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De Backer, J.; Razzokov, J.; Hammerschmid, D.; Mensch, C.; Hafideddine, Z.; Kumar, N.; van Raemdonck, G.; Yusupov, M.; Van Doorslaer, S.; Johannessen, C.; Sobott, F.; Bogaerts, A.; Dewilde, S. |
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Title  |
The effect of reactive oxygen and nitrogen species on the structure of cytoglobin: A potential tumor suppressor |
Type |
A1 Journal article |
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Year |
2018 |
Publication |
Redox Biology |
Abbreviated Journal |
Redox Biol |
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Volume |
19 |
Issue |
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Pages |
1-10 |
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Keywords |
A1 Journal article; Plasma Lab for Applications in Sustainability and Medicine – Antwerp (PLASMANT); Molecular Spectroscopy (MolSpec) |
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Abstract |
Many current anti-cancer therapies rely on increasing the intracellular reactive oxygen and nitrogen species (RONS) contents with the aim to induce irreparable damage, which subsequently results in tumor cell death. A novel tool in cancer therapy is the use of cold atmospheric plasma (CAP), which has been found to be very effective in the treatment of many different cancer cell types in vitro as well as in vivo, mainly through the vast generation of RONS. One of the key determinants of the cell's fate will be the interaction of RONS, generated by CAP, with important proteins, i.e. redox-regulatory proteins. One such protein is cytoglobin (CYGB), a recently discovered globin proposed to be involved in the protection of the cell against oxidative stress. In this study, the effect of plasma-produced RONS on CYGB was investigated through the treatment of CYGB with CAP for different treatment times. Spectroscopic analysis of CYGB showed that although chemical modifications occur, its secondary structure remains intact. Mass spectrometry experiments identified these modifications as oxidations of mainly sulfur-containing and aromatic amino acids. With longer treatment time, the treatment was also found to induce nitration of the heme. Furthermore, the two surface-exposed cysteine residues of CYGB were oxidized upon treatment, leading to the formation of intermolecular disulfide bridges, and potentially also intramolecular disulfide bridges. In addition, molecular dynamics and docking simulations confirmed, and further show, that the formation of an intramolecular disulfide bond, due to oxidative conditions, affects the CYGB 3D structure, thereby opening the access to the heme group, through gate functioning of His117. Altogether, the results obtained in this study (1) show that plasma-produced RONS can extensively oxidize proteins and (2) that the oxidation status of two redox-active cysteines lead to different conformations of CYGB. |
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Wos |
000449722100002 |
Publication Date |
2018-07-24 |
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ISSN |
2213-2317 |
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Additional Links |
UA library record; WoS full record; WoS citing articles |
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Impact Factor |
6.337 |
Times cited |
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Open Access |
OpenAccess |
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Notes |
M.Y. and N.K. gratefully acknowledge financial support from the Research Foundation – Flanders (FWO), Grant nos. 1200216N and 12J5617N. The computational work was carried out using the Turing HPC infrastructure at the CalcUA core facility of the Universiteit Antwerpen (UA), a division of the Flemish Supercomputer Center VSC, funded by the Hercules Foundation, the Flemish Government (department EWI). C.M acknowledges the financial support provided by the Flemish Community and the University of Antwerp (BOF-NOI) for the pre-doctoral scholarship is under grant number/project ID: 28465. S.V.D., S. D. and Z.H. acknowledge the FWO (Grant G.0687.13) and the GOA-BOF UA 2013–2016 (project-ID 28312) for funding. The computational resources and services used in this work were provided by the HPC core facility CalcUA of the Universiteit Antwerpen, and VSC (Flemish Supercomputer Center), funded by the Research Foundation – Flanders (FWO) and the Flemish Government – department EWI. |
Approved |
Most recent IF: 6.337 |
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Call Number |
PLASMANT @ plasmant @c:irua:152818 |
Serial |
5006 |
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Author |
de Backer, W.; Vos, W.; Van Holsbeke, C.; Vinchurkar, S.; Claes, R.; Hufkens, A.; Parizel, P.M.; Bedert, L.; de Backer, J. |
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Title |
The effect of roflumilast in addition to LABA/LAMA/ICS treatment in COPD patients |
Type |
L1 Letter to the editor |
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Year |
2014 |
Publication |
European Respiratory Journal |
Abbreviated Journal |
Eur Respir J |
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44 |
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2 |
Pages |
527-529 |
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L1 Letter to the editor; Biophysics and Biomedical Physics; Condensed Matter Theory (CMT); Antwerp Surgical Training, Anatomy and Research Centre (ASTARC); Laboratory Experimental Medicine and Pediatrics (LEMP) |
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Copenhagen |
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000340017300029 |
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2014-05-03 |
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0903-1936;1399-3003; |
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Additional Links |
UA library record; WoS full record; WoS citing articles |
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Impact Factor |
10.569 |
Times cited |
26 |
Open Access |
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Notes |
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Approved |
Most recent IF: 10.569; 2014 IF: 7.636 |
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Call Number |
UA @ lucian @ c:irua:117335 |
Serial |
832 |
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De Backer, L.; Vos, W.; Dieriks, B.; Daems, D.; Verhulst, S.; Vinchurkar, S.; Ides, K.; de Backer, J.; Germonpré, P.; de Backer, W. |
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Title |
The effects of long-term noninvasive ventilation in hypercapnic COPD patients : a randomized controlled pilot study |
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A1 Journal article |
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Year |
2011 |
Publication |
International journal of chronic obstructive pulmonary disease |
Abbreviated Journal |
Int J Chronic Obstr |
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6 |
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615-624 |
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Keywords |
A1 Journal article; Condensed Matter Theory (CMT); Laboratory Experimental Medicine and Pediatrics (LEMP) |
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Introduction: Noninvasive ventilation (NIV) is a well-established treatment for acute-on-chronic respiratory failure in hypercapnic COPD patients. Less is known about the effects of a long-term treatment with NIV in hypercapnic COPD patients and about the factors that may predict response in terms of improved oxygenation and lowered CO2 retention.Methods: In this study, we randomized 15 patients to a routine pharmacological treatment (n = 5, age 66 [standard deviation ± 6] years, FEV1 30.5 [±5.1] %pred, PaO2 65 [±6] mmHg, PaCO2 52.4 [±6.0] mmHg) or to a routine treatment and NIV (using the Synchrony BiPAP device [Respironics, Inc, Murrsville, PA]) (n = 10, age 65 [±7] years, FEV1 29.5 [±9.0] %pred, PaO2 59 [±13] mmHg, PaCO2 55.4 [±7.7] mmHg) for 6 months. We looked at arterial blood gasses, lung function parameters and performed a low-dose computed tomography of the thorax, which was later used for segmentation (providing lobe and airway volumes, iVlobe and iVaw) and post-processing with computer methods (providing airway resistance, iRaw) giving overall a functional image of the separate airways and lobes.Results: In both groups there was a nonsignificant change in FEV1 (NIV group 29.5 [9.0] to 38.5 [14.6] %pred, control group 30.5 [5.1] to 36.8 [8.7] mmHg). PaCO2 dropped significantly only in the NIV group (NIV: 55.4 [7.7] → 44.5 [4.70], P = 0.0076; control: 52.4 [6.0] → 47.6 [8.2], NS). Patients actively treated with NIV developed a more inhomogeneous redistribution of mass flow than control patients. Subsequent analysis indicated that in NIV-treated patients that improve their blood gases, mass flow was also redistributed towards areas with higher vessel density and less emphysema, indicating that flow was redistributed towards areas with better perfusion. There was a highly significant correlation between the % increase in mass flow towards lobes with a blood vessel density of >9% and the increase in PaO2. Improved ventilation–perfusion match and recruitment of previously occluded small airways can explain the improvement in blood gases.Conclusion: We can conclude that in hypercapnic COPD patients treated with long-term NIV over 6 months, a mass flow redistribution occurs, providing a better ventilation–perfusion match and hence better blood gases and lung function. Control patients improve homogeneously in iVaw and iRaw, without improvement in gas exchange since there is no improved ventilation/perfusion ratio or increased alveolar ventilation. These differences in response can be detected through functional imaging, which gives a more detailed report on regional lung volumes and resistances than classical lung function tests do. Possibly only patients with localized small airway disease are good candidates for long-term NIV treatment. To confirm this and to see if better arterial blood gases also lead to better health related quality of life and longer survival, we have to study a larger population. |
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000208709800066 |
Publication Date |
2011-11-18 |
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1178-2005; |
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Additional Links |
UA library record; WoS full record; WoS citing articles |
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Impact Factor |
3.157 |
Times cited |
28 |
Open Access |
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Approved |
Most recent IF: 3.157; 2011 IF: NA |
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Call Number |
UA @ lucian @ c:irua:93164 |
Serial |
866 |
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Author |
De Backer, J. |
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Title |
The versatile nature of cytoglobin, the Swiss army knife among globins, with a preference for oxidative stress |
Type |
Doctoral thesis |
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Year |
2023 |
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Abbreviated Journal |
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Pages |
XVIII, 232 p. |
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Keywords |
Doctoral thesis; Pharmacology. Therapy; Plasma Lab for Applications in Sustainability and Medicine – Antwerp (PLASMANT); Proteinscience, proteomics and epigenetic signaling (PPES) |
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Abstract |
Since its discovery 20 years ago, many studies have been performed to gain insight into the functional role of cytoglobin (Cygb). However, Cygb has been proven to be a promiscuous protein. Yet, there is a consensus that Cygb is a cytoprotective protein involved in redox homeostasis. CYGB is a ubiquitously expressed hexacoordinated globin that is highly expressed in melanocytes and is often found to be downregulated during melanocyte-to-melanoma transition. In Chapter III, we investigated the molecular mechanism through which CYGB could be involved in redox regulation. Here, we showed that CYGB contains two redox-sensitive cysteine residues and that the formation of an intramolecular disulfide bridge resulted in the heme group becoming more accessible to external ligands. This supports the hypothesis that Cys38 and Cys83 serve as sensitive redox sensors. In Chapter IV we showed that CYGB mRNA and protein levels were elevated upon exposure to hypoxia. Interestingly, this upregulation was most likely HIF-2α-dependent. We propose that in melanoma, HIF-2α, rather than HIF-1α, positively regulates CYGB under hypoxic conditions in a cell type specific way. In Chapter V, the cytotoxic effect of indirect NTP treatment in two melanoma cell lines with divergent endogenous CYGB expression levels was investigated. We confirmed that NTP endows cytotoxicity that induces cell death through apoptosis and that this was mediated through the production of ROS. Moreover, we showed that CYGB protects melanoma cells from ROS-induced apoptosis by the scavenging of ROS. Interestingly, CYGB expression influenced the expression of NRF2 and HO-1. We identified the lncRNA MEG3 as a possible mechanism through which NRF2 expression and its downstream target HO-1 can be regulated by CYGB. In chapter VI, increased basal ROS levels and higher degree of lipid peroxidation upon RSL3 treatment contributed to the increased sensitivity of CYGB knockdown G361 cells to ferroptosis. Furthermore, transcriptome analysis demonstrates the enrichment of multiple cancer malignancy pathways upon CYGB knockdown, supporting a tumor-suppressive role for CYGB. Remarkably, CYGB expression regulation was identified as a critical determinant of the ferroptosis–pyroptosis therapy response. This suggests that CYGB is involved in the regulation of multiple modes of programmed cell death. FInally, we sought to delineate the RONS that are responsible for plasma-induced ICD. Our results highlight the importance of the short-lived species. Furthermore, we are first to demonstrate that NTP-created vaccine is safely prepared and offers complete protection. Moreover, we provide conclusive evidence that direct application of NTP induces ICD in melanoma. |
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Most recent IF: NA |
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Call Number |
UA @ admin @ c:irua:193568 |
Serial |
7277 |
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de Backer, J.W.; Vos, W.G.; Vinchurkar, S.C.; Claes, R.; Drollmann, A.; Wulfrank, D.; Parizel, P.M.; Germonpré, P.; de Backer, W. |
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Validation of computational fluid dynamics in CT-based airway models with SPECT/CT1 |
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A1 Journal article |
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2010 |
Publication |
Radiology |
Abbreviated Journal |
Radiology |
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Volume |
257 |
Issue |
3 |
Pages |
854-862 |
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Keywords |
A1 Journal article; Condensed Matter Theory (CMT); Vision lab; Antwerp Surgical Training, Anatomy and Research Centre (ASTARC); Laboratory Experimental Medicine and Pediatrics (LEMP) |
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Purpose: To compare the results obtained by using numerical flow simulations with the results of combined single photon emission computed tomography (SPECT) and computed tomography (CT) and to demonstrate the importance of correct boundary conditions for the numerical methods to account for the large amount of interpatient variability in airway geometry. Materials and Methods: This study was approved by all relevant institutional review boards. All patients gave their signed informed consent. In this study, six patients with mild asthma (three men; three women; overall mean age, 46 years ± 17 [standard deviation]) underwent CT at functional residual capacity and total lung capacity, as well as SPECT/CT. CT data were used for segmentation and computational fluid dynamics (CFD) simulations. A comparison was made between airflow distribution, as derived with (a) SPECT/CT through tracer concentration analysis, (b) CT through lobar expansion measurement, and (c) CFD through flow computer simulation. Also, the heterogeneity of the ventilation was examined. Results: Good agreement was found between SPECT/CT, CT, and CFD in terms of airflow distribution and hot spot detection. The average difference for the internal airflow distribution was less than 3% for CFD and CT versus SPECT/CT. Heterogeneity in ventilation patterns could be detected with SPECT/CT and CFD. Conclusion: This results of this study show that patient-specific computer simulations with appropriate boundary conditions yield information that is similar to that obtained with functional imaging tools, such as SPECT/CT. |
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Easton, Pa |
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000284469300031 |
Publication Date |
2010-11-17 |
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0033-8419;1527-1315; |
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Additional Links |
UA library record; WoS full record; WoS citing articles |
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Impact Factor |
7.296 |
Times cited |
100 |
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Notes |
; Supported by Novartis. ; |
Approved |
Most recent IF: 7.296; 2010 IF: 6.069 |
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Call Number |
UA @ lucian @ c:irua:85379 |
Serial |
3831 |
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