
 Mahmoud L, Al-Saif M, Amer HM, Sheikh M, Almajhdi FN, Khabar KS.
  Abstract
The interferon (IFN) response is initiated by a variety of triggers, including viruses and foreign RNA, and involves several receptors and intracellular mediators. Although there are common cis-acting consensus sequences in the promoters of many genes stimulated during the IFN response, they exhibit core and context heterogeneity that may lead to differential transcriptional activity. We have developed and validated a live cell-based enhanced green fluorescent protein (EGFP) reporter system employing more than a hundred constructs containing multiple viruses and IFN response elements derived from a variety of promoters involved in immunity to viruses. Common and distinct response patterns were observed due to promoter heterogeneity in response to different stimuli, including IFN-£, TLR3-agonist double-stranded RNA, and several viruses. This information should serve as a resource in selecting specific reporters for sensing nonself ligands.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 Biochemical and Biophysical Research Communications. 2011, 405(1):102-6. doi: 10.1016/j.bbrc.2010.12.135.
 Identifying cell and molecular stress after radiation in a three-dimensional (3-D) model of oral mucositis
 
 
 Parsa C, Mulamalla H, Orlando R, Lau B, Huang Y, Pon D, Chow M, Lambros MP
  Abstract
Mucositis is a debilitating adverse effect of chemotherapy and radiation treatment. It is important to develop a simple and reliable in vitro model, which can routinely be used to screen new drugs for prevention and treatment of mucositis. Furthermore, identifying cell and molecular stresses especially in the initiation phase of mucositis in this model will help towards this end. We evaluated a three-dimensional (3-D) human oral cell culture that consisted of oral keratinocytes and fibroblasts as a model of oral mucositis. The 3-D cell culture model was irradiated with 12 or 2 Gy. Six hours after the irradiation we evaluated microscopic sections of the cell culture for evidence of morphologic changes including apoptosis. We used microarrays to compare the expression of several genes from the irradiated tissue with identical genes from tissue that was not irradiated. We found that irradiation with 12 Gy induced significant histopathologic effects including cellular apoptosis. Irradiation significantly affected the expression of several genes of the NF-kB pathway and several inflammatory cytokines, such as IL-1B, 1L-8, NF-kB1, and FOS compared to tissue that was not irradiated. We identified significant upregulation of several genes that belong to damage-associated molecular patterns (DAMPs) such as HMB1, S100A13, SA10014, and SA10016 in the 3-D tissues that received 12 Gy but not in tissues that received 2 Gy. In conclusion, this model quantifies radiation damage and this is an important first step towards the development 3-D tissue as a screening tool.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 Clin Transl Sci. 2010, 3(4):158-69. doi: 10.1111/j.1752-8062.2010.00212.x.
 A New Class of Human Mast Cell and Peripheral Blood Basophil Stabilizers that Differentially Control Allergic Mediator Release
 
 
 Sarah K. Norton, Anthony Dellinger, Zhiguo Zhou, Robert Lenk, Darren MacFarland, Becky Vonakis, Daniel Conrad, Christopher L. Kepley
  Abstract
Treatments for allergic disease block the effects of mediators released from activated mast cells and blood basophils. A panel of fullerene derivatives was synthesized and tested for their ability to preempt the release of allergic mediators in vitro and in vivo. The fullerene C(70)-tetraglycolic acid significantly inhibited degranulation and cytokine production from mast cells and basophils, while C(70)-tetrainositol blocked only cytokine production in mast cells and degranulation and cytokine production in basophils. The early phase of FcepsilonRI inhibition was dependent on the blunted release of intracellular calcium stores, elevations in reactive oxygen species, and several signaling molecules. Gene microarray studies further showed the two fullerene derivatives inhibited late phase responses in very different ways. C(70)-tetraglycolic acid was able to block mast cell-driven anaphylaxis in vivo, while C(70)-tetrainositol did not. No toxicity was observed with either compound. These findings demonstrate the biological effects of fullerenes critically depends on the moieties added to the carbon cage and suggest they act on different FcepsilonRI-specific molecules in mast cells and basophils. These next generation fullerene derivatives represent a new class of compounds that interfere with FcepsilonRI signaling pathways to stabilize mast cells and basophils. Thus, fullerene-based therapies may be a new approach for treating allergic diseases.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 CLINICAL ANDVACCINE IMMUNOLOGY. 2010, 17(12):1909-16. doi: 10.1128/CVI.00194-10.
 Serum Intercellular Adhesion Molecule 1 Variations in Young Children with Acute Otitis Media
 
 
 Keyi Liu, Janet Casey, and Michael Pichichero
  Abstract
Acute otitis media (AOM) is an inflammatory reaction in the middle ear, most often occurring in young children. Streptococcus pneumoniae, nontypeable Haemophilus influenzae, and Moraxella catarrhalis are the most common bacteria isolated. Intercellular adhesion molecule 1 (ICAM-1) is involved in the innate immune response to infection by microorganisms, in effective antigen presentation, and in subsequent T-cell activation. Here we prospectively studied levels of serum soluble ICAM-1 (sICAM-1) before, at the time of, and after antimicrobial treatment of AOM in a group of 138 children ages 6 to 30 months. Middle ear fluids were collected by tympanocentesis to identify otopathogens. We found that (i) serum levels of sICAM-1 were significantly higher in S. pneumoniae-, nontypeable H. influenzae-, and M. catarrhalis-infected children than in well children (P < 0.001), confirming that a systemic inflammatory response occurs during AOM; (ii) sICAM-1 levels varied from no elevation (110 ng/ml) to elevation to high levels (maximum, 1,470 ng/ml) among children with AOM; (iii) in paired samples, sICAM-1 levels increased 4- to 20-fold when children developed AOM compared to their sICAM-1 levels before infection; and (iv) the level of sICAM-1 returned to the pre-AOM level at the convalescent stage of AOM after successful antimicrobial therapy. We conclude that AOM often causes a systemic inflammatory reaction, as measured by elevation of the serum sICAM-1 level, and that a high variability in sICAM-1 responses occurs with the presence of otopathogens during AOM.
   

  ✔本篇論文使用華聯產品:Mouse OneArray  
 Biomedicine & Pharmacotherapy. 2011, 65(5):339-44. doi: 10.1016/j.biopha.2011.04.013.
 Interleukin 1 receptor antagonist reduces lethality and intestinal toxicity of 5-?uorouracil in a mouse mucositis model.
 
 
 Zhenqian Wu, Xiaodong Han, Shenyin Qin, Qi Zheng, Zhigang Wang, Di Xiang, Jing Zhang, Huili Lu, Mingyuan Wu, Shunying Zhu, Yan Yu, Yu Wang and Wei Han.
  Abstract
Chemotherapy-induced intestinal mucositis is still an unmet medical problem. 5-Fluorouracil (5-Fu), a chemotherapy drug, was used to create the animal model of mucositis. Global gene expression array was applied to identify genetic signals involved in the pathogenesis of mucositis. Interleukin 1 receptor antagonist (IL-1Ra) was one of the candidates with the characteristic gene expression profile. Its temporal expression pattern correlated to the damage and regeneration phase of the small intestine after a single injection of 5-Fu to mice. Administration of recombinant IL-1Ra to the mouse model of intestinal mucositis induced by 5-Fu demonstrated its therapeutic effects to the symptoms and pathology of the disease. The IL-1Ra treatment reduced the acute lethality, accelerated their body weight recovery, and eliminated severe diarrhea. The symptomatic benefits were supported by the pathological benefits, in which the mice treated with IL-1Ra had less damage and faster recovery of the structure integrity of their small intestine than that of the mice treated with vehicle control. To deliver the therapeutics to the unmet medical condition, further mechanism and translational studies of IL-1Ra in the settings of chemotherapy-induced intestinal mucositis are warranted.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 Vaccine. 2010, 28(31):4945-54.
 Immunomodulatory and adjuvant activities of a polysaccharide extract of Ganoderma lucidum in vivo and in vitro.
 
 
 Lai CY, Hung JT, Lin HH, Yu AL, Chen SH, Tsai YC, Shao LE, Yang WB, Yu J.
  Abstract
We had isolated a high molecular weight polysaccharide fraction, designated as F3, and performed a comprehensive analysis of its immunomodulatory and adjuvant activities in vivo and in vitro. In vivo, F3-treated mice showed an increase in the number of dendritic cells as well as CD4, CD8, regulatory T, B, plasma, NK, and NKT cells in the spleen. F3 also elevated the levels of multiple cytokines and chemokines in the blood of mice. F3 displayed potent adjuvant activity for tetanus toxoid in the absence of alum and potentiated antibody responses to alum-containing tetanus toxoid in mice. In addition, F3 also boosted Th1 and Th2 response in vivo. In vitro, F3 induced the maturation of dendritic cells derived from human monocytes by upregulating CD40, CD54, CD80, CD83, CD86, and HLA-DR, enhanced mixed lymphocyte reaction, and stimulated the production of ten cytokines and six chemokines. In microarray analysis, expressions of 7688 genes were modulated in dendritic cells after treatment with F3, including cytokine and chemokine genes. These results provide F3 polysaccharide extract further insight into the mechanisms of action for these immunomodulatory and adjuvant activities of from Ganoderma lucidum and also offer preclinical evidence for its development as a vaccine adjuvant.