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Heirman, P.; Verswyvel, H.; Bauwens, M.; Yusupov, M.; De Waele, J.; Lin, A.; Smits, E.; Bogaerts, A. |
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Title |
Effect of plasma-induced oxidation on NK cell immune checkpoint ligands: A computational-experimental approach |
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A1 Journal Article |
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Year |
2024 |
Publication |
Redox Biology |
Abbreviated Journal |
Redox Biology |
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Volume |
77 |
Issue |
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Pages |
103381 |
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Keywords |
A1 Journal Article; Non-thermal plasma Natural killer cells Immune checkpoints Cancer immunotherapy Umbrella sampling Oxidative stress; Plasma, laser ablation and surface modeling Antwerp (PLASMANT) ; |
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Abstract  |
Non-thermal plasma (NTP) shows promise as a potent anti-cancer therapy with both cytotoxic and immunomodulatory effects. In this study, we investigate the chemical and biological effects of NTP-induced oxidation on several key, determinant immune checkpoints of natural killer (NK) cell function. We used molecular dynamics (MD) and umbrella sampling simulations to investigate the effect of NTP-induced oxidative changes on the MHCI complexes HLA-Cw4 and HLA-E. Our simulations indicate that these chemical alterations do not significantly affect the binding affinity of these markers to their corresponding NK cell receptor, which is supported with
experimental read-outs of ligand expression on human head and neck squamous cell carcinoma cells after NTP application. Broadening our scope to other key ligands for NK cell reactivity, we demonstrate rapid reduction in CD155 and CD112, target ligands of the inhibitory TIGIT axis, and in immune checkpoint CD73 immediately after treatment. Besides these transient chemical alterations, the reactive species in NTP cause a cascade of downstream cellular reactions. This is underlined by the upregulation of the stress proteins MICA/B, potent ligands for NK cell activation, 24 h post treatment. Taken together, this work corroborates the immunomodulatory potential of NTP, and sheds light on the interaction mechanisms between NTP and cancer cells. |
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Publication Date |
2024-10-01 |
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ISSN |
2213-2317 |
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Impact Factor |
11.4 |
Times cited |
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Notes |
This research was funded by the Impuls project of the University of Antwerp, grant number 46381. We acknowledge financial support from the Fund for Scientific Research (FWO) Flanders (Grant ID 1100421N (Pepijn Heirman), 1S67621N (Hanne Verswyvel), G044420N (Abraham Lin) and G033020N (Pepijn Heirman, Annemie Bogaerts)). M.Y. ac knowledges the Agency for Innovative Development of the Republic of Uzbekistan, grant number AL-4821012320. The computational sources and services used in this work were provided by the HPC core facility CalcUA of the Universiteit Antwerpen, and VSC (Flemish percomputer Center), funded by the Research Foundation – Flanders (FWO) and the Flemish Government. This article is based upon work from COST Action CA20114 PlasTHER “Therapeutical Applications of Cold Plasmas”, supported by COST (European Cooperation in Science and Technology). We would also like to thank several patrons, as part of this research was funded by donations from different donors, including Dedert Schilde vzw, Mr Willy Floren, and the Vereycken family. Finally, we thank Robin De Meyer, Rani Vertongen and Louize Brants for their valuable input. |
Approved |
Most recent IF: 11.4; 2024 IF: 6.337 |
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Call Number |
PLASMANT @ plasmant @ |
Serial |
9331 |
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Author |
Yusupov, M.; Privat-Maldonado, A.; Cordeiro, R.M.; Verswyvel, H.; Shaw, P.; Razzokov, J.; Smits, E.; Bogaerts, A. |
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Title |
Oxidative damage to hyaluronan–CD44 interactions as an underlying mechanism of action of oxidative stress-inducing cancer therapy |
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A1 Journal article |
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Year |
2021 |
Publication |
Redox Biology |
Abbreviated Journal |
Redox Biol |
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Volume |
43 |
Issue |
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Pages |
101968 |
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Keywords |
A1 Journal article; Plasma Lab for Applications in Sustainability and Medicine – Antwerp (PLASMANT); Center for Oncological Research (CORE) |
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Abstract |
Multiple cancer therapies nowadays rely on oxidative stress to damage cancer cells. Here we investigated the biological and molecular effect of oxidative stress on the interaction between CD44 and hyaluronan (HA), as interrupting their binding can hinder cancer progression. Our experiments demonstrated that the oxidation of HA decreased its recognition by CD44, which was further enhanced when both CD44 and HA were oxidized. The reduction of CD44–HA binding negatively affected the proliferative state of cancer cells. Our multi-level atomistic simulations revealed that the binding free energy of HA to CD44 decreased upon oxidation. The effect of HA and CD44 oxidation on CD44–HA binding was similar, but when both HA and CD44 were oxidized, the effect was much larger, in agreement with our experiments. Hence, our experiments and computations support our hypothesis on the role of oxidation in the disturbance of CD44–HA interaction, which can lead to the inhibition of proliferative signaling pathways inside the tumor cell to induce cell death. |
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000657371800005 |
Publication Date |
2021-04-14 |
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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 |
Fwo; The authors acknowledge the Turing HPC infrastructure at the CalcUA core facility of the University of Antwerp (UA), a division of the Flemish Supercomputer Center VSC, funded by the Hercules Foundation, the Flemish Government (department EWI) and the UA, where all computational work was performed. |
Approved |
Most recent IF: 6.337 |
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Call Number |
PLASMANT @ plasmant @c:irua:177780 |
Serial |
6750 |
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Author |
De Backer, J.; Lin, A.; Berghe, W.V.; Bogaerts, A.; Hoogewijs, D. |
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Title |
Cytoglobin inhibits non-thermal plasma-induced apoptosis in melanoma cells through regulation of the NRF2-mediated antioxidant response |
Type |
A1 Journal article |
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Year |
2022 |
Publication |
Redox Biology |
Abbreviated Journal |
Redox Biol |
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Volume |
55 |
Issue |
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Pages |
102399 |
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Keywords |
A1 Journal article; Plasma Lab for Applications in Sustainability and Medicine – Antwerp (PLASMANT); Proteinscience, proteomics and epigenetic signaling (PPES) |
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Abstract |
Melanoma arises from pigment-producing cells called melanocytes located in the basal layers of the epidermis of the skin. Cytoglobin (CYGB) is a ubiquitously expressed hexacoordinated globin that is highly enriched in melanocytes and frequently downregulated during melanomagenesis. Previously, we showed that non-thermal plasma (NTP)-produced reactive oxygen and nitrogen species (RONS) lead to the formation of an intra molecular disulfide bridge that would allow CYGB to function as a redox-sensitive protein. Here, we investigate the cytotoxic effect of indirect NTP treatment in two melanoma cell lines with divergent endogenous CYGB expression levels, and we explore the role of CYGB in determining treatment outcome. Our findings are consistent with previous studies supporting that NTP cytotoxicity is mediated through the production of RONS and leads to apoptotic cell death in melanoma cells. Furthermore, we show that NTP-treated solutions elicit an antioxidant response through the activation of nuclear factor erythroid 2–related factor 2 (NRF2). The knock down and overexpression of CYGB respectively sensitizes and protects melanoma cells from RONS-induced apoptotic cell death. The presence of CYGB enhances heme-oxygenase 1 (HO-1) and NRF2 protein expression levels, whereas the absence impairs their expression. Moreover, analysis of the CYGB-dependent transcriptome demonstrates the tumor suppressor long non-coding RNA maternally expressed 3 (MEG3) as a hitherto unde scribed link between CYGB and NRF2. Thus, the presence of CYGB, at least in melanoma cells, seems to play a central role in determining the therapeutic outcome of RONS-inducing anticancer therapies, like NTP-treated solutions, possessing both tumor-suppressive and oncogenic features. Hence, CYGB expression could be of in terest either as a biomarker or as a candidate for future targeted therapies in melanoma. |
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000844595100002 |
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0000-00-00 |
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2213-2317 |
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Additional Links |
UA library record; WoS full record; WoS citing articles |
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Impact Factor |
11.4 |
Times cited |
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Open Access |
OpenAccess |
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Notes |
This work was funded in part by the Research Foundation – Flanders (FWO) and the Flemish Government. The FWO fellowships and grants that funded this work include: 12S9221 N (Abraham Lin) and G044420 N (Abraham Lin and Annemie Bogaerts). Joey De Backer acknowledges a visiting fellowship from the University of Fribourg. David Hoogewijs acknowledges support by the Swiss National Science Foundation (grants 31003A173000 and 310030207460). |
Approved |
Most recent IF: 11.4 |
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Call Number |
PLASMANT @ plasmant @c:irua:190635 |
Serial |
7101 |
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Author |
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 |
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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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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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000449722100002 |
Publication Date |
2018-07-24 |
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ISSN |
2213-2317 |
ISBN |
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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 |
Oliveira, M.C.; Verswyvel, H.; Smits, E.; Cordeiro, R.M.; Bogaerts, A.; Lin, A. |
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Title |
The pro- and anti-tumoral properties of gap junctions in cancer and their role in therapeutic strategies |
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A1 Journal article |
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Year |
2022 |
Publication |
Redox Biology |
Abbreviated Journal |
Redox Biol |
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Volume |
57 |
Issue |
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Pages |
102503 |
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Keywords |
A1 Journal article; Plasma Lab for Applications in Sustainability and Medicine – Antwerp (PLASMANT); Center for Oncological Research (CORE) |
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Abstract |
Gap junctions (GJs), essential structures for cell-cell communication, are made of two hemichannels (commonly called connexons), one on each adjacent cell. Found in almost all cells, GJs play a pivotal role in many physiological and cellular processes, and have even been linked to the progression of diseases, such as cancer. Modulation of GJs is under investigation as a therapeutic strategy to kill tumor cells. Furthermore, GJs have also been studied for their key role in activating anti-cancer immunity and propagating radiation- and oxidative stress-induced cell death to neighboring cells, a process known as the bystander effect. While, gap junction (GJ)based therapeutic strategies are being developed, one major challenge has been the paradoxical role of GJs in both tumor progression and suppression, based on GJ composition, cancer factors, and tumoral context. Therefore, understanding the mechanisms of action, regulation, and the dual characteristics of GJs in cancer is critical for developing effective therapeutics. In this review, we provide an overview of the current under standing of GJs structure, function, and paradoxical pro- and anti-tumoral role in cancer. We also discuss the treatment strategies to target these GJs properties for anti-cancer responses, via modulation of GJ function. |
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000871090800004 |
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0000-00-00 |
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ISSN |
2213-2317 |
ISBN |
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Additional Links |
UA library record; WoS full record |
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Impact Factor |
11.4 |
Times cited |
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Open Access |
OpenAccess |
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Notes |
We thank Coordination of Superior Level Staff Improvement (CAPES, Brazil) for the scholarship granted, and the Turing HPC infrastructure at the CalcUA core facility of the University of Antwerp, a division of the Flemish Supercomputer Center VSC, funded by the Hercules Foundation, the Flemish Government (department EWI) and the University of Antwerp, for providing the computational resources needed for running the simulations. This work was also funded in part by the funded by the Research Foundation – Flanders (FWO) and the Flemish Government. The FWO fellowships and grants that funded this work include: 12S9221N (Abraham Lin), G044420N (Abraham Lin and Annemie Bogaerts), and 1S67621N (Hanne Verswyvel). Figs. 1, 4 and 5 were created in BioRender.com. |
Approved |
Most recent IF: 11.4 |
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Call Number |
PLASMANT @ plasmant @c:irua:191362 |
Serial |
7112 |
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