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- 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.
- ItemGas Flow Shaping via Novel Modular Nozzle System (MoNoS) Augments kINPen-Mediated Toxicity and Immunogenicity in Tumor Organoids(Basel : MDPI, 2023) Berner, Julia; Miebach, Lea; Herold, Luise; Höft, Hans; Gerling, Torsten; Mattern, Philipp; Bekeschus, SanderMedical gas plasma is an experimental technology for anticancer therapy. Here, partial gas ionization yielded reactive oxygen and nitrogen species, placing the technique at the heart of applied redox biomedicine. Especially with the gas plasma jet kINPen, anti-tumor efficacy was demonstrated. This study aimed to examine the potential of using passive flow shaping to enhance the medical benefits of atmospheric plasma jets (APPJ). We used an in-house developed, proprietary Modular Nozzle System (MoNoS; patent-pending) to modify the flow properties of a kINPen. MoNoS increased the nominal plasma jet-derived reactive species deposition area and stabilized the air-plasma ratio within the active plasma zone while shielding it from external flow disturbances or gas impurities. At modest flow rates, dynamic pressure reduction (DPR) adapters did not augment reactive species deposition in liquids or tumor cell killing. However, MoNoS operated at kINPen standard argon fluxes significantly improved cancer organoid growth reduction and increased tumor immunogenicity, as seen by elevated calreticulin and heat-shock protein expression, along with a significantly spurred cytokine secretion profile. Moreover, the safe application of MoNoS gas plasma jet adapters was confirmed by their similar-to-superior safety profiles assessed in the hen’s egg chorioallantoic membrane (HET-CAM) coagulation and scar formation irritation assay.
- 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.
- ItemBiological Risk Assessment of Three Dental Composite Materials following Gas Plasma Exposure(Basel : MDPI, 2022) Bekeschus, Sander; Miebach, Lea; Pommerening, Jonas; Clemen, Ramona; Witzke, KatharinaGas plasma is an approved technology that generates a plethora of reactive oxygen species, which are actively applied for chronic wound healing. Its particular antimicrobial action has spurred interest in other medical fields, such as periodontitis in dentistry. Recent work has indicated the possibility of performing gas plasma-mediated biofilm removal on teeth. Teeth frequently contain restoration materials for filling cavities, e.g., resin-based composites. However, it is unknown if such materials are altered upon gas plasma exposure. To this end, we generated a new in-house workflow for three commonly used resin-based composites following gas plasma treatment and incubated the material with human HaCaT keratinocytes in vitro. Cytotoxicity was investigated by metabolic activity analysis, flow cytometry, and quantitative high-content fluorescence imaging. The inflammatory consequences were assessed using quantitative analysis of 13 different chemokines and cytokines in the culture supernatants. Hydrogen peroxide served as the control condition. A modest but significant cytotoxic effect was observed in the metabolic activity and viability after plasma treatment for all three composites. This was only partially treatment time-dependent and the composites alone affected the cells to some extent, as evident by differential secretion profiles of VEGF, for example. Gas plasma composite modification markedly elevated the secretion of IL6, IL8, IL18, and CCL2, with the latter showing the highest correlation with treatment time (Pearson’s r > 0.95). Cell culture media incubated with gas plasma-treated composite chips and added to cells thereafter could not replicate the effects, pointing to the potential that surface modifications elicited the findings. In conclusion, our data suggest that gas plasma treatment modifies composite material surfaces to a certain extent, leading to measurable but overall modest biological effects.
- 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.
- ItemHmox1 Upregulation Is a Mutual Marker in Human Tumor Cells Exposed to Physical Plasma-Derived Oxidants(Basel : MDPI, 2018-10-27) Bekeschus, Sander; Freund, Eric; Wende, Kristian; Gandhirajan, Rajesh; Schmidt, AnkeIncreasing numbers of cancer deaths worldwide demand for new treatment avenues. Cold physical plasma is a partially ionized gas expelling a variety of reactive oxygen and nitrogen species, which can be harnesses therapeutically. Plasmas and plasma-treated liquids have antitumor properties in vitro and in vivo. Yet, global response signatures to plasma treatment have not yet been identified. To this end, we screened eight human cancer cell lines to investigate effects of low-dose, tumor-static plasma-treated medium (PTM) on cellular activity, immune-modulatory properties, and transcriptional levels of 22 redox-related genes. With PTM, a moderate reduction of metabolic activity and modest modulation of chemokine/cytokine pattern and markers of immunogenic cell death was observed. Strikingly, the Nuclear factor (erythroid-derived 2)-like 2 (nrf2) target heme oxygenase 1 (hmox1) was upregulated in all cell lines 4 h post PTM-treatment. nrf2 was not changed, but its baseline expression inversely and significantly correlated with hmox1 expression after exposure to PTM. Besides awarding hmox1 a central role with plasma-derived oxidants, we present a transcriptional redox map of 22 targets and chemokine/cytokine secretion map of 13 targets across eight different human tumor cell lines of four tumor entities at baseline activity that are useful for future studies in this field.
- ItemModulation of the Tumor-Associated Immuno-Environment by Non-Invasive Physical Plasma(Basel : MDPI, 2023) Förster, Sarah; Niu, Yuequn; Eggers, Benedikt; Nokhbehsaim, Marjan; Kramer, Franz-Josef; Bekeschus, Sander; Mustea, Alexander; Stope, Matthias B.Over the past 15 years, investigating the efficacy of non-invasive physical plasma (NIPP) in cancer treatment as a safe oxidative stress inducer has become an active area of research. So far, most studies focused on the NIPP-induced apoptotic death of tumor cells. However, whether NIPP plays a role in the anti-tumor immune responses need to be deciphered in detail. In this review, we summarized the current knowledge of the potential effects of NIPP on immune cells, tumor–immune interactions, and the immunosuppressive tumor microenvironment. In general, relying on their inherent anti-oxidative defense systems, immune cells show a more resistant character than cancer cells in the NIPP-induced apoptosis, which is an important reason why NIPP is considered promising in cancer management. Moreover, NIPP treatment induces immunogenic cell death of cancer cells, leading to maturation of dendritic cells and activation of cytotoxic CD8+ T cells to further eliminate the cancer cells. Some studies also suggest that NIPP treatment may promote anti-tumor immune responses via other mechanisms such as inhibiting tumor angiogenesis and the desmoplasia of tumor stroma. Though more evidence is required, we expect a bright future for applying NIPP in clinical cancer management.
- 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.
- ItemChemotherapeutics Used for High-Risk Neuroblastoma Therapy Improve the Efficacy of Anti-GD2 Antibody Dinutuximab Beta in Preclinical Spheroid Models(Basel : MDPI, 2023) Troschke-Meurer, Sascha; Zumpe, Maxi; Meißner, Lena; Siebert, Nikolai; Grabarczyk, Piotr; Forkel, Hannes; Maletzki, Claudia; Bekeschus, Sander; Lode, Holger N.Anti-disialoganglioside GD2 antibody ch14.18/CHO (dinutuximab beta, DB) improved the outcome of patients with high-risk neuroblastoma (HR-NB) in the maintenance phase. We investigated chemotherapeutic compounds used in newly diagnosed patients in combination with DB. Vincristine, etoposide, carboplatin, cisplatin, and cyclophosphamide, as well as DB, were used at concentrations achieved in pediatric clinical trials. The effects on stress ligand and checkpoint expression by neuroblastoma cells and on activation receptors of NK cells were determined by using flow cytometry. NK-cell activity was measured with a CD107a/IFN-γ assay. Long-term cytotoxicity was analyzed in three spheroid models derived from GD2-positive neuroblastoma cell lines (LAN-1, CHLA 20, and CHLA 136) expressing a fluorescent near-infrared protein. Chemotherapeutics combined with DB in the presence of immune cells improved cytotoxic efficacy up to 17-fold compared to in the controls, and the effect was GD2-specific. The activating stress and inhibitory checkpoint ligands on neuroblastoma cells were upregulated by the chemotherapeutics up to 9- and 5-fold, respectively, and activation receptors on NK cells were not affected. The CD107a/IFN-γ assay revealed no additional activation of NK cells by the chemotherapeutics. The synergistic effect of DB with chemotherapeutics seems primarily attributed to the combined toxicity of antibody-dependent cellular cytotoxicity and chemotherapy, which supports further clinical evaluation in frontline induction therapy.