Effect of head group and lipid tail oxidation in the cell membrane revealed through integrated simulations and experiments

Abstract

We report on multi-level atomistic simulations for the interaction of reactive oxygen species (ROS) with the head groups of the phospholipid bilayer, and the subsequent effect of head group and lipid tail oxidation on the structural and dynamic properties of the cell membrane. Our simulations are validated by experiments using a cold atmospheric plasma as external ROS source. We found that plasma treatment leads to a slight initial rise in membrane rigidity, followed by a strong and persistent increase in fluidity, indicating a drop in lipid order. The latter is also revealed by our simulations. This study is important for cancer treatment by therapies producing (extracellular) ROS, such as plasma treatment. These ROS will interact with the cell membrane, first oxidizing the head groups, followed by the lipid tails. A drop in lipid order might allow them to penetrate into the cell interior (e.g., through pores created due to oxidation of the lipid tails) and cause intracellular oxidative damage, eventually leading to cell death. This work in general elucidates the underlying mechanisms of ROS interaction with the cell membrane at the atomic level.In recent years, cold atmospheric plasmas (CAPs) are gaining increasing interest for cancer treatment, i.e., so-called "plasma oncology" [1][2][3][4] . In a recent review, Schlegel et al. 1 summarize the results of several studies on plasma oncology and show the progress in the potential use of CAPs to effectively kill cancer cells (either by apoptosis or necrosis), in vitro as well as in vivo. CAP sources seem to be a powerful tool for cancer treatment, either alone or in combination with other conventional therapies. Indeed, recent experimental results showed that CAPs could enhance the effects of conventional chemotherapy even in resistant tumorous cells; the resistant cell population, if pre-treated with CAP, becomes sensitive to treatment with chemotherapy 5,6 . Moreover, it was demonstrated that plasma treatment, both in vitro and in vivo, is able to attack a wide range of cancer cell lines without damaging their normal counterparts 1, 2 . Thus, preliminary results seem very promising. Nevertheless, the application of CAPs for cancer treatment is still in its initial stage, and there is an enormous need for a better understanding of the underlying mechanisms.CAPs generate reactive oxygen species (ROS, e.g., OH, HO 2 , H 2 O 2 ) and reactive nitrogen species (RNS, e.g., NO, NO 2 , ONOO − ), which are generally believed to play a key role in plasma treatment 3,4,7 . Several studies showed that CAPs elevate intracellular ROS levels, thereby inducing oxidative damage in cancer cells, which can lead to cell death, i.e., apoptosis 3,8 . Normal cells, on the other hand, are able to defend themselves from this harmful effect of ROS by activating multiple anti-oxidative systems that reduce the increased oxidative stress and restore the balance 9, 10 . Besides, also the RNS generated by CAP might play an important role in cancer therapy (see ref. 4 and references therein). ...

Combination Treatment with Cold Physical Plasma and Pulsed Electric Fields Augments ROS Production and Cytotoxicity in Lymphoma

“…Oxidized membranes are known to be more easily electropermeabilized [32]. Therefore, we hypothesized that plasma-generated ROS enhance PEF-induced membrane electroporation and cytotoxicity [27,33]. Our second hypothesis was that the combination of plasma and PEF augments ROS production cell death signaling [29,34,35].…”

Plasma Medicine: A Field of Applied Redox Biology

“…The schematic overview in Figure 4 summarizes the state of knowledge on molecular patterns in wound healing in response to CAP treatment and aligns these results with insights from redox biology and research on molecular biology of healing processes in acute wounds (90,117,124,132). Briefly, it is assumed that CAP treatment leads to a transient and reversible modification of proteins and the lipid bilayer, which contribute to normal or pathologic stages of wound healing (117,140,141). This is crucially mediated by the Nrf2 pathway (90,116,117).…”

Possible Mechanism of Glucose Uptake Enhanced by Cold Atmospheric Plasma: Atomic Scale Simulations

“…To study the effect of oxidized PLs, we used aldehyde oxidation products (see Figure 1b, DOPC-ALD), which are one of the major oxidation products [19]. Note that CAP yields a cocktail of reactive species and thus, could possibly form a range of products upon oxidation of the PLB, but the formation of aldehyde groups (i.e., DOPC-ALD) was prominently observed in CAP-treated vesicles [13]. These oxidation products were also used in our recent simulation studies on various properties of the PLB [13][14][15].…”

“…Note that CAP yields a cocktail of reactive species and thus, could possibly form a range of products upon oxidation of the PLB, but the formation of aldehyde groups (i.e., DOPC-ALD) was prominently observed in CAP-treated vesicles [13]. These oxidation products were also used in our recent simulation studies on various properties of the PLB [13][14][15]. The force field parameters for the aldehyde groups in the oxidized PLs were obtained from [20] and the parameters of glucose were based on [21].…”

“…Specifically, we studied the effect of lipid oxidation on phosphatidylserine translocation across the plasma membrane, which plays a vital role in apoptosis signaling [12]. Furthermore, we investigated the ROS oxidation of the head groups and lipid tails in the membrane [13], the permeation of ROS across oxidized and non-oxidized membranes, including the synergistic effect of plasma oxidation and electric field [14], and the hampering effect of cholesterol [15,16]. In general, our investigations showed that oxidation of the membrane leads to an increase in its fluidity and permeability to ROS, thereby affecting the abovementioned processes.…”