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Johannes Klose, Stefan Trefz, Tobias Wagner, Luca Steffen, Arsalie Preißendörfer Charrier, Praveen Radhakrishnan, Claudia Volz, Thomas Schmidt, Alexis Ulrich, Sebastian M Dieter, Claudia Ball, Hanno Glimm, Martin Schneider
OBJECTIVES: Salinomycin is a polyether antibiotic with selective activity against human cancer stem cells. The impact of salinomycin on patient-derived primary human colorectal cancer cells has not been investigated so far. Thus, here we aimed to investigate the activity of salinomycin against tumor initiating cells isolated from patients with colorectal cancer. METHODS: Primary tumor-initiating cells (TIC) isolated from human patients with colorectal liver metastases or from human primary colon carcinoma were exposed to salinomycin and compared to treatment with 5-FU and oxaliplatin...
2019: PloS One
Monica Armida, Alessandra Matteucci, Antonella Pèzzola, Younis Baqi, Christa E Müller, Patrizia Popoli, Rosa Luisa Potenza
Amyotrophic lateral sclerosis (ALS) is a fatal progressing neurodegenerative disease; to date, despite the intense research effort, only two therapeutic options, with very limited effects, are available. The purinergic system has been indicated as a possible new therapeutic target for ALS, but the results are often contradictory and generally confused. The present study was designed to determine whether P1 adenosine receptor ligands affected disease progression in a transgenic model of ALS. SOD1G93A mice were chronically treated, from presymptomatic stage, with a selective adenosine A2A receptor agonist (CGS21680), antagonist (KW6002) or the A1 receptor antagonist DPCPX...
February 12, 2019: Neurochemical Research
Natalia Cichon, Michal Bijak, Ewelina Synowiec, Elzbieta Miller, Tomasz Sliwinski, Joanna Saluk-Bijak
Oxidative stress plays the most important role in the pathogenesis of stroke. Extremely low frequency electromagnetic field (ELF-EMF) therapy may be complementary in post-stroke therapy, as it modulates oxidative stress. The aim of this study was to evaluate the messenger ribonucleic acid (mRNA) levels of certain antioxidant genes in post-stroke patients given ELF-EMF therapy. Forty-eight post-stroke patients were divided into two groups: an ELF-EMF group and a non-ELF-EMF group. All patients underwent the same program of physical therapy, but the ELF-EMF group was additionally given ELF-EMF treatment...
November 2018: Scandinavian Journal of Clinical and Laboratory Investigation
Anna Bille, Kristine Steen Jensen, Sandipan Mohanty, Mikael Akke, Anders Irbäck
Using NMR and Monte Carlo (MC) methods, we investigate the stability and dynamics of superoxide dismutase 1 (SOD1) in homogeneous crowding environments, where either bovine pancreatic trypsin inhibitor (BPTI) or the B1 domain of streptococcal protein G (PGB1) serves as a crowding agent. By NMR, we show that both crowders, and especially BPTI, cause a drastic loss in the overall stability of SOD1 in its apo monomeric form. Additionally, we determine chemical shift perturbations indicating that SOD1 interacts with the crowder proteins in a residue-specific manner that further depends on the identity of the crowding protein...
February 12, 2019: Journal of Physical Chemistry. B
David Gnutt, Stepan Timr, Jonas Ahlers, Benedikt König, Emily Manderfeld, Matthias Heyden, Fabio Sterpone, Simon Ebbinghaus
In cells, proteins are embedded in a crowded environment that controls their properties via manifold avenues including weak protein-macromolecule interactions. A molecular level understanding of these quinary interactions and their contribution to protein stability, function and localization in the cell is central to modern structural biology. Using a mutational analysis to quantify the energetic contributions of single amino acids to the stability of the ALS related protein superoxide dismutase I (SOD1) in mammalian cells, we show that quinary interactions destabilize SOD1 by a similar energetic offset for most of the mutants, but there are notable exceptions: Mutants that alter its surface properties can even lead to a stabilization of the protein in the cell compared to the test tube...
February 11, 2019: Journal of the American Chemical Society
Chih Ming Kao, Wei-Jen Ou, Heng-Dao Lin, Ari Wahyuni Eva, Tzu-Ling Wang, Ssu Ching Chen
Diuron is an herbicide, which is used to control a wide variety of annual and perennial broadleaf, grassy weeds, and mosses. However, the toxicity of diuron in HepG2 cells and zebrafish embryos was unclear. In this study, HpeG2 cells and zebrafish embryos were exposed to different concentrations of diuron for 24 h and 48 h, respectively. Results reveal the diuron caused cytotoxicity and the generation of reactive oxygen species (ROS) in the treated HepG2 cells. The effects of diuron on the expression of catalase and superoxide dismutase (SOD1 and SOD2), an antioxidant enzyme, were investigated...
February 5, 2019: Ecotoxicology and Environmental Safety
Cui Li, Yan Li, Ziqi Zhao, Yuanyuan Lv, Boya Gu, Li Zhao
Aerobic exercise lowers blood pressure in patients with hypertension, but the underlying mechanisms remain incompletely understood. The hypothalamic paraventricular nucleus (PVN) plays a key role in the control of sympathetic outflow and cardiovascular tone. We examined whether chronic aerobic exercise altered synaptic transmission and reactive oxygen species (ROS) production in the PVN. In the present study, spontaneously hypertensive rats (SHRs) were subjected to exercise training for 8 weeks, five times per week, with Wistar Kyoto (WKY) rats as the cohort control...
February 5, 2019: Brain Research
Fernanda A Sala, Gareth S A Wright, Svetlana V Antonyuk, Richard C Garratt, S Samar Hasnain
Superoxide dismutase-1 (SOD1) maturation comprises a string of posttranslational modifications which transform the nascent peptide into a stable and active enzyme. The successive folding, metal ion binding, and disulphide acquisition steps in this pathway can be catalysed through a direct interaction with the copper chaperone for SOD1 (CCS). This process confers enzymatic activity and reduces access to noncanonical, aggregation-prone states. Here, we present the functional mechanisms of human copper chaperone for SOD1 (hCCS)-catalysed SOD1 activation based on crystal structures of reaction precursors, intermediates, and products...
February 8, 2019: PLoS Biology
Bing Zhao, Xiaoyu Zhuang, Xinyu Bian, Zifeng Pi, Shu Liu, Zhiqiang Liu, Fengrui Song
Considering aprotic solvents are often used as cosolvents in investigating the interactions between small molecules and proteins, we assessed the effects of five aprotic solvents represented by dimethyl-formamide (DMF) on the structure stabilities of metal-free SOD1 (apo-SOD1) by native electrospray ionization-ion mobility-mass spectrometry (ESI-IM-MS). These aprotic solvents include DMF, 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl-sulfoxide (DMSO), acetonitrile (ACN) and tetrahydrofuran (THF). Results indicated that DMI, DMSO and DMF at low percentage concentration could reduce the average charge and the dimer dissociation of apo-SOD1...
February 8, 2019: Journal of Mass Spectrometry: JMS
Stefanie Schreiber, Frank Schreiber, Cornelia Garz, Grazyna Debska-Vielhaber, Anne Assmann, Valentina Perosa, Susanne Petri, Reinhard Dengler, Peter Nestor, Stefan Vielhaber
INTRODUCTION: We aimed to identify ALS patients displaying suspected peripheral nervous system (PNS) inflammation, to compare them to those with suspected PNS degeneration. METHODS: We measured sonographic median and ulnar nerve cross-sectional area (CSA) and CSF albumin/serum albumin ratio (Qalb ) in ALS patients, to classify them as having suspected PNS degeneration (small CSA/low Qalb ) or inflammation (larger CSA/high Qalb ). RESULTS: 57% of patients had suspected PNS degeneration, 21% had suspected PNS inflammation, and 21% displayed suspected "normal PNS state"...
February 7, 2019: Muscle & Nerve
Karina Joppe, Anna-Elisa Roser, Fabian Maass, Paul Lingor
The homeostasis of iron is of fundamental importance in the central nervous system (CNS) to ensure biological processes such as oxygen transport, mitochondrial respiration or myelin synthesis. Dyshomeostasis and accumulation of iron can be observed during aging and both are shared characteristics of several neurodegenerative diseases. Iron-mediated generation of reactive oxygen species (ROS) may lead to protein aggregation and cellular toxicity. The process of misfolding and aggregation of neuronal proteins such as α-synuclein, Tau, amyloid beta (Aβ), TDP-43 or SOD1 is a common hallmark of many neurodegenerative disorders and iron has been shown to facilitate protein aggregation...
2019: Frontiers in Neuroscience
Susanna Zucca, Stella Gagliardi, Cecilia Pandini, Luca Diamanti, Matteo Bordoni, Daisy Sproviero, Maddalena Arigoni, Martina Olivero, Orietta Pansarasa, Mauro Ceroni, Raffaele Calogero, Cristina Cereda
Coding and long non-coding RNA (lncRNA) metabolism is now revealing its crucial role in Amyotrophic Lateral Sclerosis (ALS) pathogenesis. In this work, we present a dataset obtained via Illumina RNA-seq analysis on Peripheral Blood Mononuclear Cells (PBMCs) from sporadic and mutated ALS patients (mutations in FUS, TARDBP, SOD1 and VCP genes) and healthy controls. This dataset allows the whole-transcriptome characterization of PBMCs content, both in terms of coding and non-coding RNAs, in order to compare the disease state to the healthy controls, both for sporadic patients and for mutated patients...
February 5, 2019: Scientific Data
Xiaodi Qiu, Xianfang Rong, Jin Yang, Yi Lu
BACKGROUND: To compare the protective effects of the histone deacetylase inhibitors (HDACis) β-hydroxybutyrate (βOHB), trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA) on human lens epithelial cells(HLECs) following ultraviolet-B (UVB) exposure. METHODS: HLECs were divided into subgroups: four HDACi groups, a control group, a UVB-treated group and a DMSO group (cells treated with DMSO and UVB irradiation). In the HDACi groups, HLECs were cultured with different concentrations of HDACis 12 h prior to UVB irradiation...
February 4, 2019: BMC Ophthalmology
Evgenii D Kryl'skii, Tatyana N Popova, Olga A Safonova, Anna O Stolyarova, Grigorii A Razuvaev, Miguel Angelo Pinheiro de Carvalho
The article studies the effect of melatonin on the intensity of free radical oxidation, the functioning of the enzymatic components of the antioxidant system and their transcriptional regulation in rats with experimental cerebral ischemia/reperfusion of the brain. The development of ischemia/reperfusion was characterized by the activation of apoptotic processes and the accumulation of mRNA of the genes Sod1, Cat, Gpx1, Gsr, Hif-1α, Nrf2, Nfkb2, and Foxo1 in the rats' brains. The use of melatonin in the presence of the pathological induction led to a change in these parameters towards the control values...
February 1, 2019: Neuroscience
Kayo Augusto Salandin Pacher, Thaís Furtado Camargo, Thiago Antônio Moretti Andrade, Helena Cristina Barbosa-Sampaio, Maria Esméria Corezola Amaral
We investigate structural and functional adaptations of the pancreas during weight cycling in animals submitted to hypoestrogenism. Female Wistar groups: ShamAL (AL: ad libitum), OVXAL (ovariectomized), and OVXcycle (dietary restriction with weight cycling). The ShamAL and OVXAL received ad libitum commercial feed, while the OVXcycle received 21 days of ad libitum commercial feed and 21 days of caloric restriction with 40% of the amount of feed consumed by the OVXAL. The tolerance tests for glucose and insulin were applied...
February 1, 2019: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
Paula Korhonen, Eveliina Pollari, Katja M Kanninen, Ekaterina Savchenko, Šárka Lehtonen, Sara Wojciechowski, Yuriy Pomeshchik, Ludo Van Den Bosch, Gundars Goldsteins, Jari Koistinaho, Tarja Malm
Inflammation is a prominent feature of the neuropathology of amyotrophic lateral sclerosis (ALS). Emerging evidence suggests that inflammatory cascades contributing to the disease progression are not restricted to the central nervous system (CNS) but also occur peripherally. Indeed, alterations in T cell responses and their secreted cytokines have been detected in ALS patients and in animal models of ALS. One key cytokine responsible for the shift in T cell responses is interleukin-33 (IL-33), which stimulates innate type 2 immune cells to produce a large amount of Th2 cytokines that are possibly beneficial in the recovery processes of CNS injuries...
June 2019: IBRO Reports
E Srinivasan, R Rajasekaran
Mutations in the gene encoding Cu/Zn Superoxide Dismutase 1 (SOD1) protein are contemplated to be a protruding reason for Amyotrophic lateral sclerosis (ALS), which leads towards protein aggregation, misfolding and destabilization. Thus, we investigated the systematic action of entire mutations reported on electrostatic loop of SOD1 protein through thermodynamical and discrete molecular dynamics (DMD) studies. Accordingly, we analyzed the outcomes distinctly for screening the mutant structures having both, deleterious and destabilizing effect...
January 30, 2019: Protein Journal
Lei Yang, Zhen Gao, Lanjie Lei, Qizhuang Lv, Qihan Zhao, Lixin Li, Xiaoming Cao, Wenxue Fu
Lycium barbarum polysaccharide (LBP) exhibits multiple pharmacological and biological effects, including displaying antioxidant and cytoprotective properties. The current study investigated the effects of LBP-supplemented culture medium on mitochondrial distribution, mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) production, mitochondrial deoxyribonucleic acid (mtDNA) copy number, reactive oxygen species (ROS) accumulation, and development of previously-cryopreserved murine two-cell embryos...
January 31, 2019: Journal of Reproduction and Development
Chen Wu, Michelle E Watts, Lee L Rubin
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons (MNs). To date, its underlying mechanisms have yet to be clarified completely, and there are no truly effective treatments. Here, we show that MAP4K4, a MAP kinase family member, regulates MN death, with its suppression not only promoting survival but preventing neurite degeneration and decreasing mutant SOD1 levels through autophagy activation. Moreover, we report that MAP4K4 signaling specifically modulates MN viability via phosphorylated JNK3 and activation of the canonical c-Jun apoptotic pathway...
January 29, 2019: Cell Reports
Ji Hyeon Ahn, Myoung Cheol Shin, Dae Won Kim, Hyunjung Kim, Minah Song, Tae-Kyeong Lee, Jae-Chul Lee, Hyeyoung Kim, Jun Hwi Cho, Young-Myeong Kim, Jong-Dai Kim, Soo Young Choi, Moo-Ho Won, Joon Ha Park
Fucoidan, a natural sulfated polysaccharide, displays various biological activities including antioxidant properties. We examined the neuroprotective effect of fucoidan against transient global cerebral ischemia (tGCI) in high-fat diet (HFD)-induced obese gerbils and its related mechanisms. Gerbils received HFD for 12 weeks and fucoidan (50 mg/kg) daily for the last 5 days during HFD exposure, and they were subjected to 5-min tGCI. Pyramidal cell death was observed only in the CA 1 area (CA1) of the hippocampus in non-obese gerbils 5 days after tGCI...
January 28, 2019: International Journal of Molecular Sciences
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