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Fumiaki Ohtake, Yasushi Saeki, Satoshi Ishido, Jun Kanno, Keiji Tanaka
Polyubiquitin chains of different topologies regulate diverse cellular processes. K48- and K63-linked chains, the two most abundant chain types, regulate proteolytic and signaling pathways, respectively. Although recent studies reported important roles for heterogeneous chains, the functions of branched ubiquitin chains remain unclear. Here, we show that the ubiquitin chain branched at K48 and K63 regulates nuclear factor κB (NF-κB) signaling. A mass-spectrometry-based quantification strategy revealed that K48-K63 branched ubiquitin linkages are abundant in cells...
October 8, 2016: Molecular Cell
Yu Chen, Xiaoling Deng, Junfang Deng, Jiehua Zhou, Yuping Ren, Shengxuan Liu, Deborah J Prusak, Thomas G Wood, Xiaoyong Bao
Human metapneumovirus (hMPV) is a major cause of lower respiratory infection in young children. Repeated infections occur throughout life, but its immune evasion mechanisms are largely unknown. We recently found that hMPV M2-2 protein elicits immune evasion by targeting mitochondrial antiviral-signaling protein (MAVS), an antiviral signaling molecule. However, the molecular mechanisms underlying such inhibition are not known. Our mutagenesis studies revealed that PDZ-binding motifs, 29-DEMI-32 and 39-KEALSDGI-46, located in an immune inhibitory region of M2-2, are responsible for M2-2-mediated immune evasion...
October 13, 2016: Virology
Jian-Jun Li, Jie Luo, Jing-Ning Lu, Xiao-Na Liang, Yi-Huan Luo, Yong-Ru Liu, Jie Yang, Hua Ding, Gui-Hui Qin, Li-Hua Yang, Yi-Wu Dang, Hong Yang, Gang Chen
OBJECTIVE: To explore the relationship between tumor necrosis factor receptor-associated factor 6 (TRAF6) and the clinicopathological features in HCC as well as its biological function. METHODS: Totally, 412 liver tissues were collected, including 171 hepatocellular carcinoma (HCC) and their corresponding non-tumor tissues, 37 cirrhosis and 33 normal liver tissues. The expression of TRAF6 was assessed by immunohistochemistry. Then, analysis of the correlations between TRAF6 expression and clinicopathological parameters in HCC was conducted...
2016: Cancer Cell International
Xinyang Liu, Zhichao Wang, Guoliang Zhang, Qikun Zhu, Hui Zeng, Tao Wang, Feng Gao, Zhan Qi, Jinwen Zhang, Rui Wang
Esophageal cancer is one of the most common types of cancer and it has a poor prognosis. The molecular mechanisms of esophageal cancer progression remain largely unknown. In this study, we aimed to investigate the clinical significance and biological function of tumor necrosis factor receptor associated factor 6 (TRAF6) in esophageal cancer. Expression of TRAF6 in esophageal cancer was examined and its correlation with clinicopathological factors and patient prognosis was analyzed. A series of functional and mechanism assays were performed to further investigate the function and underlying mechanisms in esophageal cancer...
September 30, 2016: Oncology Research
Qin Yang, Maren J Pröll, Dessie Salilew-Wondim, Rui Zhang, Dawit Tesfaye, Huitao Fan, Mehmet U Cinar, Christine Große-Brinkhaus, Ernst Tholen, Mohammad A Islam, Michael Hölker, Karl Schellander, Muhammad J Uddin, Christiane Neuhoff
Pulmonary alveolar macrophages (AMs) are important in defense against bacterial lung inflammation. Cluster of differentiation 14 (CD14) is involved in recognizing bacterial lipopolysaccharide (LPS) through MyD88-dependent and TRIF pathways of innate immunity. Sulforaphane (SFN) shows anti-inflammatory activity and suppresses DNA methylation. To identify CD14 epigenetic changes by SFN in the LPS-induced TRIF pathway, an AMs model was investigated in vitro CD14 gene expression was induced by 5 µg/ml LPS at the time point of 12 h and suppressed by 5 µM SFN...
September 29, 2016: Innate Immunity
Zigong Shao, Baoping Jiao, Tingting Liu, Ying Cheng, Hao Liu, Yongfeng Liu
OBJECTIVES: This study aims to test the effects of TAK-242 on liver transplant viability in a model of swine Maastricht-category-III cardiac death. METHODS: A swine DCD Maastricht-III model of cardiac death was established, and TAK-242 was administered prior to the induction of cardiac death. The protein and mRNA level of TLR4 signaling pathway molecules and cytokines that are important in mediating immune and inflammatory responses were assessed at different time points following the induction of cardiac death...
September 26, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
He Ma, Xiaohui Wang, Tuanzhu Ha, Ming Gao, Li Liu, Ruitao Wang, Kaijiang Yu, John H Kalbfleisch, Race L Kao, David L Williams, Chuanfu Li
BACKGROUND:  This study examined the effect of miR-125b on sepsis-induced cardiac dysfunction. METHODS:  Mouse hearts were transfected with lentivirus expressing miR-125b (LmiR-125b) seven days prior to cecal ligation and puncture (CLP) induced sepsis. Cardiac function was examined by echocardiography before and 6 hours after CLP (n=6/group). Survival outcome was monitored following CLP sepsis (n=12/group). RESULTS:  LmiR-125b transfection significantly attenuated CLP sepsis-induced cardiac dysfunction...
September 28, 2016: Journal of Infectious Diseases
Stephanie T Chan, Jiyoung Lee, Mansi Narula, J-H James Ou
: Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an important adapter molecule that mediates the TNFR family and interleukin-1/Toll-like receptor (IL-1/TLR) signaling cascades. These pathways are important for the host to control viral infections. In this report, we demonstrated that hepatitis C virus (HCV) depleted TRAF6 from its host cells through a post-translational mechanism. This depletion was independent of proteasomes, as it was not affected by the proteasome inhibitor MG132, but it was suppressed by bafilomycin A1, which led to the association of TRAF6 with autophagosomes...
September 28, 2016: Journal of Virology
Kidong Kang, Minho Won, Jae-Min Yuk, Chan-Yong Park, Hee Sun Byun, Kyeong Ah Park, So-Ra Lee, Young-Goo Kang, Han-Ming Shen, Ill Young Lee, Gang Min Hur
A specific small-molecule inhibitor of the TLR4 signaling complex upstream of the IKK would likely provide therapeutic benefit for NF-κB-mediated inflammatory disease. We previously identified brazilin as a selective upstream IKK inhibitor targeting the Myddosome complex. In this study, using a cell-based ubiquitination assay for IRAK1 and a chemical library comprising a series of structural analogues of brazilin, a novel small molecule, 2-hydroxy-5,6-dihydroisoindolo[1,2-a]isoquinoline-3,8-dione (IinQ), was identified as a selective and potent inhibitor of IRAK1-dependent NF-κB activation upon TLR4 ligation...
September 21, 2016: Biochemical Pharmacology
Yi-Yung Hung, Chin-Chuen Lin, Hong-Yo Kang, Tiao-Lai Huang
Inflammation and abnormalities in Toll-like receptor (TLR) expression and activation have been linked to major depressive disorder (MDD). However, negative regulators of TLR pathways have not been previously investigated in this context. Here, we sought to investigate the association of depression severity, measured by the 17-item Hamilton Depression Rating Scale (HAMD-17), with mRNA expression levels of negative regulators of the TLR pathway, including SOCS1, TOLLIP, SIGIRR, MyD88s, NOD2 and TNFAIP3, in peripheral blood mononuclear cells (PBMCs) from 100 patients with MDD and 53 healthy controls, before and after treatment with antidepressants...
September 15, 2016: Brain, Behavior, and Immunity
Aditya Dandekar, Yining Qiu, Hyunbae Kim, Jiemei Wang, Xia Hou, Xuebao Zhang, Ze Zheng, Roberto Mendez, Fu-Shin Yu, Ashok Kumar, Deyu Fang, Fei Sun, Kezhong Zhang
Bacterial endotoxin can induce inflammatory and metabolic changes in the host. In this study, we revealed a molecular mechanism by which a stress-inducible, liver-enriched transcription factor, cAMP-responsive element-binding protein hepatic-specific (CREBH), modulates lipid profiles to protect the liver from injuries upon the bacterial endotoxin lipopolysaccharide (LPS). LPS challenge can activate CREBH in mouse liver tissues in a toll-like receptor (TLR)/MyD88-dependent manner. Upon LPS challenge, CREBH interacts with TNF receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase that functions as a key mediator of TLR signaling, and this interaction relies on MyD88...
September 16, 2016: Journal of Biological Chemistry
Xinqi Zhong, Yi-Zhou Jiang, Peiwen Liu, Wenzhi He, Zhongtang Xiong, Weijie Chang, Jiandong Zhu, Qiliang Cui
Assisted reproductive technology (ART) is widely used for the women with infertility conditions to achieve pregnancy. However, the adverse effects of ART may lead to poor perinatal and neonatal outcomes, e.g., preterm birth and low body weight. In this study, we investigated the inflammatory molecular factors and microRNA that might be involved in ART related preterm birth. We found the elevation of Toll-like 4 receptor (TLR4), activation of NFκB pathway and down-regulation of microRNA-146a (miR-146a), a negative regulator of NFκB, in the placenta of preterm birth and ART, indicating preterm birth and ART were associated with inflammation signaling activation...
September 12, 2016: Oncotarget
Linlin Xu, Khalid S Mohammad, Hao Wu, Colin Crean, Bradley Poteat, Yinghua Cheng, Angelo A Cardoso, Christophe C Marchal, Helmut Hanenberg, Rafat Abonour, Melissa A Kacena, John M Chirgwin, Attaya Suvannasankha, Edward F Srour
Multiple myeloma (MM) is incurable once osteocytic lesions have seeded at skeletal sites, but factors mediating this deadly pathogenic advance remain poorly understood. Here we report evidence of a major role for the cell adhesion molecule CD166, which we discovered to be highly expressed in MM cell lines and primary bone marrow (BM) cells from patients. CD166+ MM cells homed more efficiently than CD166- cells to the BM of engrafted immunodeficient NSG mice. CD166 silencing in MM cells enabled longer survival, a smaller tumor burden and less osteolytic lesions, as compared to mice bearing control cells...
September 7, 2016: Cancer Research
Uğur Serbes, Özlem Dağdeviren Özsöylemez, Gül Özcan
We aim to determine the regulation of apoptosis by paclitaxel-induced and understand cancer dynamics to treatment targets for HeLa cells by identifying of decrease/increase genes expression on HeLa cells. In this study, the anti-tumor effects of Paclitaxel (PAC) on HeLa cells have been studied in order to determine the cellular and molecular mechanisms of these effects. PAC has been applied to HeLa cells in 6 different doses (3, 7.5, 15, 30, 60, 120 nM) for 48 hours and the IC50 dose MTT method, has been determined with apoptic index (AI) DAPI...
September 14, 2016: Current Pharmaceutical Biotechnology
Zhongying Cao, Zhangchuan Xia, Yaqin Zhou, Xiaodan Yang, Hua Hao, Nanfang Peng, Shi Liu, Ying Zhu
RNA virus infections are detected by the RIG-I family of receptors, which signal through the adaptor molecule mitochondrial antiviral signaling (MAVS). MAVS then recruits the adaptor's tumor necrosis factor receptor-associated factor (TRAF) 3 and TRAF6, which in turn activate IRF3 and NF-κB, respectively, to induce interferons (IFNs) and inflammatory responses. Here we show that the biotin-containing enzyme methylcrotonoyl-CoA carboxylase 1 (MCCC1) enhances virus-induced, MAVS-mediated IFN and inflammatory cytokine expression through the NF-κB signaling pathway...
2016: Scientific Reports
Li Xia He, Xiaoyun Tong, Jing Zeng, Yuanqing Tu, Saicun Wu, Manping Li, Huaming Deng, Miaomiao Zhu, Xiucun Li, Hong Nie, Li Yang, Feng Huang
In this work, we assessed the anti-inflammatory effects of paeonol (PAE) in LPS-activated N9 microglia cells, as well as its underlying molecular mechanisms. PAE had no adverse effect on the viability of murine microglia N9 cell line within a broad range (0.12∼75 μM). When N9 cell line was activated by LPS, PAE (0.6, 3, 15 μM) significantly suppressed the release of proinflammatory products, such as nitric oxide (NO), interleukin-1β (IL-1β), and prostaglandin E2 (PGE2), demonstrated by the ELISA assay...
September 13, 2016: Inflammation
Tong Wu, Tünde Mester, Shivani Gupta, Fengyuan Sun, Terry J Smith, Raymond S Douglas
BACKGROUND: Increased numbers of bone marrow-derived progenitor cells, known as fibrocytes, populate the peripheral circulation, orbit, and thyroid of patients with Graves' disease (GD). These cells have been implicated in the development of thyroid-associated ophthalmopathy. They can differentiate into myofibroblasts or adipocytes, produce inflammatory cytokines, and remodel tissue. This study sought to determine whether thyrotropin (TSH) and CD40 ligand (CD40L), implicated in the pathogenesis of GD, induce interleukin-12 (IL-12) in human fibrocytes...
October 18, 2016: Thyroid: Official Journal of the American Thyroid Association
Jared M Dickinson, Paul T Reidy, David M Gundermann, Michael S Borack, Dillon K Walker, Andrew C D'Lugos, Elena Volpi, Blake B Rasmussen
Essential amino acid (EAA) ingestion enhances postexercise muscle protein synthesis, and in particular, the anabolic response of older adults appears sensitive to the quantity of ingested leucine. The effect of leucine ingestion on muscle breakdown following resistance exercise (RE) is less understood. The purpose of this study was to identify the impact of postexercise leucine ingestion on the ubiquitin proteasome and autophagosomal-lysosomal systems following acute RE in older men. Subjects (72±2yr) performed RE and 1h postexercise ingested 10g of EAA containing a leucine quantity similar to quality protein (Control, 1...
September 1, 2016: Journal of Applied Physiology
Xiao-Ming Dong, En-Dong Liu, Yun-Xiao Meng, Chao Liu, Ya-Lan Bi, Huan-Wen Wu, Yan-Chao Jin, Jing-Hui Yao, Liu-Jun Tang, Jian Wang, Min Li, Chao Zhang, Miao Yu, Yi-Qun Zhan, Hui Chen, Chang-Hui Ge, Xiao-Ming Yang, Chang-Yan Li
Toll-like receptors (TLRs) have critical roles in innate immunity and inflammation and the detailed mechanisms by which TLR signaling is fine tuned remain unclear. Keratin 8 (CK8) belongs to the type II keratin family and is the major compontent of the intermediate filaments of simple or single-layered epithelia. Here we report that down-regulation of CK8 in mice enhanced TLR-mediated responses, rendering mice more susceptible to lipopolysaccharide (LPS)-induced endotoxin shock and Escherichia coli-caused septic peritonitis with reduced survival, elevated levels of inflammation cytokines and more severe tissue damage...
2016: Scientific Reports
Wan-Wei Sun, Xin-Xu Zhang, Wei-Song Wan, Shu-Qi Wang, Xiao-Bo Wen, Huai-Ping Zheng, Yue-Ling Zhang, Sheng-Kang Li
Tumor necrosis factor receptor-associated factor 6 (TRAF6) is a key cytoplasm signal adaptor that mediates signals activated by tumor necrosis factor receptor (TNFR) superfamily and the Interleukin-1 receptor/Toll-like receptor (IL-1/TLR) superfamily. The full-length 2492 bp TRAF6 (Sp-TRAF6) from Scylla paramamosain contains 1800 bp of open reading frame (ORF) encoding 598 amino acids, including an N-terminal RING-type zinc finger, two TRAF-type zinc fingers and a conserved C-terminal meprin and TRAF homology (MATH) domain...
August 28, 2016: Developmental and Comparative Immunology
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