Search Results
Plasma-derived reactive species shape a differentiation profile in human monocytes
2019, Freund, Eric, Moritz, Juliane, Stope, Matthias, Seebauer, Christian, Schmidt, Anke, Bekeschus, Sander
Background: 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.
Antitumor Effects in Gas Plasma-Treated Patient-Derived Microtissues—An Adjuvant Therapy for Ulcerating Breast Cancer?
2021, Akbari, Zahra, Saadati, Fariba, Mahdikia, Hamed, Freund, Eric, Abbasvandi, Fereshteh, Shokri, Babak, Zali, Hakimeh, Bekeschus, Sander
Despite global research and continuous improvement in therapy, cancer remains a challenging disease globally, substantiating the need for new treatment avenues. Medical gas plasma technology has emerged as a promising approach in oncology in the last years. Several investigations have provided evidence of an antitumor action in vitro and in vivo, including our recent work on plasma-mediated reduction of breast cancer in mice. However, studies of gas plasma exposure on patient-derived tumors with their distinct microenvironment (TME) are scarce. To this end, we here investigated patient-derived breast cancer tissue after gas plasma-treated ex vivo. The tissues were disjoint to pieces smaller than 100 µm, embedded in collagen, and incubated for several days. The viability of the breast cancer tissue clusters and their outgrowth into their gel microenvironment declined with plasma treatment. This was associated with caspase 3-dependent apoptotic cell death, paralleled by an increased expression of the anti-metastatic adhesion molecule epithelial (E)-cadherin. Multiplex chemokine/cytokine analysis revealed a marked decline in the release of the interleukins 6 and 8 (IL-6, IL-8) and monocyte-chemoattractant-protein 1 (MCP) known to promote a cancer-promoting milieu in the TME. In summary, we provide here, for the first time, evidence of a beneficial activity of gas plasma exposure on human patient-derived breast cancer tissue.
ROS Cocktails as an Adjuvant for Personalized Antitumor Vaccination?
2021, Clemen, Ramona, Bekeschus, Sander
Cancer is the second leading cause of death worldwide. Today, the critical role of the immune system in tumor control is undisputed. Checkpoint antibody immunotherapy augments existing antitumor T cell activity with durable clinical responses in many tumor entities. Despite the presence of tumor-associated antigens and neoantigens, many patients have an insufficient repertoires of antitumor T cells. Autologous tumor vaccinations aim at alleviating this defect, but clinical success is modest. Loading tumor material into autologous dendritic cells followed by their laboratory expansion and therapeutic vaccination is promising, both conceptually and clinically. However, this process is laborious, time-consuming, costly, and hence less likely to solve the global cancer crisis. Therefore, it is proposed to re-focus on personalized anticancer vaccinations to enhance the immunogenicity of autologous therapeutic tumor vaccines. Recent work re-established the idea of using the alarming agents of the immune system, oxidative modifications, as an intrinsic adjuvant to broaden the antitumor T cell receptor repertoire in cancer patients. The key novelty is the use of gas plasma, a multi-reactive oxygen and nitrogen species-generating technology, for diversifying oxidative protein modifications in a, so far, unparalleled manner. This significant innovation has been successfully used in proof-of-concept studies and awaits broader recognition and implementation to explore its chances and limitations of providing affordable personalized anticancer vaccines in the future. Such multidisciplinary advance is timely, as the current COVID-19 crisis is inexorably reflecting the utmost importance of innovative and effective vaccinations in modern times.
Gas Plasma Exposure of Glioblastoma Is Cytotoxic and Immunomodulatory in Patient-Derived GBM Tissue
2022, Bekeschus, Sander, Ispirjan, Mikael, Freund, Eric, Kinnen, Frederik, Moritz, Juliane, Saadati, Fariba, Eckroth, Jacqueline, Singer, Debora, Stope, Matthias B., Wende, Kristian, Ritter, Christoph A., Schroeder, Henry W. S., Marx, Sascha
Glioblastoma multiforme (GBM) is the most common primary malignant adult brain tumor. Therapeutic options for glioblastoma are maximal surgical resection, chemotherapy, and radiotherapy. Therapy resistance and tumor recurrence demand, however, new strategies. Several experimental studies have suggested gas plasma technology, a partially ionized gas that generates a potent mixture of reactive oxygen species (ROS), as a future complement to the existing treatment arsenal. However, aspects such as immunomodulation, inflammatory consequences, and feasibility studies using GBM tissue have not been addressed so far. In vitro, gas plasma generated ROS that oxidized cells and led to a treatment time-dependent metabolic activity decline and G2 cell cycle arrest. In addition, peripheral blood-derived monocytes were co-cultured with glioblastoma cells, and immunomodulatory surface expression markers and cytokine release were screened. Gas plasma treatment of either cell type, for instance, decreased the expression of the M2-macrophage marker CD163 and the tolerogenic molecule SIGLEC1 (CD169). In patient-derived GBM tissue samples exposed to the plasma jet kINPen ex vivo, apoptosis was significantly increased. Quantitative chemokine/cytokine release screening revealed gas plasma exposure to significantly decrease 5 out of 11 tested chemokines and cytokines, namely IL-6, TGF-β, sTREM-2, b-NGF, and TNF-α involved in GBM apoptosis and immunomodulation. In summary, the immuno-modulatory and proapoptotic action shown in this study might be an important step forward to first clinical observational studies on the future discovery of gas plasma technology’s potential in neurosurgery and neuro-oncology especially in putative adjuvant or combinatory GBM treatment settings.
Cold Atmospheric Pressure Plasma in Wound Healing and Cancer Treatment
2020, Boeckmann, Lars, Schäfer, Mirijam, Bernhardt, Thoralf, Semmler, Marie Luise, Jung, Ole, Ojak, Gregor, Fischer, Tobias, Peters, Kirsten, Nebe, Barbara, Müller-Hilke, Brigitte, Seebauer, Christian, Bekeschus, Sander, Emmert, Steffen
Plasma medicine is gaining increasing attention and is moving from basic research into clinical practice. While areas of application are diverse, much research has been conducted assessing the use of cold atmospheric pressure plasma (CAP) in wound healing and cancer treatment—two applications with entirely different goals. In wound healing, a tissue-stimulating effect is intended, whereas cancer therapy aims at killing malignant cells. In this review, we provide an overview of the latest clinical and some preclinical research on the efficacy of CAP in wound healing and cancer therapy. Furthermore, we discuss the current understanding of molecular signaling mechanisms triggered by CAP that grant CAP its antiseptic and tissue regenerating or anti-proliferative and cell death-inducing properties. For the efficacy of CAP in wound healing, already substantial evidence from clinical studies is available, while evidence for therapeutic effects of CAP in oncology is mainly from in vitro and in vivo animal studies. Efforts to elucidate the mode of action of CAP suggest that different components, such as ultraviolet (UV) radiation, electromagnetic fields, and reactive species, may act synergistically, with reactive species being regarded as the major effector by modulating complex and concentration-dependent redox signaling pathways.
Gas Plasma-Augmented Wound Healing in Animal Models and Veterinary Medicine
2021, Bekeschus, Sander, Kramer, Axel, Schmidt, Anke
The loss of skin integrity is inevitable in life. Wound healing is a necessary sequence of events to reconstitute the body’s integrity against potentially harmful environmental agents and restore homeostasis. Attempts to improve cutaneous wound healing are therefore as old as humanity itself. Furthermore, nowadays, targeting defective wound healing is of utmost importance in an aging society with underlying diseases such as diabetes and vascular insufficiencies being on the rise. Because chronic wounds’ etiology and specific traits differ, there is widespread polypragmasia in targeting non-healing conditions. Reactive oxygen and nitrogen species (ROS/RNS) are an overarching theme accompanying wound healing and its biological stages. ROS are signaling agents generated by phagocytes to inactivate pathogens. Although ROS/RNS’s central role in the biology of wound healing has long been appreciated, it was only until the recent decade that these agents were explicitly used to target defective wound healing using gas plasma technology. Gas plasma is a physical state of matter and is a partially ionized gas operated at body temperature which generates a plethora of ROS/RNS simultaneously in a spatiotemporally controlled manner. Animal models of wound healing have been vital in driving the development of these wound healing-promoting technologies, and this review summarizes the current knowledge and identifies open ends derived from in vivo wound models under gas plasma therapy. While gas plasma-assisted wound healing in humans has become well established in Europe, veterinary medicine is an emerging field with great potential to improve the lives of suffering animals.
Protective role of sphingomyelin in eye lens cell membrane model against oxidative stress
2021, Ravandeh, Mehdi, Coliva, Giulia, Kahlert, Heike, Azinfar, Amir, Helm, Christiane A., Fedorova, Maria, Wende, Kristian
In the eye lens cell membrane, the lipid composition changes during the aging process: the proportion of sphingomyelins (SM) increases, that of phosphatidylcholines decreases. To investigate the protective role of the SMs in the lens cell membrane against oxidative damage, analytical techniques such as electrochemistry, high-resolution mass spectrometry (HR-MS), and atomic force microscopy (AFM) were applied. Supported lipid bilayers (SLB) were prepared to mimic the lens cell membrane with different fractions of PLPC/SM (PLPC: 1-palmitoyl-2-linoleoylsn-glycero-3-phosphocholine). The SLBs were treated with cold physical plasma. A protective effect of 30% and 44% in the presence of 25%, and 75% SM in the bilayer was observed, respectively. PLPC and SM oxidation products were determined via HR-MS for SLBs after plasma treatment. The yield of fragments gradually decreased as the SM ratio increased. Topographic images obtained by AFM of PLPC-bilayers showed SLB degradation and pore formation after plasma treatment, no degradation was observed in PLPC/SM bilayers. The results of all techniques confirm the protective role of SM in the membrane against oxidative damage and support the idea that the SM content in lens cell membrane is increased during aging in the absence of effective antioxidant systems to protect the eye from oxidative damage and to prolong lens transparency.