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Po-Han Chen, Jen-Tsan Chi, Michael Boyce
In metazoans, thousands of intracellular proteins are modified with O-linked β-N-acetylglucosamine (O-GlcNAc) in response to a wide range of stimuli and stresses. In particular, a complex and evolutionarily conserved interplay between O-GlcNAcylation and oxidative stress has emerged in recent years. Here, we review the current literature on the connections between O-GlcNAc and oxidative stress, with a particular emphasis on major signaling pathways, such as KEAP1/NRF2, FOXO, NFκB, p53 and cell metabolism...
March 14, 2018: Glycobiology
Min Huang, Li Zhu, Jacqueline S Garcia, Michael X Li, Andrew J Gentles, Beverly S Mitchell
We have recently reported that activation of Brd4 is associated with the presence of autophagy in NPMc+ and MLL AML cells. In order to determine the mechanisms underlying this relationship, we have examined the role of Brd4 in regulating the expression of several genes that are central to the process of autophagy. We found that Brd4 binds to the promoters of ATG 3, 7 and CEBPβ, and expression of these genes is markedly reduced by inhibitors of Brd4, as well as by Brd4-shRNA and depletion of CEBPβ. Inhibitors of Brd4 also dramatically suppress the transcription of Keap1, thereby increasing the expression of anti-oxidant genes through the Nrf2 pathway and reducing the cytotoxicity induced by Brd4 inhibitors...
February 20, 2018: Oncotarget
Eiki Yoshida, Takafumi Suzuki, Masanobu Morita, Keiko Taguchi, Kohei Tsuchida, Hozumi Motohashi, Minoru Doita, Masayuki Yamamoto
Keap1 is a negative regulator of Nrf2, a master transcription factor that regulates cytoprotection against oxidative and electrophilic stresses. Although several studies have suggested that the Keap1-Nrf2 system contributes to bone formation besides the maintenance of redox homeostasis, how Nrf2 hyperactivation by Keap1 deficiency affects the bone formation remains to be explored, as the Keap1-null mice are juvenile lethal. To overcome this problem, we used viable Keap1-deficient mice that we have generated by deleting the esophageal Nrf2 in Keap1-null mice (NEKO mice)...
March 15, 2018: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Tawfeeq Shekh-Ahmad, Ramona Eckel, Sharadha Dayalan Naidu, Maureen Higgins, Masayuki Yamamoto, Albena T Dinkova-Kostova, Stjepana Kovac, Andrey Y Abramov, Matthew C Walker
Hippocampal sclerosis is a common acquired disease that is a major cause of drug-resistant epilepsy. A mechanism that has been proposed to lead from brain insult to hippocampal sclerosis is the excessive generation of reactive oxygen species, and consequent mitochondrial failure. Here we use a novel strategy to increase endogenous antioxidant defences using RTA 408, which we show activates nuclear factor erythroid 2-related factor 2 (Nrf2, encoded by NFE2L2) through inhibition of kelch like ECH associated protein 1 (KEAP1) through its primary sensor C151...
March 12, 2018: Brain: a Journal of Neurology
Julie George, Vonn Walter, Martin Peifer, Ludmil B Alexandrov, Danila Seidel, Frauke Leenders, Lukas Maas, Christian Müller, Ilona Dahmen, Tiffany M Delhomme, Maude Ardin, Noemie Leblay, Graham Byrnes, Ruping Sun, Aurélien De Reynies, Anne McLeer-Florin, Graziella Bosco, Florian Malchers, Roopika Menon, Janine Altmüller, Christian Becker, Peter Nürnberg, Viktor Achter, Ulrich Lang, Peter M Schneider, Magdalena Bogus, Matthew G Soloway, Matthew D Wilkerson, Yupeng Cun, James D McKay, Denis Moro-Sibilot, Christian G Brambilla, Sylvie Lantuejoul, Nicolas Lemaitre, Alex Soltermann, Walter Weder, Verena Tischler, Odd Terje Brustugun, Marius Lund-Iversen, Åslaug Helland, Steinar Solberg, Sascha Ansén, Gavin Wright, Benjamin Solomon, Luca Roz, Ugo Pastorino, Iver Petersen, Joachim H Clement, Jörg Sänger, Jürgen Wolf, Martin Vingron, Thomas Zander, Sven Perner, William D Travis, Stefan A Haas, Magali Olivier, Matthieu Foll, Reinhard Büttner, David Neil Hayes, Elisabeth Brambilla, Lynnette Fernandez-Cuesta, Roman K Thomas
Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: "type I LCNECs" with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and "type II LCNECs" enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC...
March 13, 2018: Nature Communications
Richard J Steel, Maria A O'Connell, Mark Searcey
The Nrf2/Keap1 interaction is a target in the development of new therapeutic agents, where inhibition of the interaction activates Nrf2 and leads to the generation of downstream anti-inflammatory effects. Peptides that mimic the β-turn in the Keap1 active site and are constrained by a disulfide bridge have high affinity for Keap1 but no intracellular activity. The introduction of a perfluoroalkyl-bridging group to constrain the peptides, coupled with a glutamic acid to proline replacement leads to a new peptide with a Ki of 6...
March 3, 2018: Bioorganic & Medicinal Chemistry Letters
Helena Yu, Ken Suzawa, Emmet J Jordan, Ahmet Zehir, Andy Ni, Hyunjae Ryan Kim, Mark G Kris, Matthew D Hellmann, Bob T Li, Romel Somwar, David B Solit, Michael F Berger, Maria E Arcila, Gregory J Riely, Marc Ladanyi
PURPOSE: To identify molecular factors that determine duration of response to EGFR tyrosine kinase inhibitors and to identify novel mechanisms of drug resistance, we molecularly profiled EGFR mutant tumors prior to treatment and after progression on EGFR TKI using targeted next-generation sequencing.      Experimental Design: Targeted next-generation sequencing was performed on 374 consecutive patients with metastatic EGFR mutant lung cancer. Clinical data were collected and correlated with somatic mutation data...
March 12, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
George Vavougios, Sotirios G Zarogiannis, Triantafylos Doskas
Recent research has outlined that Dimethyl Fumarate (DMF) functions as a gene regulator via multiple pathways, critical among which is the NRF2 cytoprotective cascade. PARK7/DJ-1 is a multifunctional protein that acts as a redox sensor and effector of multiple cytoprotective pathways, including NRF2. Specifically, it prevents the association of NRF2 with its inhibitor KEAP1, allowing NRF2 to enter the nucleus and mediate cytoprotective and antioxidant cascades. It is our hypothesis that while the NRF2-KEAP1 inhibitory complex is reported the main pharmacological target for DMF's NRF dependent functions, no study to date has explored the effects of DMF on DJ-1's expression, and vice-versa, the possibility of a regulatory inadequacy in the upstream, oxidant-responsive DJ-1 activator of the NRF2 cascade...
February 26, 2018: Multiple Sclerosis and related Disorders
Sarah A Best, David P De Souza, Ariena Kersbergen, Antonia N Policheni, Saravanan Dayalan, Dedreia Tull, Vivek Rathi, Daniel H Gray, Matthew E Ritchie, Malcolm J McConville, Kate D Sutherland
The lung presents a highly oxidative environment, which is tolerated through engagement of tightly controlled stress response pathways. A critical stress response mediator is the transcription factor nuclear factor erythroid-2-related factor 2 (NFE2L2/NRF2), which is negatively regulated by Kelch-like ECH-associated protein 1 (KEAP1). Alterations in the KEAP1/NRF2 pathway have been identified in 23% of lung adenocarcinomas, suggesting that deregulation of the pathway is a major cancer driver. We demonstrate that inactivation of Keap1 and Pten in the mouse lung promotes adenocarcinoma formation...
March 2, 2018: Cell Metabolism
June Lee, Karabasappa Mailar, Ok-Kyung Yoo, Won Jun Choi, Young-Sam Keum
Heme oxygenase-1 (HO-1) catalyzes the enzymatic degradation of heme to produce three anti-oxidant molecules: carbon monoxide (CO), ferrous ion (Fe2+ ), and biliverdin. Induction of HO-1 is currently considered as a feasible strategy to treat oxidative stress-related diseases. In the present study, we identified marliolide as a novel inducer of HO-1 in human normal keratinocyte HaCaT cells. Mechanism-based studies demonstrated that the induction of HO-1 by marliolide occurred through activation of NRF2/ARE via direct binding of marliolide to KEAP1...
February 23, 2018: European Journal of Medicinal Chemistry
Lisha Zhao, Xufeng Tao, Yan Qi, Lina Xu, Lianhong Yin, Jinyong Peng
Clinical application of doxorubicin (DOX) is limited because of its cardiotoxicity. Thus, exploration of effective lead compounds against DOX-induced cardiotoxicity is necessary. The aim of the present study was to investigate the effects and possible mechanisms of dioscin against DOX-induced cardiotoxicity. The in vitro model of DOX- treated H9C2 cells and the in vivo models of DOX-treated rats and mice were used in this study. The results showed that discoin markedly increased H9C2 cell viability, decreased the levels of CK, LDH, and improved histopathological and electrocardio- gram changes in rats and mice to protect DOX-induced cardiotoxicity...
March 6, 2018: Redox Biology
Almesh Kadakol, Vajir Malek, Santosh Kumar Goru, Anuradha Pandey, Anil Bhanudas Gaikwad
OBJECTIVES: Although cardioprotective effects of telmisartan are well explored, its effects on epigenetic alterations associated with type 2 diabetic (T2D) cardiomyopathy remain unmapped. Thus, the present study was designed to evaluate the potential of esculetin and telmisartan combination to reverse histone posttranslational modifications (PTMs) in curbing T2D cardiomyopathy. MATERIALS AND METHODS: T2D was induced by high-fat diet feeding along with low dose of streptozotocin (35 mg/kg, I...
September 2017: Indian Journal of Pharmacology
Dionysios V Chartoumpekis, Yoko Yagishita, Marco Fazzari, Dushani L Palliyaguru, Uma Nm Rao, Apostolos Zaravinos, Nicholas Kh Khoo, Francisco J Schopfer, Kurt R Weiss, George K Michalopoulos, Ian Sipula, Robert M O'Doherty, Thomas W Kensler, Nobunao Wakabayashi
Insulin resistance is associated with increased incidence and enhanced progression of cancers. However, little is known about strategies that can effectively ameliorate insulin resistance and consequently halt cancer progression. Herein, we propose that the transcription factor Nrf2 (also known as Nfe2l2) may be such a target, given its central role in disease prevention. To this end, we developed a mouse that overexpresses the Notch intracellular domain in adipocytes (AdNICD), leading to lipodystrophy-induced severe insulin resistance and subsequent development of sarcomas, as a model reflecting that Notch signaling is deregulated in cancers and shows positive associations with insulin resistance and fatty liver disease in humans...
March 8, 2018: JCI Insight
Jiusheng Wang
Asthma is one of the most common chronic inflammatory diseases of childhood, characterized by airway inflammation, mucus hypersecretion, and accumulation of extracellular matrix proteins. Casticin is an active compound that possesses broad biological activities including anti-inflammatory effect. However, the effect of casticin on asthma remains unknown. The aim of the present study was to evaluate the effect and mechanism of casticin on inflammatory responses and expression of mucus and extracellular matrix in human airway epithelial cells...
March 6, 2018: Phytotherapy Research: PTR
Jiyoun Yeo, Diego A Morales, Tian Chen, Erin L Crawford, Xiaolu Zhang, Thomas M Blomquist, Albert M Levin, Pierre P Massion, Douglas A Arenberg, David E Midthun, Peter J Mazzone, Steven D Nathan, Ronald J Wainz, Patrick Nana-Sinkam, Paige F S Willey, Taylor J Arend, Karanbir Padda, Shuhao Qiu, Alexei Federov, Dawn-Alita R Hernandez, Jeffrey R Hammersley, Youngsook Yoon, Fadi Safi, Sadik A Khuder, James C Willey
BACKGROUND: There is a need for more powerful methods to identify low-effect SNPs that contribute to hereditary COPD pathogenesis. We hypothesized that SNPs contributing to COPD risk through cis-regulatory effects are enriched in genes comprised by bronchial epithelial cell (BEC) expression patterns associated with COPD. METHODS: To test this hypothesis, normal BEC specimens were obtained by bronchoscopy from 60 subjects: 30 subjects with COPD defined by spirometry (FEV1/FVC < 0...
March 5, 2018: BMC Pulmonary Medicine
Emily L Yarosz, Cheong-Hee Chang
T lymphocytes rely on several metabolic processes to produce the high amounts of energy and metabolites needed to drive clonal expansion and the development of effector functions. However, many of these pathways result in the production of reactive oxygen species (ROS), which have canonically been thought of as cytotoxic agents due to their ability to damage DNA and other subcellular structures. Interestingly, ROS has recently emerged as a critical second messenger for T cell receptor signaling and T cell activation, but the sensitivity of different T cell subsets to ROS varies...
February 2018: Immune Network
Ajeet Kumar Verma, Arti Yadav, Sarvendra Vikram Singh, Pratibha Mishra, Srikanta Kumar Rath
AIMS: Long-term treatment of Isoniazid (INH) in tuberculosis (TB) patients can lead to anti-tuberculosis drug-induced hepatotoxicity. To understand the mechanism of hepatotoxicity, an attempt has been made to elucidate the role of Nrf2, a transcription factor induced by oxidative stress, in INH induced apoptosis liver cancer cell lines. MATERIALS AND METHODS: Cytotoxicity was evaluated by MTT assay. Apoptosis and reactive oxygen species (ROS) generation was performed by flow cytometry...
February 27, 2018: Life Sciences
Ilaria Bellezza, Ileana Giambanco, Alba Minelli, Rosario Donato
Nrf2 and its endogenous inhibitor, Keap1, function as a ubiquitous, evolutionarily conserved intracellular defense mechanism to counteract oxidative stress. Sequestered by cytoplasmic Keap1 and targeted to proteasomal degradation in basal conditions, in case of oxidative stress Nrf2 detaches from Keap1 and translocates to the nucleus, where it heterodimerizes with one of the small Maf proteins. The heterodimers recognize the AREs, that are enhancer sequences present in the regulatory regions of Nrf2 target genes, essential for the recruitment of key factors for transcription...
February 27, 2018: Biochimica et Biophysica Acta
Mandy M Liu, Kevin M Huang, Li Qian, Payal Chatterjee, Suhui Zhang, Rui Li, Su Zhou, Zhijun Wang, Yun Luo, Ying Huang
BACKGROUND: The nuclear factor erythroid 2-related factor 2 (Nrf2) is a potential molecular target for cancer chemoprevention. Si-Wu-Tang (SWT), a popular traditional Chinese medicine for women's health, was reported with a novel activity of cancer prevention. PURPOSE: The present study was aimed to identify the bioactive constituents in SWT responsible for the Nrf2 activating and cancer preventive activity and explore the pharmacological mechanisms. METHODS: Nine compounds detectable from various batches of SWT were ranked using in silico molecular docking based on their ability to interfere the forming of Nrf2-Keap1 complex...
February 1, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Nicola Amodio, Maria Angelica Stamato, Giada Juli, Eugenio Morelli, Mariateresa Fulciniti, Martina Manzoni, Elisa Taiana, Luca Agnelli, Maria Eugenia Gallo Cantafio, Enrica Romeo, Lavinia Raimondi, Daniele Caracciolo, Valeria Zuccalà, Marco Rossi, Antonino Neri, Nikhil C Munshi, Pierosandro Tagliaferri, Pierfrancesco Tassone
The biological role and therapeutic potential of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) are still to be investigated. Here, we studied the functional significance and the druggability of the oncogenic lncRNA MALAT1 in MM. Targeting MALAT1 by novel LNA-gapmeR antisense oligonucleotide antagonized MM cell proliferation and triggered apoptosis both in vitro and in vivo in a murine xenograft model of human MM. Of note, antagonism of MALAT1 downmodulated the two major transcriptional activators of proteasome subunit genes, namely NRF1 and NRF2, and resulted in reduced trypsin, chymotrypsin and caspase-like proteasome activities and in accumulation of polyubiquitinated proteins...
February 22, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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