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Zhu-Ling Guo, Des R Richardson, Danuta S Kalinowski, Zaklina Kovacevic, Kian Cheng Tan-Un, Godfrey Chi-Fung Chan
BACKGROUND: Neuroblastoma is a relatively common and highly belligerent childhood tumor with poor prognosis by current therapeutic approaches. A novel anti-cancer agent of the di-2-pyridylketone thiosemicarbazone series, namely di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), demonstrates promising anti-tumor activity. Recently, a second-generation analogue, namely di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), has entered multi-center clinical trials for the treatment of advanced and resistant tumors...
September 27, 2016: Journal of Hematology & Oncology
Brandon Jon Reeder
<i>Significance:</i> Erythrocyte hemoglobin and myocyte myoglobin, although primarily oxygen carrying proteins, have the capacity to do redox chemistry. Such redox activity in the wider family of globins now appears to have important associations with the mechanisms of cell stress response. In turn an understanding of such mechanisms <i>in vivo</i> may have a potential in the understanding of cancer therapy resistance and neurodegenerative disorders such as Alzheimer's. <i>Recent Advances:</i> There has been an enhanced understanding of the redox chemistry of the globin superfamily in recent years, leading to advances in development of hemoglobin-based blood substitutes and in hypotheses relating to specific disease mechanisms...
September 16, 2016: Antioxidants & Redox Signaling
Jonas Koch, Julia Lüdemann, Rieke Spies, Marco Last, Chris T Amemiya, Thorsten Burmester
Myoglobin is a respiratory protein that serves as a model system in a variety of biological fields. Its main function is to deliver and store O2 in the heart and skeletal muscles, but myoglobin is also instrumental in homeostasis of nitric oxide (NO) and detoxification of reactive oxygen species (ROS). Almost every vertebrate harbors a single myoglobin gene; only some cyprinid fishes have two recently duplicated myoglobin genes. Here we show that the West African lungfish Protopterus annectens has at least seven distinct myoglobin genes (PanMb1-7), which diverged early in the evolution of lungfish and showed an enhanced evolutionary rate...
August 10, 2016: Molecular Biology and Evolution
A Jasmijn Hubers, Daniëlle A M Heideman, Sylvia Duin, Birgit I Witte, Harry J de Koning, Harry J M Groen, Clemens F M Prinsen, Anne S Bolijn, Mandy Wouters, Susanne E van der Meer, Renske D M Steenbergen, Peter J F Snijders, Anne Uyterlinde, Hans Berkhof, Egbert F Smit, Erik Thunnissen
AIMS: Lung cancer is the major contributor to cancer mortality due to metastasised disease at time of presentation. The current study investigated DNA hypermethylation of biomarkers RASSF1A, APC, cytoglobin, 3OST2, FAM19A4, PHACTR3 and PRDM14 in sputum of asymptomatic high-risk individuals from the NELSON lung cancer low-dose spiral CT screening trial to detect lung cancer at preclinical stage. METHODS: Subjects were selected with (i) lung cancer in follow-up (cases; n=65), (ii) minor cytological aberrations (controls; n=120) and (iii) a random selection of subjects without cytological aberrations (controls; n=99)...
August 5, 2016: Journal of Clinical Pathology
Barbara Tae, Kelen Carneiro Oliveira, Rodrigo Rodrigues da Conceição, Vitor Engrácia Valenti, Janaina Sena de Souza, Roberto Laureano-Melo, Monica Akemi Sato, Rui Monteiro de Barros Maciel, Gisele Giannocco
The side stream cigarette smoke (SSCS) is a contributing factor in the pathogenesis of cigarette smoking-induced toxicity. Hemoglobin (Hb), myoglobin (Mb), neuroglobin (Ngb), and cytoglobin (Cygb) are globins with different distributions and functions in the tissues and have similar actions by providing O2 (oxygen) for respiratory chain, detoxification of ROS and nitric oxide (NO), and protect tissues against irreversible lesions. We aimed to investigate the effects of SSCS exposure on gene and protein expression of Ngb, Cygb, and Mb in different tissue...
July 21, 2016: Environmental Toxicology
N J O'Farrell, R Feighery, S L Picardo, N Lynam-Lennon, M Biniecka, S A McGarrigle, J J Phelan, F MacCarthy, D O'Toole, E J Fox, N Ravi, J V Reynolds, J O'Sullivan
BACKGROUND: Barrett's esophagus follows the classic step-wise progression of metaplasia-dysplasia-adenocarcinoma. While Barrett's esophagus is a leading known risk factor for esophageal adenocarcinoma, the pathogenesis of this disease sequence is poorly understood. Mitochondria are highly susceptible to mutations due to high levels of reactive oxygen species (ROS) coupled with low levels of DNA repair. The timing and levels of mitochondria instability and dysfunction across the Barrett's disease progression is under studied...
2016: BMC Cancer
Paola Corti, Jianmin Xue, Jesús Tejero, Nadeem Wajih, Ming Sun, Donna B Stolz, Michael Tsang, Daniel B Kim-Shapiro, Mark T Gladwin
The discovery of novel globins in diverse organisms has stimulated intense interest in their evolved function, beyond oxygen binding. Globin X (GbX) is a protein found in fish, amphibians, and reptiles that diverged from a common ancestor of mammalian hemoglobins and myoglobins. Like mammalian neuroglobin, GbX was first designated as a neuronal globin in fish and exhibits six-coordinate heme geometry, suggesting a role in intracellular electron transfer reactions rather than oxygen binding. Here, we report that GbX to our knowledge is the first six-coordinate globin and the first globin protein apart from hemoglobin, found in vertebrate RBCs...
July 26, 2016: Proceedings of the National Academy of Sciences of the United States of America
Stefan Reuss, Sylvia Wystub, Ursula Disque-Kaiser, Thomas Hankeln, Thorsten Burmester
Cytoglobin (Cygb) is a vertebrate globin with so far poorly defined function. It is expressed in the fibroblast cell-lineage but has also been found in neurons. Here we provide, using immunohistochemistry, a detailed study on the distribution of Cygb in the mouse brain. While Cygb is a cytoplasmic protein in active cells of the supportive tissue, in neurons it is located in the cytoplasm and the nucleus. We found the expression of Cygb in all brain regions, although only a fraction of the neurons was Cygb-positive...
2016: Frontiers in Neuroanatomy
Le Thi Thanh Thuy, Tuong Thi Van Thuy, Yoshinari Matsumoto, Hoang Hai, Yoshihiro Ikura, Katsutoshi Yoshizato, Norifumi Kawada
Cytoglobin (Cygb) was identified in hepatic stellate cells (HSCs) and pericytes of all organs; however, the effects of Cygb on cellular functions remain unclear. Here, we report spontaneous and age-dependent malformations in multiple organs of Cygb(-/-) mice. Twenty-six percent of young Cygb(-/-) mice (<1 year old) showed heart hypertrophy, cystic disease in the kidney or ovary, loss of balance, liver fibrosis and lymphoma. Furthermore, 71.3% (82/115) of aged Cygb(-/-) mice (1-2 years old) exhibited abnormalities, such as heart hypertrophy and cancer development in multiple organs; by contrast, 5...
2016: Scientific Reports
Zhen Li, Wei Wei, Bohong Chen, Gaotai Cai, Xin Li, Ping Wang, Jinping Tang, Wenqi Dong
This study aims to investigate whether the use of recombinant human cytoglobin (rhCygb) impact on hepatic fibrogenesis caused by CCl4. SD (n = 150) rats were randomly divided into three groups of normal, CCl4 model and rhCygb groups. After model establishment, rats in rhCygb groups were administered daily with rhCygb (2 mg/kg, s.c.). Histological lesions were staged according to metavir. Serum parameters including ALT, AST, HA, LN, Col III and Col IV were determined. The liver proteins were separated by 2-DE and identified...
2016: Scientific Reports
Katsutoshi Yoshizato, Le Thi Thanh Thuy, Goshi Shiota, Norifumi Kawada
Cytoglobin (CYGB), a new member of the globin family, was discovered in 2001 as a protein associated with stellate cell activation (stellate cell activation-associated protein [STAP]). Knowledge of CYGB, including its crystal, gene, and protein structures as well as its physiological and pathological importance, has increased progressively. We investigated the roles of oxygen (O2)-binding CYGB as STAP in hepatic stellate cells (HSCs) to understand the part played by this protein in their pathophysiological activities...
2016: Proceedings of the Japan Academy. Series B, Physical and Biological Sciences
Jesús Tejero, Alexandr A Kapralov, Matthew P Baumgartner, Courtney E Sparacino-Watkins, Tamil S Anthonymutu, Irina I Vlasova, Carlos J Camacho, Mark T Gladwin, Hülya Bayir, Valerian E Kagan
Cytoglobin (Cygb) is a hexa-coordinated hemoprotein with yet to be defined physiological functions. The iron coordination and spin state of the Cygb heme group are sensitive to oxidation of two cysteine residues (Cys38/Cys83) and/or the binding of free fatty acids. However, the roles of redox vs lipid regulators of Cygb's structural rearrangements in the context of the protein peroxidase competence are not known. Searching for physiologically relevant lipid regulators of Cygb, here we report that anionic phospholipids, particularly phosphatidylinositolphosphates, affect structural organization of the protein and modulate its iron state and peroxidase activity both conjointly and/or independently of cysteine oxidation...
May 2016: Biochimica et Biophysica Acta
Cong Zhao, Weihong Du
Cytoglobin (Cgb) is a member of hemoprotein family with roles in NO metabolism, fibrosis, and tumourigenesis. Similar to other hemoproteins, Cgb structure and functions are markedly influenced by distal key residues. The sixth ligand His(81) (E7) is crucial to exogenous ligand binding, heme pocket conformation, and physiological roles of this protein. However, the effects of other key residues on heme pocket and protein biological functions are not well known. In this work, a molecular dynamics (MD) simulation study of two single mutants in CO-ligated Cgb (L46FCgbCO and L46VCgbCO) and two double mutants (L46FH81QCgbCO and L46VH81QCgbCO) was conducted to explore the effects of the key distal residues Leu(46)(B10) and His(81)(E7) on Cgb structure and functions...
April 2016: Journal of Biological Inorganic Chemistry: JBIC
Kim Rohlfing, Friederike Stuhlmann, Margaret F Docker, Thorsten Burmester
BACKGROUND: During development, humans and other jawed vertebrates (Gnathostomata) express distinct hemoglobin genes, resulting in different hemoglobin tetramers. Embryonic and fetal hemoglobin have higher oxygen affinities than the adult hemoglobin, sustaining the oxygen demand of the developing organism. Little is known about the expression of hemoglobins during development of jawless vertebrates (Agnatha). RESULTS: We identified three hemoglobin switches in the life cycle of the sea lamprey...
2016: BMC Evolutionary Biology
Paola Corti, Matthew Ieraci, Jesús Tejero
Neuroglobin (Ngb) and cytoglobin (Cygb) are two six-coordinate heme proteins of unknown physiological function. Although studies on the mammalian proteins have elucidated aspects of Ngb and Cygb biophysics and indicated potential functions, the properties of non-mammalian Ngbs and Cygbs are largely uncharacterized. We have expressed the recombinant zebrafish proteins Ngb, Cygb1, and Cygb2 in Escherichia coli and characterized their nitrite reduction rates, spectral properties, autoxidation rate constants, redox potentials and lipid binding properties...
February 29, 2016: Nitric Oxide: Biology and Chemistry
Norifumi Kawada
Myofibroblasts play important roles in inflammation, fibrosis and tumorigenesis in chronically inflamed liver. Liver myofibroblasts originate from hepatic stellate cells, portal fibroblasts or mesothelial cells, and they are localized in and around fibrotic septum and portal tracts. Liver myofibroblasts are the source of extracellular matrix materials, including type I collagen and multiple fibrogenic growth factors, such as transforming growth factor-β and vascular endothelial growth factor. Although a detailed characterization of the function of individual myofibroblasts has not been conducted, owing to the lack of appropriate cell markers, recent lineage-tracing technology has revealed the limited contribution of myofibroblasts that are derived from portal fibroblasts to various types of liver fibrosis, as compared with the contribution of hepatic stellate cells...
2015: Frontiers in Physiology
Thi Thanh Thuy Le, Nguyen Thi Thanh Hai, Hoang Hai, Norifumi Kawada
Cytoglobin (Cygb), a stellate cell-specific globin, has recently drawn attention due to its association with liver fibrosis and cancer. In human and rodent livers, Cygb is expressed only in stellate cells and can be utilized as a marker to distinguish stellate cells from hepatic fibroblast-derived myofibroblasts. Loss of Cygb accelerates liver fibrosis and cancer development despite its etiology in mouse models of chronic liver injury. This review discusses the current perception of the distribution, regulation and function of Cygb with regard to liver diseases, with an emphasis on its role in tumorigenesis...
March 2016: Histology and Histopathology
Tatsha C Bholah, Vidushi S Neergheen-Bhujun, Nikolas J Hodges, Sabrina D Dyall, Theeshan Bahorun
The search for biomarkers to detect the earliest glimpse of cancer has been one of the primary objectives of cancer research initiatives. These endeavours, in spite of constant clinical challenges, are now more focused as early cancer detection provides increased opportunities for different interventions and therapies, with higher potential for improving patient survival and quality of life. With the progress of the omics technologies, proteomics and metabolomics are currently being used for identification of biomarkers...
2015: BioMed Research International
Kelen Carneiro Oliveira, Rodrigo Rodrigues da Conceição, Gisele Constantinov Piedade, Janaina Sena de Souza, Monica Akemi Sato, Rui Monteiro de Barros Maciel, Gisele Giannocco
Thyroid hormones (THs) are essential and crucial for brain development, playing a role in growth and differentiation. Two globins named neuroglobin (Ngb) and cytoglobin (Cygb) are located in the brain, and each one has different distribution and function: They seem to have similar action by providing O(2) for respiratory chain, and detoxification of reactive oxygen species (ROS) and nitric oxide (NO) protecting tissues against irreversible lesions. We aimed to investigate the influence of thyroid state in Ngb and Cygb metabolism in different brain regions and evaluate their responses in cerebellum, hippocampus and cerebral cortex (hereafter called as cortex) after supraphysiological doses at different time points of TH administration...
December 2015: Metabolic Brain Disease
Juliana C Ferreira, Marcelo F Marcondes, Marcelo Y Icimoto, Thyago H S Cardoso, Aryane Tofanello, Felipe S Pessoto, Erica G A Miranda, Tatiana Prieto, Otaciro R Nascimento, Vitor Oliveira, Iseli L Nantes
We characterized the peroxidase mechanism of recombinant rat brain cytoglobin (Cygb) challenged by hydrogen peroxide, tert-butylhydroperoxide and by cumene hydroperoxide. The peroxidase mechanism of Cygb is similar to that of myoglobin. Cygb challenged by hydrogen peroxide is converted to a Fe4+ oxoferryl π cation, which is converted to Fe4+ oxoferryl and tyrosyl radical detected by direct continuous wave-electron paramagnetic resonance and by 3,5-dibromo-4-nitrosobenzene sulfonate spin trapping. When organic peroxides are used as substrates at initial reaction times, and given an excess of peroxide present, the EPR signals of the corresponding peroxyl radicals precede those of the direct tyrosyl radical...
2015: PloS One
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