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Chun Wang, Susan Hockerman, E Jon Jacobsen, Yael Alippe, Shaun R Selness, Heidi R Hope, Jeffrey L Hirsch, Stephen J Mnich, Matthew J Saabye, William F Hood, Sheri L Bonar, Yousef Abu-Amer, Ariela Haimovich, Hal M Hoffman, Joseph B Monahan, Gabriel Mbalaviele
p38α activation of multiple effectors may underlie the failure of global p38α inhibitors in clinical trials. A unique inhibitor (CDD-450) was developed that selectively blocked p38α activation of the proinflammatory kinase MK2 while sparing p38α activation of PRAK and ATF2. Next, the hypothesis that the p38α-MK2 complex mediates inflammasome priming cues was tested. CDD-450 had no effect on NLRP3 expression, but it decreased IL-1β expression by promoting IL-1β mRNA degradation. Thus, IL-1β is regulated not only transcriptionally by NF-κB and posttranslationally by the inflammasomes but also posttranscriptionally by p38α-MK2...
March 16, 2018: Journal of Experimental Medicine
Heather N Carter, Marion Pauly, Liam D Tryon, David A Hood
Mitochondrial impairments are often noted in aged skeletal muscle. The transcriptional coactivator PGC-1α is integral to maintaining mitochondria, and its expression declines in aged muscle. It remains unknown whether this is due to a transcriptional deficit during aging. Our study examined PGC-1α transcription in muscle from young and old F344BN rats. Using a rat PGC-1α promoter-reporter construct, we found that PGC-1α transcription was reduced by ~65% in aged TA muscle, accompanied by decreases in PGC-1α mRNA and transcript stability...
March 15, 2018: Journal of Applied Physiology
Robert James Shute, Matthew William Heesch, Roksana Barbara Zak, Jodi L Kreiling, Dustin R Slivka
PGC-1α mRNA is increased with both exercise and exposure to cold temperature. However, transcriptional control has yet to be examined during exercise in the cold. Additionally, the need for environmental cold exposure after exercise may not be a practical recovery modality. The purpose of this study was to determine mitochondrial-related gene expression and transcriptional control of PGC-1α following exercise in a cold compared to room temperature environment. Eleven recreationally trained males completed two 1-h cycling bouts in a cold (7 {degree sign}C) or room temperature (20 {degree sign}C) environment followed by 3 h of supine recovery in standard room conditions...
March 14, 2018: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Melanie Tingler, Sabrina Kurz, Markus Maerker, Tim Ott, Franziska Fuhl, Axel Schweickert, Janine M LeBlanc-Straceski, Stéphane Noselli, Martin Blum
Anatomical and functional asymmetries are widespread in the animal kingdom [1, 2]. In vertebrates, many visceral organs are asymmetrically placed [3]. In snails, shells and inner organs coil asymmetrically, and in Drosophila, genitalia and hindgut undergo a chiral rotation during development. The evolutionary origin of these asymmetries remains an open question [1]. Nodal signaling is widely used [4], and many, but not all, vertebrates use cilia for symmetry breaking [5]. In Drosophila, which lacks both cilia and Nodal, the unconventional myosin ID (myo1d) gene controls dextral rotation of chiral organs [6, 7]...
February 20, 2018: Current Biology: CB
Adrian J Giovannone, Christine Winterstein, Pallavi Bhattaram, Elena Reales, Seng Hui Low, Julie E Baggs, Mimi Xu, Matthew A Lalli, John B Hogenesch, Thomas Weimbs
Syntaxins are a conserved family of SNARE proteins and contain C-terminal transmembrane anchors required for their membrane fusion activity. Here we show that syntaxin 3 (Stx3) unexpectedly also functions as a nuclear regulator of gene expression. We found that alternative splicing creates a soluble isoform, we termed Stx3S, lacking the transmembrane anchor. Soluble Stx3S binds to the nuclear import factor RAN-binding protein 5 (RanBP5), targets to the nucleus and interacts physically and functionally with several transcription factors, including ETS variant 4 (ETV4) and activating transcription factor 2 (ATF2)...
February 23, 2018: Journal of Biological Chemistry
Oksana Voloshanenko, Uwe Schwartz, Dominique Kranz, Benedikt Rauscher, Michael Linnebacher, Iris Augustin, Michael Boutros
Wnt signaling is an evolutionarily conserved signaling route required for development and homeostasis. While canonical, β-catenin-dependent Wnt signaling is well studied and has been linked to many forms of cancer, much less is known about the role of non-canonical, β-catenin-independent Wnt signaling. Here, we aimed at identifying a β-catenin-independent Wnt target gene signature in order to understand the functional significance of non-canonical signaling in colon cancer cells. Gene expression profiling was performed after silencing of key components of Wnt signaling pathway and an iterative signature algorithm was applied to predict pathway-dependent gene signatures...
February 16, 2018: Scientific Reports
Daniel Vázquez-Ramírez, Yvonne Genzel, Ingo Jordan, Volker Sandig, Udo Reichl
Increasing the yield and the productivity in cell culture-based vaccine manufacturing using high-cell-density (HCD) cultivations faces a number of challenges. For example, medium consumption should be low to obtain a very high concentration of viable host cells in an economical way but must be balanced against the requirement that accumulation of toxic metabolites and limitation of nutrients have to be avoided. HCD cultivations should also be optimized to avoid unwanted induction of apoptosis or autophagy during the early phase of virus infection...
February 9, 2018: Vaccine
Haijing Zhou, Lin Cai, Xiupeng Zhang, Ailin Li, Yuan Miao, Qingchang Li, Xueshan Qiu, Enhua Wang
Rho guanine nucleotide exchange factor 39 (ARHGEF39), also called C9orf100, is a new member of the Dbl-family of guanine nucleotide exchange factors. Although ARHGEF39 has been proven to regulate tumor progression in hepatocellular carcinoma, the downstream signaling pathway of ARHGEF39 and its clinical associations in non-small cell lung cancer (NSCLC) are currently unknown. In the present study, using MTT, colony formation, flow cytometry, mice xenografts, wound healing, and transwell assays, we showed that ARHGEF39 promoted tumor proliferation, migration, and invasion...
January 30, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
Hongkai Shang, Liping Sun, Thorsten Braun, Qi Si, Jinyi Tong
Dexamethasone (DEX) could induce low birth weight of infant, and low birth weight has close associations with glucocorticoid levels, insulin resistance, hypertension, and metabolic syndrome in adulthood. This study was designed to reveal the action mechanisms of DEX on the birth weight of infant.Using quantitative real-time polymerase chain reaction (qRT-PCR), trophoblast cells of human placenta were identified and the optimum treatment time of DEX were determined. Trophoblast cells were treated by DEX (DEX group) or ethanol (control group) (each group had 3 samples), and then were performed with RNA-sequencing...
January 2018: Medicine (Baltimore)
Xianlong Gao, Xiaomin Wu, Jiajie Yan, Jingqun Zhang, Weiwei Zhao, Dominic DeMarco, Yongguo Zhang, Mamdouh Bakhos, Gregory Mignery, Jun Sun, Zhenyu Li, Michael Fill, Xun Ai
Introduction: c-jun N-terminal kinase (JNK) is a critical stress response kinase that activates in a wide range of physiological and pathological cellular processes. We recently discovered a pivotal role of JNK in the development of atrial arrhythmias in the aged heart, while cardiac CaMKIIδ, another pro-arrhythmic molecule, was also found to enhance atrial arrhythmogenicity. Here, we aimed to reveal a regulatory role of the stress kinase JNK2 isoform on CaMKIIδ expression. Methods and Results: Activated JNK2 leads to increased CaMKIIδ protein expression in aged human and mouse atria, evidenced from the reversal of CaMKIIδ up-regulation in JNK2 inhibitor treated wild-type aged mice...
January 19, 2018: Cardiovascular Research
Y-H Taguchi
BACKGROUND: Although post-traumatic stress disorder (PTSD) is primarily a mental disorder, it can cause additional symptoms that do not seem to be directly related to the central nervous system, which PTSD is assumed to directly affect. PTSD-mediated heart diseases are some of such secondary disorders. In spite of the significant correlations between PTSD and heart diseases, spatial separation between the heart and brain (where PTSD is primarily active) prevents researchers from elucidating the mechanisms that bridge the two disorders...
December 21, 2017: BMC Medical Genomics
Xin Chen, Yan Ling, Yanping Wei, Jing Tang, Yibing Ren, Baohua Zhang, Feng Jiang, Hengyu Li, Ruoyu Wang, Wen Wen, Guishuai Lv, Mengchao Wu, Lei Chen, Liang Li, Hongyang Wang
In the context of diabetes, obesity, and metabolic syndrome, the inflammatory signaling has critical roles in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), but the underlying mechanisms remain poorly delineated. Herein, early and persistently elevated, proinflammatory cytokine HMGB1 expression was detected in a high-fat diet (HFD)-induced NAFLD model in C57BL/6 mice. The expression and extracellular release of HMGB1 was rapidly and dramatically induced by saturated palmitic acid in vitro HFD-induced inflammatory response and liver function impairment were both mitigated after the inhibition of endogenous HMGB1 by neutralizing antibody in vivo The up-regulation of HMGB1 was thought to be modified by dual channels: in the transcriptional level, it was regulated by JNK1/JNK2-ATF2 axis; post-transcriptionally, it was regulated by the microRNA (miR)-200 family, especially miR-429...
January 3, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Sanoji Wijenayake, Bryan E Luu, Jing Zhang, Shannon N Tessier, Julian F Quintero-Galvis, Juan Diego Gaitán-Espitia, Roberto F Nespolo, Kenneth B Storey
Hibernation is a period of torpor and heterothermy that is typically associated with a strong reduction in metabolic rate, global suppression of transcription and translation, and upregulation of various genes/proteins that are central to the cellular stress response such as protein kinases, antioxidants, and heat shock proteins. The current study examined cell signaling cascades in hibernating monito del monte, Dromiciops gliroides, a South American marsupial of the Order Microbiotheria. Responses to hibernation by members of the mitogen-activated protein kinase (MAPK) pathways, and their roles in coordinating hibernator metabolism were examined in liver, kidney, heart and brain of control and versus hibernating (4days continuous torpor) D...
December 13, 2017: Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology
Wu-Chang Zhang, Lin-Juan Du, Xiao-Jun Zheng, Xiao-Qing Chen, Chaoji Shi, Bo-Yan Chen, Xue-Nan Sun, Chao Li, Yu-Yao Zhang, Yan Liu, Hui Xiao, Qibin Leng, Xinquan Jiang, Zhiyuan Zhang, Shuyang Sun, Sheng-Zhong Duan
Type I IFN production and signaling in macrophages play critical roles in innate immune responses. High salt ( i.e. high concentrations of NaCl) has been proposed to be an important environmental factor that influences immune responses in multiple ways. However, it remains unknown whether high salt regulates type I IFN production and signaling in macrophages. Here, we demonstrated that high salt promoted IFNβ production and its signaling in both human and mouse macrophages, and consequentially primed macrophages for strengthened immune sensing and signaling when challenged with viruses or viral nucleic acid analogues...
January 19, 2018: Journal of Biological Chemistry
Min-Hee Kang, Joydeep Das, Sangiliyandi Gurunathan, Hwan-Woo Park, Hyuk Song, Chankyu Park, Jin-Hoi Kim
Rationale : Dimethyl sulfoxide (DMSO) is commonly used as a solvent for water-insoluble substances, a vehicle for drug therapy, and a cryoprotectant for cultured cells. DMSO induced embryonic defects and its mechanism of action remains unclear. The rationale is based on the assumption that DMSO supplementation should induce long-term negative effects on both pre- and post-implantation embryo development. Methods: DMSO induced oxidative stress, ER stress, autophagy, mitophagy, signaling responsible genes and proteins were determined by RT-qPCR, Western blotting, immunofluorescence, and confocal microscopy...
2017: Theranostics
Jing Tang, Yan Liao, Shuying He, Jie Shi, Liang Peng, Xiaoping Xu, Fang Xie, Na Diao, Jinlan Huang, Qian Xie, Chuang Lin, Xiaoying Luo, Kaili Liao, Juanjuan Ma, Jingyi Li, Daichao Zhou, Zhijun Li, Jun Xu, Chao Zhong, Guozhen Wang, Lan Bai
BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (ICC) is an aggressive tumor with a high fatality rate. It was recently found that parathyroid hormone-like hormone (PTHLH) was frequently overexpressed in ICC compared with non-tumor tissue. This study aimed to elucidate the underlying mechanisms of PTHLH in ICC development. METHODS: The CCK-8 assay, colony formation assays, flow cytometry and a xenograft model were used to examine the role of PTHLH in ICC cells proliferation...
November 25, 2017: Journal of Translational Medicine
Shan Wan, Anne-Sophie Meyer, Sofia Maria Elisabeth Weiler, Christian Rupp, Marcell Tóth, Carsten Sticht, Stephan Singer, Stefan Thomann, Stephanie Roessler, Marina Schorpp-Kistner, Jennifer Schmitt, Norbert Gretz, Peter Angel, Darjus Felix Tschaharganeh, Jens Marquardt, Peter Schirmacher, Federico Pinna, Kai Breuhahn
The loss of epithelial cell polarity plays an important role in the development and progression of liver cancer. However, the specific molecular mechanisms supporting tumor initiation and progression are poorly understood. In this study, transcriptome data and immunofluorescence stains of tissue samples derived from hepatocellular carcinoma (HCC) patients revealed that overexpression associated with cytoplasmic localization of the baso-lateral cell polarity complex protein Scribble (Scrib) correlated with poor prognosis of HCC patients...
November 20, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Yuan Li, Zhiliang Lu, Yun Che, Jingnan Wang, Shouguo Sun, Jianbing Huang, Shuangshuang Mao, Yuanyuan Lei, Zhaoli Chen, Jie He
Understanding interactions between tumor and the host immune system holds great promise to uncover biomarkers for targeted therapies and clinical outcomes. However, systematical analysis of immune signatures in esophageal squamous cell carcinoma (ESCC) remains largely unstudied. In this study, immune signatures containing 708 immune related genes were curated from mRNA microarray data with tumor and paired normal tissues from 119 ESCC patients. Differential expression and survival analysis were performed with validations from Human Protein Atlas and an independent cohort of 110 ESCC patients by immunohistochemistry staining...
2017: Oncoimmunology
Linli Tian, Jiarui Zhang, Xiuxia Ren, Xinyu Liu, Wei Gao, Chen Zhang, Yanan Sun, Ming Liu
Cisplatin is a common used chemotherapeutic drug for the treatment of laryngeal cancer. However, drug-resistance is a major obstacle in platinum-based chemotherapy for laryngeal cancer. Recent studies have demonstrated that dysregulation of microRNAs (miRNAs) is responsible for chemoresistance in multiple cancers including laryngeal cancer, but the potential mechanisms are required to be explored. In the present study, we constantly exposed the laryngeal cancer cell line Hep-2 with cisplatin to establish a cisplatin-resistant laryngeal cancer cell model (Hep-2/R)...
October 3, 2017: Oncotarget
Jennifer McGinnis, Brian K Kay
Activating Transcription Factor 2 (ATF2) plays an important role in mammalian cell proliferation, apoptosis and DNA repair. Its activation is dependent on the sequential phosphorylation of residue threonine 71 (T71) followed by threonine 69 (T69) in its transactivation domain. While these modifications can be directed by a variety of kinases, the time to reach full phosphorylation is dependent on which signaling pathway has been activated, which is thought to be important for proper temporal regulation. To explore this phenomenon further, there have been ongoing efforts to generate affinity reagents for monitoring phosphorylation events in cellular assays...
October 26, 2017: New Biotechnology
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