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- ItemGas Plasma Technology Augments Ovalbumin Immunogenicity and OT-II T Cell Activation Conferring Tumor Protection in Mice(Weinheim : Wiley-VCH, 2021) Clemen, Ramona; Freund, Eric; Mrochen, Daniel; Miebach, Lea; Schmidt, Anke; Rauch, Bernhard H.; Lackmann, Jan‐Wilm; Martens, Ulrike; Wende, Kristian; Lalk, Michael; Delcea, Mihaela; Bröker, Barbara M.; Bekeschus, SanderReactive oxygen species (ROS/RNS) are produced during inflammation and elicit protein modifications, but the immunological consequences are largely unknown. Gas plasma technology capable of generating an unmatched variety of ROS/RNS is deployed to mimic inflammation and study the significance of ROS/RNS modifications using the model protein chicken ovalbumin (Ova vs oxOva). Dynamic light scattering and circular dichroism spectroscopy reveal structural modifications in oxOva compared to Ova. T cells from Ova-specific OT-II but not from C57BL/6 or SKH-1 wild type mice presents enhanced activation after Ova addition. OxOva exacerbates this activation when administered ex vivo or in vivo, along with an increased interferon-gamma production, a known anti-melanoma agent. OxOva vaccination of wild type mice followed by inoculation of syngeneic B16F10 Ova-expressing melanoma cells shows enhanced T cell number and activation, decreased tumor burden, and elevated numbers of antigen-presenting cells when compared to their Ova-vaccinated counterparts. Analysis of oxOva using mass spectrometry identifies three hot spots regions rich in oxidative modifications that are associated with the increased T cell activation. Using Ova as a model protein, the findings suggest an immunomodulating role of multi-ROS/RNS modifications that may spur novel research lines in inflammation research and for vaccination strategies in oncology.
- ItemMedical Gas Plasma Jet Technology Targets Murine Melanoma in an Immunogenic Fashion(Weinheim : Wiley-VCH, 2020) Bekeschus, Sander; Clemen, Ramona; Nießner, Felix; Sagwal, Sanjeev Kumar; Freund, Eric; Schmidt, AnkeMedical technologies from physics are imperative in the diagnosis and therapy of many types of diseases. In 2013, a novel cold physical plasma treatment concept was accredited for clinical therapy. This gas plasma jet technology generates large amounts of different reactive oxygen and nitrogen species (ROS). Using a melanoma model, gas plasma technology is tested as a novel anticancer agent. Plasma technology derived ROS diminish tumor growth in vitro and in vivo. Varying the feed gas mixture modifies the composition of ROS. Conditions rich in atomic oxygen correlate with killing activity and elevate intratumoral immune-infiltrates of CD8+ cytotoxic T-cells and dendritic cells. T-cells from secondary lymphoid organs of these mice stimulated with B16 melanoma cells ex vivo show higher activation levels as well. This correlates with immunogenic cancer cell death and higher calreticulin and heat-shock protein 90 expressions induced by gas plasma treatment in melanoma cells. To test the immunogenicity of gas plasma treated melanoma cells, 50% of mice vaccinated with these cells are protected from tumor growth compared to 1/6 and 5/6 mice negative control (mitomycin C) and positive control (mitoxantrone), respectively. Gas plasma jet technology is concluded to provide immunoprotection against malignant melanoma both in vitro and in vivo.
- 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.
- 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.
- ItemActivation of murine immune cells upon co-culture with plasma-treated B16F10 melanoma cells(Basel : MDPI, 2019) Rödder, Katrin; Moritz, Juliane; Miller, Vandana; Weltmann, Klaus-Dieter; Metelmann, Hans-Robert; Gandhirajan, Rajesh; Bekeschus, SanderRecent advances in melanoma therapy increased median survival in patients. However, death rates are still high, motivating the need of novel avenues in melanoma treatment. Cold physical plasma expels a cocktail of reactive species that have been suggested for cancer treatment. High species concentrations can be used to exploit apoptotic redox signaling pathways in tumor cells. Moreover, an immune-stimulatory role of plasma treatment, as well as plasma-killed tumor cells, was recently proposed, but studies using primary immune cells are scarce. To this end, we investigated the role of plasma-treated murine B16F10 melanoma cells in modulating murine immune cells' activation and marker profile. Melanoma cells exposed to plasma showed reduced metabolic and migratory activity, and an increased release of danger signals (ATP, CXCL1). This led to an altered cytokine profile with interleukin-1β (IL-1β) and CCL4 being significantly increased in plasma-treated mono- and co-cultures with immune cells. In T cells, plasma-treated melanoma cells induced extracellular signal-regulated Kinase (ERK) phosphorylation and increased CD28 expression, suggesting their activation. In monocytes, CD115 expression was elevated as a marker for activation. In summary, here we provide proof of concept that plasma-killed tumor cells are recognized immunologically, and that plasma exerts stimulating effects on immune cells alone. © 2019 by the authors.
- 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.
- ItemMedical Gas Plasma—A Potent ROS-Generating Technology for Managing Intraoperative Bleeding Complications(Basel : MDPI, 2022) Miebach, Lea; Poschkamp, Broder; van der Linde, Julia; Bekeschus, SanderCold medical gas plasmas are under pre-clinical investigation concerning their hemostatic activity and could be applied for intra-operative bleeding control in the future. The technological leap innovation was their generation at body temperature, thereby causing no thermal harm to the tissue and ensuring tissue integrity. This directly contrasts with current techniques such as electrocautery, which induces hemostasis by carbonizing the tissue using a heated electrode. However, the necrotized tissue is prone to fall, raising the risk of post-operative complications such as secondary bleedings or infection. In recent years, various studies have reported on the ability of medical gas plasmas to induce blood coagulation, including several suggestions concerning their mode of action. As non-invasive and gentle hemostatic agents, medical gas plasmas could be particularly eligible for vulnerable tissues, e.g., colorectal surgery and neurosurgery. Further, their usage could be beneficial regarding the prevention of post-operative bleedings due to the absence or sloughing of eschar. However, no clinical trials or individual healing attempts for medical gas plasmas have been reported to pave the way for clinical approvement until now, despite promising results in experimental animal models. In this light, the present mini-review aims to emphasize the potential of medical gas plasmas to serve as a hemostatic agent in clinical procedures. Providing a detailed overview of the current state of knowledge, feasible application fields are discussed, and possible obstacles are addressed.
- 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.
- 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.
- ItemLack of Adverse Effects of Cold Physical Plasma-Treated Blood from Leukemia Patients: A Proof-of-Concept Study(Basel : MDPI, 2021) Golpour, Monireh; Alimohammadi, Mina; Mohseni, Alireza; Zaboli, Ehsan; Sohbatzadeh, Farshad; Bekeschus, Sander; Rafiei, AlirezaChronic lymphocytic leukemia (CLL) is the most common blood malignancy with multiple therapeutic challenges. Cold physical plasma has been considered a promising approach in cancer therapy in recent years. In this study, we aimed to evaluate the cytotoxic effect of cold plasma or plasma-treated solutions (PTS) on hematologic parameters in the whole blood of CLL patients. The mean red blood cell count, white blood cell (WBC) count, platelet and hemoglobin counts, and peripheral blood smear images did not significantly differ between treated and untreated samples in either CLL or healthy individuals. However, both direct plasma and indirect PTS treatment increased lipid peroxidation and RNS deposition in the whole blood of CLL patients and in healthy subjects. In addition, the metabolic activity of WBCs was decreased with 120 s of cold plasma or PTS treatment after 24 h and 48 h. However, cold plasma and PTS treatment did not affect the prothrombin time, partial thromboplastin time, nor hemolysis in either CLL patients or in healthy individuals. The present study identifies the components of cold plasma to reach the blood without disturbing the basic parameters important in hematology, confirming the idea that the effect of cold plasma may not be limited to solid tumors and possibly extends to hematological disorders. Further cellular and molecular studies are needed to determine which cells in CLL patients are targeted by cold plasma or PTS.