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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
Eliana Baez, Valentina Echeverria, Ricardo Cabezas, Marco Ávila-Rodriguez, Luis Miguel Garcia-Segura, George E Barreto
Astrocytes play an important role in physiological, metabolic, and structural functions, and when impaired, they can be involved in various pathologies including Alzheimer, focal ischemic stroke, and traumatic brain injury. These disorders involve an imbalance in the blood flow and nutrients such as glucose and lactate, leading to biochemical and molecular changes that cause neuronal damage, which is followed by loss of cognitive and motor functions. Previous studies have shown that astrocytes are more resilient than neurons during brain insults as a consequence of their more effective antioxidant systems, transporters, and enzymes, which made them less susceptible to excitotoxicity...
2016: Frontiers in Neurology
Navjot Singh Athwal, Jagannathan Alagurajan, Amy H Andreotti, Mark S Hargrove
Reduction of hydroxylamine to ammonium by phytoglobin, a plant hexacoordinate hemoglobin, is much faster than that of other hexacoordinate hemoglobins or pentacoordinate hemoglobins such as myoglobin, leghemoglobin, and red blood cell hemoglobin. The reason for differences in reactivity is not known but could be intermolecular electron transfer between protein molecules in support of the required two-electron reduction, hydroxylamine binding, or active site architecture favoring the reaction. Experiments were conducted with phytoglobins from rice, tomato, and soybean along with human neuroglobin and soybean leghemoglobin that reveal hydroxylamine binding as the rate-limiting step...
October 5, 2016: Biochemistry
Kin Tung Tam, Ping Kei Chan, Wei Zhang, Pui Pik Law, Zhipeng Tian, Godfrey Chi Fung Chan, Sjaak Philipsen, Richard Festenstein, Kian Cheng Tan-Un
Neuroglobin (NGB) is predominantly expressed in the brain and retina. Studies suggest that NGB exerts protective effects to neuronal cells and is implicated in reducing the severity of stroke and Alzheimer's disease. However, little is known about the mechanisms which regulate the cell type-specific expression of the gene. In this study, we hypothesized that distal regulatory elements (DREs) are involved in optimal expression of the NGB gene. By chromosome conformation capture we identified two novel DREs located -70 kb upstream and +100 kb downstream from the NGB gene...
September 19, 2016: Nucleic Acids Research
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
Andrej Fabrizius, Daniel Andre, Tilmann Laufs, Anne Bicker, Stefan Reuss, Elena Porto, Thorsten Burmester, Thomas Hankeln
Neuroglobin (Ngb) is a respiratory protein that is almost exclusively expressed in the vertebrate nervous system. Despite many years of research, the exact function and even the expression sites of Ngb are still a matter of debate. However, to investigate hypotheses surrounding the potential roles of Ngb, a detailed knowledge of its major and minor expression sites is indispensable. We have therefore evaluated Ngb expression by extensive bioinformatic analysis using publicly available transcriptome data (RNA-Seq)...
August 16, 2016: Neuroscience
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
Ran Fan, Tao Yu, Jia-Li Lin, Guang-Dong Ren, Yi Li, Xiao-Xing Liao, Zi-Tong Huang, Chong-Hui Jiang
In this study, we investigated the effects of remote ischemic preconditioning on post resuscitation cerebral function in a rat model of cardiac arrest and resuscitation. The animals were randomized into six groups: 1) sham operation, 2) lateral ventricle injection and sham operation, 3) cardiac arrest induced by ventricular fibrillation, 4) lateral ventricle injection and cardiac arrest, 5) remote ischemic preconditioning initiated 90min before induction of ventricular fibrillation, and 6) lateral ventricle injection and remote ischemic preconditioning before cardiac arrest...
October 1, 2016: Brain Research
Nicolas Toro-Urrego, Luis M Garcia-Segura, Valentina Echeverria, George E Barreto
Testosterone is a hormone that has been shown to confer neuroprotection from different insults affecting the central nervous system (CNS). Testosterone induces this protection by different mechanisms that include the activation of anti-apoptotic pathways that are directly implicated in neuronal survival. However, little attention has been devoted to its actions on glial cells. In the present study, we have assessed whether testosterone exerts protection in a human astrocyte cell model, the T98G cells. Our results indicate that testosterone improves cell survival and mitochondrial membrane potential and reduces nuclear fragmentation and reactive oxygen species (ROS) generation...
2016: Frontiers in Aging Neuroscience
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
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
Stanislav Trashin, Mats de Jong, Evi Luyckx, Sylvia Dewilde, Karolien De Wael
The true function of neuroglobin (Ngb) and, particularly, human Ngb (NGB) has been under debate since its discovery 15 years ago. It has been expected to play a role in oxygen binding/supply, but a variety of other functions have been put forward, including NO dioxygenase activity. However, in vitro studies that could unravel these potential roles have been hampered by the lack of an Ngb-specific reductase. In this work, we used electrochemical measurements to investigate the role of an intermittent internal disulfide bridge in determining NO oxidation kinetics at physiological NO concentrations...
September 2, 2016: Journal of Biological Chemistry
Alexandra Kleinknecht, Blagovesta Popova, Diana F Lázaro, Raquel Pinho, Oliver Valerius, Tiago F Outeiro, Gerhard H Braus
Parkinson´s disease (PD) is characterized by the presence of proteinaceous inclusions called Lewy bodies that are mainly composed of α-synuclein (αSyn). Elevated levels of oxidative or nitrative stresses have been implicated in αSyn related toxicity. Phosphorylation of αSyn on serine 129 (S129) modulates autophagic clearance of inclusions and is prominently found in Lewy bodies. The neighboring tyrosine residues Y125, Y133 and Y136 are phosphorylation and nitration sites. Using a yeast model of PD, we found that Y133 is required for protective S129 phosphorylation and for S129-independent proteasome clearance...
June 2016: PLoS Genetics
Michela Guglielmotto, Stefania Reineri, Andrea Iannello, Giulio Ferrero, Ludovica Vanzan, Valentina Miano, Laura Ricci, Elena Tamagno, Michele De Bortoli, Santina Cutrupi
Estrogens are neuroprotective factors in several neurological diseases. Neuroglobin (NGB) is one of the estrogen target genes involved in neuroprotection, but little is known about its transcriptional regulation. Estrogen genomic pathway in gene expression regulation is mediated by estrogen receptors (ERα and ERβ) that bind to specific regulatory genomic regions. We focused our attention on 17β-estradiol (E2)-induced NGB expression in human differentiated neuronal cell lines (SK-N-BE and NT-2). Previously, using bioinformatics analysis we identified a putative enhancer in the first intron of NGB locus...
2016: Frontiers in Cellular Neuroscience
Marco Fiocchetti, Manuela Cipolletti, Stefano Leone, Paolo Ascenzi, Maria Marino
Although paclitaxel (Taxol) is an active chemotherapeutic agent for the treatment of breast cancer, not all breast tumors are sensitive to this drug. In particular, there is a wide agreement on the low sensitivity of estrogen receptor (ER) α-positive breast cancer to paclitaxel treatment. However, the ERα-based insensitivity to paclitaxel is still elusive. Here, the effect of the E2/ERα-dependent upregulation of neuroglobin (NGB), an antiapoptotic globin, on the reduced sensitivity of breast cancer cells to paclitaxel-induced apoptosis has been evaluated in ERα-containing MCF-7 cells...
August 2016: IUBMB Life
Claudia L Ramírez, Ariel Petruk, Mauro Bringas, Dario A Estrin, Adrian E Roitberg, Marcelo A Marti, Luciana Capece
Heme proteins are ubiquitous in nature and perform many diverse functions in all kingdoms of life. Many of these functions are related to large-scale conformational transitions and allosteric processes. Sampling of these large conformational changes is computationally very challenging. In this context, coarse-grain simulations emerge as an efficient approach to explore the conformational landscape. In this work, we present a coarse-grained model of the heme group and thoroughly validate this model in different benchmark examples, which include the monomeric heme proteins myoglobin and neuroglobin and the tetrameric human hemoglobin where we evaluated the method's ability to explore conformational changes (as the formation of hexacoordinated species) and allosteric transitions (as the well-known R → T transition)...
July 12, 2016: Journal of Chemical Theory and Computation
Marco Avila-Rodriguez, Luis Miguel Garcia-Segura, Oscar Hidalgo-Lanussa, Eliana Baez, Janneth Gonzalez, George E Barreto
Tibolone, a synthetic steroid used for the prevention of osteoporosis and the treatment of climacteric symptoms in post-menopausal women, may exert tissue selective estrogenic actions acting on estrogen receptors (ERs). We previously showed that tibolone protects human T98G astroglial cells against glucose deprivation (GD). In this study we have explored whether the protective effect of tibolone on these cells is mediated by ERs. Experimental studies showed that both ERα and ERβ were involved in the protection by tibolone on GD cells, being ERβ preferentially involved on these actions over ERα...
September 15, 2016: Molecular and Cellular Endocrinology
Marco Fiocchetti, Manuela Cipolletti, Stefano Leone, Antonella Naldini, Fabio Carraro, Daniela Giordano, Cinzia Verde, Paolo Ascenzi, Maria Marino
The over-expression of human neuroglobin (NGB), a heme-protein preferentially expressed in the brain, displays anti-apoptotic effects against hypoxic/ischemic and oxidative stresses enhancing neuron survival. As hypoxic and oxidative stress injury frequently occurs in fast proliferating neoplastic tissues, here, the effect of these stressors on the level, localization, and anti-apoptotic function of NGB in wild type and NGB-stable-silenced MCF-7 breast cancer cells has been assessed. The well-known endogenous NGB inducer 17β-estradiol (E2) has been used as positive control...
2016: PloS One
Lei-Bin Wu, Hong Yuan, Hu Zhou, Shu-Qin Gao, Chang-Ming Nie, Xiangshi Tan, Ge-Bo Wen, Ying-Wu Lin
Disulfide bond plays crucial roles in stabilization of protein structure and in fine-tuning protein functions. To explore an approach for rational heme protein design, we herein rationally introduced a pair of cysteines (F46C/M55C) into the scaffold of myoglobin (Mb), mimicking those in native neuroglobin. Molecular modeling suggested that it is possible for Cys46 and Cys55 to form an intramolecular disulfide bond, which was confirmed experimentally by ESI-MS analysis, DTNB reaction and CD spectrum. Moreover, it was shown that the spontaneously formed disulfide bond of Cys46-Cys55 fine-tunes not only the heme active site structure, but also the protein functions...
June 15, 2016: Archives of Biochemistry and Biophysics
Nozomu Takahashi, Keisuke Wakasugi
Mammalian neuroglobin (Ngb) protects neuronal cells under conditions of oxidative stress. We previously showed that human Ngb acts as a guanine nucleotide dissociation inhibitor (GDI) for the α-subunits of heterotrimeric Gi/o proteins and inhibits the decrease in cAMP concentration, leading to protection against cell death. In the present study, we used an eukaryotic expression vector driving high-level expression of human wild-type Ngb or Ngb mutants that either exhibit or lack GDI activities in human cells...
2016: Scientific Reports
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