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Author: Wende, Kristian × Start date: 2020 ×

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    Non-thermal plasma modulates cellular markers associated with immunogenicity in a model of latent HIV-1 infection
    (San Francisco, California, US : PLOS, 2021) Mohamed, Hager; Clemen, Ramona; Freund, Eric; Lackmann, Jan-Wilm; Wende, Kristian; Connors, Jennifer; Haddad, Elias K.; Dampier, Will; Wigdahl, Brian; Miller, Vandana; Bekeschus, Sander; Krebs, Fred C.; Kashanchi, Fatah
    Effective control of infection by human immunodeficiency virus type 1 (HIV-1), the causative agent of the acquired immunodeficiency syndrome (AIDS), requires continuous and life-long use of anti-retroviral therapy (ART) by people living with HIV-1 (PLWH). In the absence of ART, HIV-1 reemergence from latently infected cells is ineffectively suppressed due to suboptimal innate and cytotoxic T lymphocyte responses. However, ART-free control of HIV-1 infection may be possible if the inherent immunological deficiencies can be reversed or restored. Herein we present a novel approach for modulating the immune response to HIV-1 that involves the use of non-thermal plasma (NTP), which is an ionized gas containing various reactive oxygen and nitrogen species (RONS). J-Lat cells were used as a model of latent HIV-1 infection to assess the effects of NTP application on viral latency and the expression of pro-phagocytic and pro-chemotactic damage-associated molecular patterns (DAMPs). Exposure of J-Lat cells to NTP resulted in stimulation of HIV-1 gene expression, indicating a role in latency reversal, a necessary first step in inducing adaptive immune responses to viral antigens. This was accompanied by the release of pro-inflammatory cytokines and chemokines including interleukin-1β (IL-1β) and interferon-γ (IFN-γ); the display of pro-phagocytic markers calreticulin (CRT), heat shock proteins (HSP) 70 and 90; and a correlated increase in macrophage phagocytosis of NTP-exposed J-Lat cells. In addition, modulation of surface molecules that promote or inhibit antigen presentation was also observed, along with an altered array of displayed peptides on MHC I, further suggesting methods by which NTP may modify recognition and targeting of cells in latent HIV-1 infection. These studies represent early progress toward an effective NTP-based ex vivo immunotherapy to resolve the dysfunctions of the immune system that enable HIV-1 persistence in PLWH.
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    Short- and long-term polystyrene nano- and microplastic exposure promotes oxidative stress and divergently affects skin cell architecture and Wnt/beta-catenin signaling
    (London : BioMed Central, 2023) Schmidt, Anke; da Silva Brito, Walison Augusto; Singer, Debora; Mühl, Melissa; Berner, Julia; Saadati, Fariba; Wolff, Christina; Miebach, Lea; Wende, Kristian; Bekeschus, Sander
    Nano- and microplastic particles (NMP) are strong environmental contaminants affecting marine ecosystems and human health. The negligible use of biodegradable plastics and the lack of knowledge about plastic uptake, accumulation, and functional consequences led us to investigate the short- and long-term effects in freshly isolated skin cells from mice. Using fluorescent NMP of several sizes (200 nm to 6 µm), efficient cellular uptake was observed, causing, however, only minor acute toxicity as metabolic activity and apoptosis data suggested, albeit changes in intracellular reactive species and thiol levels were observed. The internalized NMP induced an altered expression of various targets of the nuclear factor-2-related transcription factor 2 pathway and were accompanied by changed antioxidant and oxidative stress signaling responses, as suggested by altered heme oxygenase 1 and glutathione peroxide 2 levels. A highly increased beta-catenin expression under acute but not chronic NMP exposure was concomitant with a strong translocation from membrane to the nucleus and subsequent transcription activation of Wnt signaling target genes after both single-dose and chronic long-term NMP exposure. Moreover, fibroblast-to-myofibroblast transdifferentiation accompanied by an increase of α smooth muscle actin and collagen expression was observed. Together with several NMP-induced changes in junctional and adherence protein expression, our study for the first time elucidates the acute and chronic effects of NMP of different sizes in primary skin cells' signaling and functional biology, contributing to a better understanding of nano- and microplastic to health risks in higher vertebrates.
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    Insight into the Impact of Oxidative Stress on the Barrier Properties of Lipid Bilayer Models
    (Basel : Molecular Diversity Preservation International (MDPI), 2022) Nasri, Zahra; Ahmadi, Mohsen; Striesow, Johanna; Ravandeh, Mehdi; von Woedtke, Thomas; Wende, Kristian
    As a new field of oxidative stress-based therapy, cold physical plasma is a promising tool for several biomedical applications due to its potential to create a broad diversity of reactive oxygen and nitrogen species (RONS). Although proposed, the impact of plasma-derived RONS on the cell membrane lipids and properties is not fully understood. For this purpose, the changes in the lipid bilayer functionality under oxidative stress generated by an argon plasma jet (kINPen) were investigated by electrochemical techniques. In addition, liquid chromatography-tandem mass spectrometry was employed to analyze the plasma-induced modifications on the model lipids. Various asymmetric bilayers mimicking the structure and properties of the erythrocyte cell membrane were transferred onto a gold electrode surface by Langmuir-Blodgett/Langmuir-Schaefer deposition techniques. A strong impact of cholesterol on membrane permeabilization by plasma-derived species was revealed. Moreover, the maintenance of the barrier properties is influenced by the chemical composition of the head group. Mainly the head group size and its hydrogen bonding capacities are relevant, and phosphatidylcholines are significantly more susceptible than phosphatidylserines and other lipid classes, underlining the high relevance of this lipid class in membrane dynamics and cell physiology.
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    Reactive species driven oxidative modifications of peptides—Tracing physical plasma liquid chemistry
    (Melville, NY : American Inst. of Physics, 2021) Wenske, Sebastian; Lackmann, Jan-Wilm; Busch, Larissa Milena; Bekeschus, Sander; von Woedtke, Thomas; Wende, Kristian
    The effluence of physical plasma consists of a significant share of reactive species, which may interact with biomolecules and yield chemical modifications comparable to those of physiological processes, e.g., post-translational protein modifications (oxPTMs). Consequentially, the aim of this work is to understand the role of physical plasma-derived reactive species in the introduction of oxPTM-like modifications in proteins. An artificial peptide library consisting of ten peptides was screened against the impact of two plasma sources, the argon-driven MHz-jet kINPen and the helium-driven RF-jet COST-Jet. Changes in the peptide molecular structure were analyzed by liquid chromatography–mass spectrometry. The amino acids cysteine, methionine, tyrosine, and tryptophan were identified as major targets. The introduction of one, two, or three oxygen atoms was the most common modification observed. Distinct modification patterns were observed for nitration (+N + 2O–H), which occurred in kINPen only (peroxynitrite), and chlorination (+Cl–H) that was exclusive for the COST-Jet in the presence of chloride ions (atomic oxygen/hypochlorite). Predominantly for the kINPen, singlet oxygen-related modifications, e.g., cleavage of tryptophan, were observed. Oxidation, carbonylation, and double oxidations were attributed to the impact of hydroxyl radicals and atomic oxygen. Leading to a significant change in the peptide side chain, most of these oxPTM-like modifications affect the secondary structure of amino acid chains, and amino acid polarity/functionality, ultimately modifying the performance and stability of cellular proteins.
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    On a heavy path – determining cold plasma-derived short-lived species chemistry using isotopic labelling
    (London : RSC Publishing, 2020) Wende, Kristian; Bruno, Giuliana; Lalk, Michael; Weltmann, Klaus-Dieter; von Woedtke, Thomas; Bekeschus, Sander; Lackmann, Jan-Wilm
    Cold atmospheric plasmas (CAPs) are promising medical tools and are currently applied in dermatology and epithelial cancers. While understanding of the biomedical effects is already substantial, knowledge on the contribution of individual ROS and RNS and the mode of activation of biochemical pathways is insufficient. Especially the formation and transport of short-lived reactive species in liquids remain elusive, a situation shared with other approaches involving redox processes such as photodynamic therapy. Here, the contribution of plasma-generated reactive oxygen species (ROS) in plasma liquid chemistry was determined by labeling these via admixing heavy oxygen 18O2 to the feed gas or by using heavy water H218O as a solvent for the bait molecule. The inclusion of heavy or light oxygen atoms by the labeled ROS into the different cysteine products was determined by mass spectrometry. While products like cysteine sulfonic acid incorporated nearly exclusively gas phase-derived oxygen species (atomic oxygen and/or singlet oxygen), a significant contribution of liquid phase-derived species (OH radicals) was observed for cysteine-S-sulfonate. The role, origin, and reaction mechanisms of short-lived species, namely hydroxyl radicals, singlet oxygen, and atomic oxygen, are discussed. Interactions of these species both with the target cysteine molecule as well as the interphase and the liquid bulk are taken into consideration to shed light onto several reaction pathways resulting in observed isotopic oxygen incorporation. These studies give valuable insight into underlying plasma–liquid interaction processes and are a first step to understand these interaction processes between the gas and liquid phase on a molecular level.
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    Influence of aerosol injection on the liquid chemistry induced by an RF argon plasma jet
    (Bristol : IOP Publ., 2021) Sremački, Ivana; Bruno, Giuliana; Jablonowski, Helena; Leys, Christophe; Nikiforov, Anton; Wende, Kristian
    A radio-frequency driven plasma jet in annular geometry coupled with an aerosol injection into the effluent is proposed for the controllable reactive oxygen species (ROS)/reactive nitrogen species (RNS) production and delivery on biological targets in the context of plasma medicine, e.g. wound care. The role of the aqueous aerosol in modulating the reactive species production is investigated by combining physical and chemical analytics. Optical emission spectroscopy, electron paramagnetic resonance spectroscopy, and a biochemical model based on cysteine as a tracer molecule have been applied, revealing that aerosol injection shifts the production of ROS from atomic and singlet oxygen toward hydroxyl radicals, which are generated in the droplets. Species generation occurred mainly at the droplets boundary layer during their transport through the effluent, leading to a limited cysteine turnover upon introduction into the aerosol solution. The subsequent delivery of unmodified cysteine molecules at a target suggested the application of the plasma source for the topical delivery of drugs, expanding the potential applicability and effectiveness. The presence of RNS was negligible regardless of aerosol injection and only traces of the downstream products nitrate and nitrate were detected. In summary, the aerosol injection into the effluent opens new avenues to control UV radiation and reactive species output for the biomedical applications of non-thermal plasma sources, reaching out toward the regulation, safety, and efficacy of targeted applications.
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    Development of an electrochemical sensor for in-situ monitoring of reactive species produced by cold physical plasma
    (Amsterdam [u.a.] : Elsevier Science, 2021) Nasri, Zahra; Bruno, Giuliana; Bekeschus, Sander; Weltmann, Klaus-Dieter; von Woedtke, Thomas; Wende, Kristian
    The extent of clinical applications of oxidative stress-based therapies such as photodynamic therapy (PDT) or respiratory chain disruptors are increasing rapidly, with cold physical plasma (CPP) emerging as a further option. According to the current knowledge, the biological effects of CPP base on reactive oxygen and nitrogen species (RONS) relevant in cell signaling. To monitor the safety and the biological impact of the CPP, determining the local generation of RONS in the same environment in which they are going to be applied is desirable. Here, for the first time, the development of an electrochemical sensor for the simple, quick, and parallel determination of plasma-generated reactive species is described. The proposed sensor consists of a toluidine blue redox system that is covalently attached to a gold electrode surface. By recording chronoamperometry at different potentials, it is possible to follow the in-situ production of the main long-lived reactive oxygen and nitrogen species like hydrogen peroxide, nitrite, hypochlorite, and chloramine with time. The applicability of this electrochemical sensor for the in-situ assessment of reactive species in redox-based therapies is demonstrated by the precise analysis of hydrogen peroxide dynamics in the presence of blood cancer cells.
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    Non-steroidal anti-inflammatory drugs: recent advances in the use of synthetic COX-2 inhibitors
    (Cambridge : Royal Society of Chemistry, 2022) Ahmadi, Mohsen; Bekeschus, Sander; Weltmann, Klaus-Dieter; von Woedtke, Thomas; Wende, Kristian
    Cyclooxygenase (COX) enzymes comprise COX-1 and COX-2 isoforms and are responsible for prostaglandin production. Prostaglandins have critical roles in the inflammation pathway and must be controlled by administration of selective nonsteroidal anti-inflammatory drugs (NSAIDs). Selective COX-2 inhibitors have been among the most used NSAIDs during the ongoing coronavirus 2019 pandemic because they reduce pain and protect against inflammation-related diseases. In this framework, the mechanism of action of both COX isoforms (particularly COX-2) as inflammation mediators must be reviewed. Moreover, proinflammatory cytokines such as tumor necrosis factor-α and interleukin (IL)-6, IL-1β, and IL-8 must be highlighted due to their major participation in upregulation of the inflammatory reaction. Structural and functional analyses of selective COX-2 inhibitors within the active-site cavity of COXs could enable introduction of lead structures with higher selectivity and potency against inflammation with fewer adverse effects. This review focuses on the biological activity of recently discovered synthetic COX-2, dual COX-2/lipoxygenase, and COX-2/soluble epoxide hydrolase hybrid inhibitors based primarily on the active motifs of related US Food and Drug Administration-approved drugs. These new agents could provide several advantages with regard to anti-inflammatory activity, gastrointestinal protection, and a safer profile compared with those of the NSAIDs celecoxib, valdecoxib, and rofecoxib.
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    X-ray Ptychographic Imaging and Spectroscopic Studies of Plasma-Treated Plastic Films
    (Basel : MDPI, 2022) Ravandeh, Mehdi; Mehrjoo, Masoud; Kharitonov, Konstantin; Schäfer, Jan; Quade, Antje; Honnorat, Bruno; Ruiz-Lopez, Mabel; Keitel, Barbara; Kreis, Svea; Pan, Rui; Gang, Seung-gi; Wende, Kristian; Plönjes, Elke
    Polyethylene terephthalate (PET) is a thermoplastic polyester with numerous applications in industry. However, it requires surface modification on an industrial scale for printing and coating processes and plasma treatment is one of the most commonly used techniques to increase the hydrophilicity of the PET films. Systematic improvement of the surface modification by adaption of the plasma process can be aided by a comprehensive understanding of the surface morphology and chemistry. However, imaging large surface areas (tens of microns) with a resolution that allows understanding the surface quality and modification is challenging. As a proof-of-principle, plasma-treated PET films were used to demonstrate the capabilities of X-ray ptychography, currently under development at the soft X-ray free-electron laser FLASH at DESY, for imaging macroscopic samples. In combination with scanning electron microscopy (SEM), this new technique was used to study the effects of different plasma treatment processes on PET plastic films. The studies on the surface morphology were complemented by investigations of the surface chemistry using X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FT-IR). While both imaging techniques consistently showed an increase in roughness and change in morphology of the PET films after plasma treatment, X-ray ptychography can provide additional information on the three-dimensional morphology of the surface. At the same time, the chemical analysis shows an increase in the oxygen content and polarity of the surface without significant damage to the polymer, which is important for printing and coating processes.
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    Cell cycle-related genes associate with sensitivity to hydrogen peroxide-induced toxicity
    (Amsterdam [u.a.] : Elsevier, 2022) Bekeschus, Sander; Liebelt, Grit; Menz, Jonas; Singer, Debora; Wende, Kristian; Schmidt, Anke
    Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) are well-described agents in physiology and pathology. Chronic inflammation causes incessant H2O2 generation associated with disease occurrences such as diabetes, autoimmunity, and cancer. In cancer, conditioning of the tumor microenvironment, e.g., hypoxia and ROS generation, has been associated with disease outcomes and therapeutic efficacy. Many reports have investigated the roles of the action of H2O2 across many cell lines and disease models. The genes predisposing tumor cell lines to H2O2-mediated demise are less deciphered, however. To this end, we performed in-house transcriptional profiling of 35 cell lines and simultaneously investigated each cell line's H2O2 inhibitory concentration (IC25) based on metabolic activity. More than 100-fold differences were observed between the most resistant and sensitive cell lines. Correlation and gene ontology pathway analysis identified a rigid association with genes intertwined in cell cycle progression and proliferation, as such functional categories dominated the top ten significant processes. The ten most substantially correlating genes (Spearman r > 0.70 or < -0.70) were validated using qPCR, showing complete congruency with microarray analysis findings. Western blotting confirmed the correlation of cell cycle-related proteins negatively correlating with H2O2 IC25. Top genes related to ROS production or antioxidant defense were only modest in correlation (Spearman r > 0.40 or < -0.40). In conclusion, our in-house transcriptomic correlation analysis revealed a set of cell cycle-associated genes associated with a priori resistance or sensitivity to H2O2-induced cellular demise with the detailed and causative roles of individual genes remaining unclear.