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- ItemPlasma-derived reactive species shape a differentiation profile in human monocytes(Basel : MDPI, 2019) Freund, Eric; Moritz, Juliane; Stope, Matthias; Seebauer, Christian; Schmidt, Anke; Bekeschus, SanderBackground: Monocyte-derived macrophages are key regulators and producers of reactive oxygen and nitrogen species (ROS/RNS). Pre-clinical and clinical studies suggest that cold physical plasma may be beneficial in the treatment of inflammatory conditions via the release of ROS/RNS. However, it is unknown how plasma treatment affects monocytes and their differentiation profile. Methods: Naïve or phorbol-12-myristate-13-acetate (PMA)-pulsed THP-1 monocytes were exposed to cold physical plasma. The cells were analyzed regarding their metabolic activity as well as flow cytometry (analysis of viability, oxidation, surface marker expression and cytokine secretion) and high content imaging (quantitative analysis of morphology. Results: The plasma treatment affected THP-1 metabolisms, viability, and morphology. Furthermore, a significant modulation CD55, CD69, CD271 surface-expression and increase of inflammatory IL1β, IL6, IL8, and MCP1 secretion was observed upon plasma treatment. Distinct phenotypical changes in THP-1 cells arguing for a differentiation profile were validated in primary monocytes from donor blood. As a functional outcome, plasma-treated monocytes decreased the viability of co-cultured melanoma cells to a greater extent than their non-treated counterparts. Conclusions: Our results suggest plasma-derived ROS/RNS shaped a differentiation profile in human monocytes as evidenced by their increased inflammatory profile (surface marker and cytokines) as well as functional outcome (tumor toxicity). © 2019 by the authors.
- ItemTumor cytotoxicity and immunogenicity of a novel V-jet neon plasma source compared to the kINPen(London : Nature Publishing Group, 2021) Miebach, Lea; Freund, Eric; Horn, Stefan; Niessner, Felix; Sagwal, Sanjeev Kumar; von Woedtke, Thomas; Emmert, Steffen; Weltmann, Klaus-Dieter; Clemen, Ramona; Schmidt, Anke; Gerling, Torsten; Bekeschus, SanderRecent research indicated the potential of cold physical plasma in cancer therapy. The plethora of plasma-derived reactive oxygen and nitrogen species (ROS/RNS) mediate diverse antitumor effects after eliciting oxidative stress in cancer cells. We aimed at exploiting this principle using a newly designed dual-jet neon plasma source (Vjet) to treat colorectal cancer cells. A treatment time-dependent ROS/RNS generation induced oxidation, growth retardation, and cell death within 3D tumor spheroids were found. In TUM-CAM, a semi in vivo model, the Vjet markedly reduced vascularized tumors' growth, but an increase of tumor cell immunogenicity or uptake by dendritic cells was not observed. By comparison, the argon-driven single jet kINPen, known to mediate anticancer effects in vitro, in vivo, and in patients, generated less ROS/RNS and terminal cell death in spheroids. In the TUM-CAM model, however, the kINPen was equivalently effective and induced a stronger expression of immunogenic cancer cell death (ICD) markers, leading to increased phagocytosis of kINPen but not Vjet plasma-treated tumor cells by dendritic cells. Moreover, the Vjet was characterized according to the requirements of the DIN-SPEC 91315. Our results highlight the plasma device-specific action on cancer cells for evaluating optimal discharges for plasma cancer treatment.
- ItemPhysical plasma-triggered ROS induces tumor cell death upon cleavage of HSP90 chaperone([London] : Macmillan Publishers Limited, part of Springer Nature, 2019) Bekeschus, Sander; Lippert, Maxi; Diepold, Kristina; Chiosis, Gabriela; Seufferlein, Thomas; Azoitei, NinelHSP90 is a ubiquitously expressed molecular chaperone implicated in the correct folding and maturation of a plethora of proteins including protein kinases and transcription factors. While disruption of chaperone activity was associated with augmented cancer cell death and decreased tumor growth both in vitro and in vivo, the regulation of HSP90 is not clearly understood. Here we report that treatment of cancer cells with cold physical plasma, an emerging and less aggressive tumor therapy, resulted in ROS generation which subsequently triggered the cleavage of HSP90. Notably, cleavage of HSP90 was followed by the degradation of PKD2, a crucial regulator of tumor growth and angiogenesis. Pre-sensitization of cancer cells with subliminal doses of PU-H71, an HSP90 inhibitor currently under clinical evaluation, followed by treatment with cold-plasma, synergistically and negatively impacted on the viability of cancer cells. Taken together, cold-plasma can be used in conjunction with pharmacologic treatment in order to target the expression and activity of HSP90 and the downstream client proteins implicated in various cancer cell capabilities.
- ItemOxidatively Modified Proteins: Cause and Control of Diseases(Basel : MDPI, 2020) Clemen, Ramona; Bekeschus, SanderProteins succumb to numerous post-translational modifications (PTMs). These relate to enzymatic or non-enzymatic reactions taking place in either the intracellular or extracellular compartment. While intracellular oxidative changes are mainly due to redox stress, extracellular PTMs may be induced in an inflammatory micro milieu that is rich in reactive species. The increasing recognition of oxidative modifications as a causing agent or side-effect of pathophysiological states and diseases puts oxidative PTMS (oxPTMs) into the spotlight of inflammation research. Pathological hyper-modification of proteins can lead to accumulation, aggregation, cell stress, altered antigenic peptides, and damage-associated molecular pattern (DAMP)-like recognition by host immunity. Such processes are linked to cardiovascular disease and autoinflammation. At the same time, a detailed understanding of the mechanisms governing inflammatory responses to oxPTMs may capitalize on new therapeutic routes for enhancing adaptive immune responses as needed, for instance, in oncology. We here summarize some of the latest developments of oxPTMs in disease diagnosis and therapy. Potential target proteins and upcoming technologies, such as gas plasmas, are outlined for future research that may aid in identifying the molecular basis of immunogenic vs. tolerogenic oxPTMs.
- ItemCharacterization of antimicrobial effects of Plasma-Treated Water (PTW) produced by Microwave-Induced Plasma (MidiPLexc) on pseudomonas fluorescens biofilms(Basel : MDPI, 2020) Handorf, Oliver; Pauker, Viktoria Isabella; Schnabel, Uta; Weihe, Thomas; Freund, Eric; Bekeschus, Sander; Riedel, Katharina; Ehlbeck, JörgFor the decontamination of surfaces in the food production industry, plasma-generated compounds such as plasma-treated water or plasma-processed air offer many promising possibilities for future applications. Therefore, the antimicrobial effect of water treated with microwave-induced plasma (MidiPLexc) on Pseudomonas fluorescens biofilms was investigated. A total of 10 mL deionized water was treated with the MidiPLexc plasma source for 100, 300 and 900 s (pretreatment time) and the bacterial biofilms were exposed to the plasma-treated water for 1, 3 and 5 min (post-treatment time). To investigate the influence of plasma-treated water on P. fluorescens biofilms, microbiological assays (colony-forming units, fluorescence and XTT assay) and imaging techniques (fluorescence microscopy, confocal laser scanning microscopy, and atomic force microscopy) were used. The colony-forming units showed a maximum reduction of 6 log10 by using 300 s pretreated plasma water for 5 min. Additionally, a maximum reduction of 81% for the viability of the cells and a 92% reduction in the metabolic activity of the cells were achieved by using 900 s pretreated plasma water for 5 min. The microscopic images showed evident microbial inactivation within the biofilm even at the shortest pretreatment (100 s) and post-treatment (1 min) times. Moreover, reduction of the biofilm thickness and increased cluster formation within the biofilm was detected. Morphologically, the fusion of cell walls into a uniform dense cell mass was detectable. The findings correlated with a decrease in the pH value of the plasma-treated water, which forms the basis for the chemically active components of plasma-treated water and its antimicrobial effects. These results provide valuable insights into the mechanisms of inactivation of biofilms by plasma-generated compounds such as plasma-treated water and thus allow for further parameter adjustment for applications in food industry. © 2020 by the authors.
- ItemOxygen atoms are critical in rendering THP-1 leukaemia cells susceptible to cold physical plasma-induced apoptosis([London] : Macmillan Publishers Limited, part of Springer Nature, 2017-6-5) Bekeschus, Sander; Wende, Kristian; Hefny, Mohamed Mokhtar; Rödder, Katrin; Jablonowski, Helena; Schmidt, Anke; Woedtke, Thomas von; Weltmann, Klaus-Dieter; Benedikt, JanCold physical plasma has been suggested as a powerful new tool in oncology. However, some cancer cells such as THP-1 leukaemia cells have been shown to be resistant towards plasma-induced cell death, thereby serving as a good model for optimizing plasmas in order to foster pro-apoptotic anticancer effects. A helium/oxygen radio frequency driven atmospheric plasma profoundly induced apoptosis in THP-1 cells whereas helium, humidified helium, and humidified helium/oxygen plasmas were inefficient. Hydrogen peroxide – previously shown as central plasma-derived agent – did not participate in the killing reaction but our results suggest hypochlorous acid to be responsible for the effect observed. Proteomic analysis of THP-1 cells exposed to He/O2 plasma emphasized a prominent growth retardation, cell stress, apoptosis, and a pro-immunogenic profile. Altogether, a plasma setting that inactivates previously unresponsive leukaemia cells is presented. Crucial reactive species in the plasma and liquid environment were identified and discussed, deciphering the complexity of plasma from the gas phase into the liquid down to the cellular response mechanism. These results may help tailoring plasmas for clinical applications such as oxidation-insensitive types of cancer.
- ItemCold argon plasma as adjuvant tumour therapy on progressive head and neck cancer: A preclinical study(Basel : MDPI, 2019) Hasse, Sybille; Seebauer, Christian; Wende, Kristian; Schmidt, Anke; Metelmann, Hans-Robert; Woedtke, Thomas von; Bekeschus, SanderInvestigating cold argon plasma (CAP) for medical applications is a rapidly growing, innovative field of research. The controllable supply of reactive oxygen and nitrogen species through CAP has the potential for utilization in tumour treatment. Maxillofacial surgery is limited if tumours grow on vital structures such as the arteria carotis. Here CAP could be considered as an option for adjuvant intraoperative tumour therapy especially in the case of squamous cell carcinoma of the head and neck. Further preclinical research is necessary to investigate the efficacy of this technology for future clinical applications in cancer treatment. Initially, a variety of in vitro assays was performed on two cell lines that served as surrogate for the squamous cell carcinoma (SCC) and healthy tissue, respectively. Cell viability, motility and the activation of apoptosis in SCC cells (HNO97) was compared with those in normal HaCaT keratinocytes. In addition, induction of apoptosis in ex vivo CAP treated human tissue biopsies of patients with tumours of the head and neck was monitored and compared to healthy control tissue of the same patient. In response to CAP treatment, normal HaCaT keratinocytes differed significantly from their malignant counterpart HNO97 cells in cell motility only whereas cell viability remained similar. Moreover, CAP treatment of tumour tissue induced more apoptotic cells than in healthy tissue that was accompanied by elevated extracellular cytochrome c levels. This study promotes a future role of CAP as an adjuvant intraoperative tumour therapy option in the treatment of head and neck cancer. Moreover, patient-derived tissue explants complement in vitro examinations in a meaningful way to reflect an antitumoral role of CAP. © 2019 by the authors.
- ItemDifferential Sensitivity of Two Leukemia Cell Lines towards Two Major Gas Plasma Products Hydrogen Peroxide and Hypochlorous Acid(Basel : MDPI, 2022) Singer, Debora; Miebach, Lea; Bekeschus, SanderOxidative stress has major implications for health and disease. At the same time, the term collectively describes the reactions to different types of reactive oxygen species (ROS) and oxidants, including hydrogen peroxide (H2O2) and hypochlorous acid (HOCl). However, how both compare in terms of cytotoxicity and mechanism of action is less known. Using two leukemia cell lines, Jurkat and THP-1, as model systems at similar cell concentrations, we found an 8-fold greater sensitivity of the former over the latter for H2O2 exposure. Unexpectantly, this was not the case with HOCl exposure. Jurkat cells were 2-fold more resistant to HOCl-induced cytotoxicity than THP-1 cells. In each cell type, the relatively more toxic oxidant also induced activation of caspases 3 and 7 at earlier time points, as time-lapse fluorescence microscopy revealed. The effects observed did not markedly correlate with changes in intracellular GSH and GSSG levels. In addition, siRNA-mediated knockdown of the Nrf2 target HMOX-1 encoding for HO-1 protein and the growth and survival factor IL-8 revealed Jurkat cells to become more sensitive to HOCl, while HO-1 and IL-8 siRNA-mediated knockdown in THP-1 cells produced greater sensitivity towards H2O2. siRNA-mediated knockdown of catalase increased oxidant sensitivity only negligibly. Collectively, the data suggest striking HOCl-resistance of Jurkat and H2O2 resistance of THP-1 cells, showing similar protective roles of HO-1 and IL-8, while caspase activation kinetics differ.
- ItemPlasma Medicine Technologies(Basel : MDPI, 2021) Kaushik, Nagendra Kumar; Bekeschus, Sander; Tanaka, Hiromasa; Lin, Abraham; Choi, Eun HaThis Special Issue, entitled “Plasma Medicine Technologies”, covers the latest remarkable developments in the field of plasma bioscience and medicine. Plasma medicine is an interdisciplinary field that combines the principles of plasma physics, material science, bioscience, and medicine, towards the development of therapeutic strategies. A study on plasma medicine has yielded the development of new treatment opportunities in medical and dental sciences. An important aspect of this issue is the presentation of research underlying new therapeutic methods that are useful in medicine, dentistry, sterilization, and, in the current scenario, that challenge perspectives in biomedical sciences. This issue is focused on basic research on the characterization of the bioplasma sources applicable to living cells, especially to the human body, and fundamental research on the mutual interactions between bioplasma and organic–inorganic liquids, and bio or nanomaterials.
- ItemPlasma‐treated flammulina velutipes‐derived extract showed anticancer potential in human breast cancer cells(Basel : MDPI, 2020) Mitra, Sarmistha; Bhartiya, Pradeep; Kaushik, Neha; Nguyen, Linh Nhat; Wahab, Rizwan; Bekeschus, Sander; Choi, Eun Ha; Kaushik, Nagendra KumarNatural products with medicinal properties are among alternative therapies of interest due to their high body tolerance. We aimed to determine whether nonthermal gas plasma could enhance the medicinal value of Flammulina velutipes mushrooms. Generated gas plasma was characterized by its emission spectrum in ambient air, pH, temperature, and H2O2 and NOx concentrations after exposure for various periods. Phenolic and flavonoid contents in the extracts were measured using antioxidant assays and Fourier transform infrared and ultraviolet‐visible spectroscopy. We analyzed the effects of the plasma‐treated mushroom‐derived extracts against breast carcinoma using the MCF7 and MDA‐MB231 cell lines. The extracts significantly and concentration dependently inhibited the growth of breast cancer cells without inducing toxicity in normal MCF10A cells, and induced apoptosis via oxidative stress, evidenced by DNA damage (γ‐ H2AX foci formation), and increased the population of MCF7 breast cancer cells arrested in the G2/M phase of the cell cycle. The extracts also induced mitochondrion‐mediated apoptosis of MCF7 cells through cytochrome c release and caspase cleavage activity. The plasma improved the biological activity of mushrooms by increasing their phenolic compounds that prevented the growth of breast cancer cells in vitro. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
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