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| Molecule | Key physiological role(s) | Reported role in response to plasma | Redox-mediated downstream effects |
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| Transporters | | | |
| AQP1 | Water, H2O2 [302], CO2, NO, and ammonia | Favored H2O2 permeation into intracellular compartment [251] | Signalling via the Keap1/Nrf2 system [303] |
| AQP3 | Water, urea, H2O2 [304], glycerol, and ammonia. Involved in cell proliferation, invasion, and angiogenesis [305] | Unknown | Activation of the Nox-2 and PI3K/Akt or MAPK pathway [306] |
| AQP5 | Water and H2O2 [307]. Involved in tumor formation, cell proliferation, and migration [308] | Unknown | Role in tumor formation related to its phosphorylation status [309] |
| AQP8 | Water, H2O2 [310], and ammonia | Required for anticancer effect of plasma-treated medium (PTM) on glioblastoma cells [311] | EGF induces AQP8 expression via EGF/EGFR-ERK1/2 pathway [312].
H2O2 transport is controlled by redox-mediated modifications [313] |
| AQP9 | Water, H2O2 [314], urea, glycerol, lactate, and pyruvate [309]
AQP9 knockdown reduced H2O2-induced cytotoxicity [314] | Its absence does not impair H2O2 transport upon treatment with PTM in glioblastoma cells [311] | Target of protein kinase A [307]. Possible interaction with ERK1/2 and MMP9 to enhance invasion and migration of prostate cancer cells [308] |
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| Cell membrane receptors | | | |
| Epidermal growth factor receptor (EGFR) | Receptor tyrosine kinase involved in signal transduction to stimulate proliferation and cellular growth and block apoptosis | EGFR was degraded and dysfunctional in EGFR-overexpressing oral squamous carcinoma after plasma treatment [315, 316] | Moderate exogenous H2O2 induces the redox activation of EGRF and increases protein kinase activity [317]. |
| Transient receptor proteins (TRP) | Calcium-permeable and voltage-independent cation channels which act as multimodal sensors of external stimuli | Unknown | In response to oxidative stress, TRPC3 and TRPC4 increase the intracellular Ca2+ concentration that leads to cell death [318] |
| Integrins | Responsible for cell-to-matrix and cell-to-cell adhesion. Integrins transduce the external signals to the cytoskeleton | DBD/air plasma enhanced expression of α2-integrin/CD49b and β1-integrin/CD29 in HaCaT cells [295]
Marginal decrease in α5- and β1-integrins in primary fibroblasts and PAM cells [319]
Plasma activates β1-integrins on the cell surface of WTDF3 mouse fibroblasts [320]
kINPen plasma jet treatment downregulates integrin expression in MRC5 cells [122] and increases β1-integrin in HaCaT cells [132] | Integrin-linked kinase (ILK) signalling via PKB/Akt can suppress apoptosis and anoikis [321]. ILK is required to maintain redox balance [322]
NRF2-mediated oxidative stress response |
| E-cadherin | Calcium-dependent cell-to-cell adhesion receptor | kINPen plasma jet treatment decreases E-cadherin expression in HaCaT cells [122, 132]
Argon plasma modulates E-cadherin function and induces its internalization in HaCaT cells in vitro and decreases the amount of E-cadherin in mice epidermis [323]. Others report an increase in E-cadherin expression in the wounds of rats [324] | Oxidative stress causes the selective disruption of E-cadherin and beta-catenin cell adhesion complexes [325]
In response to oxidative stress, E-cadherin binds to Nrf2 to restrain Nrf2 nuclear localization and activity [326]
Assembly of E-cadherin activates several small GTPases and, in turn, the activated small GTPases control the effects of E-cadherin-mediated adhesions on epithelial biogenesis [327]
Involvement of ROS in the regulation of cell adhesion and signal transduction functions of integrins and cadherins, pointing to ROS as emerging strong candidates for modulating the molecular cross-talk between cell-matrix and cell-cell adhesion receptors [328]
Redox-regulation of EMT [329] |
| Focal adhesions | Adhesive contact that anchors the cell to the extracellular matrix that mediates mechanical and biochemical signalling | Plasma increased the amount of vinculin and the focal adhesion size in WTDF3 mouse fibroblasts [320] | Oxidative stress activates focal adhesion kinase by Src kinase- and PI3 kinase-dependent mechanisms, which accelerates cell migration [330] |
|
| Lipids | | | |
| Cholesterol | Provides rigidity to the cell membrane and controls membrane fluidity [331] | When present at low concentrations in the cell membrane, plasma oxidation facilitates pore formation and passing of ROS [179].
Unknown effect of toxic by-product 5α-OOH after plasma treatment | Oxidation by-products such as HO•2 can generate intracellular H2O2 and •OH, and propagate lipid oxidation [178]. Induction of apoptosis by 7α,β-hydroxy-, 7-oxo-, and 5,6-epoxycholesterol [230] and formation of 5α-OOH [224] |
| Phospholipids | Main component of biological membranes | Plasma oxidizes phospholipids and affects lipid mobility [104, 332]
Plasma induces apoptosis and flipping of phosphatidylserine from the inner to the outer layer of the cell membrane [140, 236, 238, 333–335]
Plasma-treated cells present disrupted cell membranes [336–338] | Apoptotic cells presenting OxPLs in the cell membrane are eliminated by M2 macrophages [234] |
| Fatty acids | Form the hydrophobic hydrocarbon tails of phospholipids | Oxidation product NO2-FAs inhibit activation of NFκB [188] | NO2-FAs stop the lipid oxidation propagation and protein nitration [240]. Peroxidation increases the rigidity of the cell membrane [339] |
| Lipid rafts | Modulate distribution of receptors and signalling molecules in the cell membrane [340]
Important in oxidative stress-induced cell death [341] | In combination with hyperthermia, plasma activates the FA receptor (abundant in lipid rafts) and causes FA-induced apoptosis [342] | Activation and aggregation of death receptors such as FAs and TNFR1 located in lipid rafts and enhanced activation of kinases recruited at the raft site [341]. Ceramides produced from the oxidation of glycosphingolipids induce apoptosis via activation of the JNK pathway and regulation of Bax [343] and bind to cathepsin D to mediate TNF-induced cell death signalling [344]. In response to H2O2, JNK activates to induce the TRAF2/RIP-dependent pathway for oxidative cell death [341]. Lipid peroxidation affects the coupling of receptors with effector systems and decreases receptor density [339] |
|
| Catalytic enzymes | | | |
| NADPH oxidase (Nox) | Transmembrane enzyme that catalyzes the reduction of extracellular oxygen to O2•− | Inhibition with DPI attenuates the intracellular presence of ROS after plasma treatment, indicating a stimulation of endogenous ROS production with plasma [14] | Contributes to the elimination of malignant cells via HOCl and the NO/ONOO- signalling pathways |
| Catalase | Membrane-bound enzyme that decomposes H2O2 into water and oxygen. When membrane-bound, it provides increased resistance to exogenous H2O2 and favors tumor progression | Plasma-generated ROS supposedly induce the formation of singlet oxygen that inactivates membrane-bound catalase to favor apoptosis [345] | In malignant cells, catalase interferes with HOCl signalling by decomposing H2O2 and interferes with NO/ONOO- signalling through oxidation of NO and decomposition of ONOO- to favor tumor progression |
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