Ozone at low concentrations does not affect motility and proliferation of cancer cells in vitro

Costanzo, Manuela; Romeo, Alessandro; Cisterna, Barbara; Calderan, Laura; Bernardi, Paolo; Covi, Viviana; Tabaracci, Gabriele; Malatesta, Manuela

doi:10.4081/ejh.2020.3119

Cited by 11 publications

(8 citation statements)

References 49 publications

(54 reference statements)

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“…It is worth noting that small local changes in the amount of reactive oxygen species (ROS), as induced by mild ozonation [ 15 ], may stimulate the polymerization of cytoskeletal actin [ 29 , 30 , 31 ] that is essential to form cell protrusions and promote adhesion [ 32 , 33 ]. However, the wound healing assay showed that the O 3 -induced increase in the surface processes was not paralleled by a higher migration rate, consistent with previous evidence that O 3 exposure does not affect the cell migration capability [ 34 ].…”

Section: Discussionsupporting

confidence: 86%

Low Ozone Concentrations Differentially Affect the Structural and Functional Features of Non-Activated and Activated Fibroblasts In Vitro

Cisterna

Costanzo

Lacavalla

et al. 2021

IJMS

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Oxygen–ozone (O2–O3) therapy is increasingly applied as a complementary/adjuvant treatment for several diseases; however, the biological mechanisms accounting for the efficacy of low O3 concentrations need further investigations to understand the possibly multiple effects on the different cell types. In this work, we focused our attention on fibroblasts as ubiquitous connective cells playing roles in the body architecture, in the homeostasis of tissue-resident cells, and in many physiological and pathological processes. Using an established human fibroblast cell line as an in vitro model, we adopted a multimodal approach to explore a panel of cell structural and functional features, combining light and electron microscopy, Western blot analysis, real-time quantitative polymerase chain reaction, and multiplex assays for cytokines. The administration of O2–O3 gas mixtures induced multiple effects on fibroblasts, depending on their activation state: in non-activated fibroblasts, O3 stimulated proliferation, formation of cell surface protrusions, antioxidant response, and IL-6 and TGF-β1 secretion, while in LPS-activated fibroblasts, O3 stimulated only antioxidant response and cytokines secretion. Therefore, the low O3 concentrations used in this study induced activation-like responses in non-activated fibroblasts, whereas in already activated fibroblasts, the cell protective capability was potentiated.

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Section: Discussionsupporting

confidence: 86%

Low Ozone Concentrations Differentially Affect the Structural and Functional Features of Non-Activated and Activated Fibroblasts In Vitro

Cisterna

Costanzo

Lacavalla

et al. 2021

IJMS

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“…Similarly, gas exposure did not affect proliferation in both LPS‐activated and LPS + DMF cells, as shown by the evaluation of both the mitotic index and BrdU‐positivity, according to previous reports on other cell types in vitro (Costanzo et al, 2020 ; Costanzo et al, 2015 ; Scassellati et al, 2017 ).…”

Section: Discussionsupporting

confidence: 82%

Ozone at low concentration modulates microglial activity in vitro: A multimodal microscopy and biomolecular study

Lacavalla

Inguscio

Cisterna

et al. 2022

Microscopy Res & Technique

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Oxygen-ozone (O 2 -O 3 ) therapy is an adjuvant/complementary treatment based on the activation of antioxidant and cytoprotective pathways driven by the nuclear factor erythroid 2-related factor 2 (Nrf2). Many drugs, including dimethyl fumarate (DMF), that are used to reduce inflammation in oxidative-stress-related neurodegenerative diseases, act through the Nrf2-pathway. The scope of the present investigation was to get a deeper insight into the mechanisms responsible for the beneficial result of O 2 -O 3 treatment in some neurodegenerative diseases. To do this, we used an integrated approach of multimodal microscopy (bright-field and fluorescence microscopy, transmission and scanning electron microscopy) and biomolecular techniques to investigate the effects of the low O 3 concentrations currently used in clinical practice in lipopolysaccharide (LPS)-activated microglial cells human microglial clone 3 (HMC3) and in DMF-treated LPS-activated (LPS + DMF) HMC3 cells. The results at light and electron microscopy showed that LPSactivation induced morphological modifications of HMC3 cells from elongated/ branched to larger roundish shape, cytoplasmic accumulation of lipid droplets, decreased electron density of the cytoplasm and mitochondria, decreased amount of Nrf2 and increased migration rate, while biomolecular data demonstrated that Heme oxygenase 1 gene expression and the secretion of the pro-inflammatory cytokines, Interleukin-6, and tumor necrosis factor-α augmented. O 3 treatment did not affect cell viability, proliferation, and morphological features of both LPS-activated and LPS + DMF cells, whereas the cell motility and the secretion of proinflammatory cytokines were significantly decreased. This evidence suggests that modulation of microglia activity may contribute to the beneficial effects of the O 2 -O 3 therapy in patients with neurodegenerative disorders characterized by chronic inflammation.

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“…The contrary can occur in cancer cells whereby a high cellular antioxidant status protects the cell from ROS leading to an increased cancer cell survival and a resistance to chemotherapy [20]. In dependence on the ozone concentrations, this effect has been explored by Costanzo and colleagues with the result that there is no effect on the motility and proliferation of cancer cells in vitro in the systemically used concentrations following the low-dose ozone concept [21,22].…”

Section: Signal Transduction and Bioregulation The Role Of Glutathionementioning

confidence: 99%

Ozone in Medicine. The Low-Dose Ozone Concept and Its Basic Biochemical Mechanisms of Action in Chronic Inflammatory Diseases

Viebahn-Haensler¹,

Fernández

2021

IJMS

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Low-dose ozone acts as a bioregulator in chronic inflammatory diseases, biochemically characterized by high oxidative stress and a blocked regulation. During systemic applications, “Ozone peroxides” are able to replace H2O2 in its specific function of regulation, restore redox signaling, and improve the antioxidant capacity. Two different mechanisms have to be understood. Firstly, there is the direct mechanism, used in topical treatments, mostly via radical reactions. In systemic treatments, the indirect, ionic mechanism is to be discussed: “ozone peroxide” will be directly reduced by the glutathione system, informing the nuclear factors to start the regulation. The GSH/GSSG balance outlines the ozone dose and concentration limiting factor. Antioxidants are regulated, and in the case of inflammatory diseases up-regulated; cytokines are modulated, here downregulated. Rheumatoid arthritis RA as a model for chronic inflammation: RA, in preclinical and clinical trials, reflects the pharmacology of ozone in a typical manner: SOD (superoxide dismutase), CAT (catalase) and finally GSH (reduced glutathione) increase, followed by a significant reduction of oxidative stress. Inflammatory cytokines are downregulated. Accordingly, the clinical status improves. The pharmacological background investigated in a remarkable number of cell experiments, preclinical and clinical trials is well documented and published in internationally peer reviewed journals. This should encourage clinicians to set up clinical trials with chronic inflammatory diseases integrating medical ozone as a complement.

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Ozone at low concentrations does not affect motility and proliferation of cancer cells in vitro

Cited by 11 publications

References 49 publications

Low Ozone Concentrations Differentially Affect the Structural and Functional Features of Non-Activated and Activated Fibroblasts In Vitro

Low Ozone Concentrations Differentially Affect the Structural and Functional Features of Non-Activated and Activated Fibroblasts In Vitro

Ozone at low concentration modulates microglial activity in vitro: A multimodal microscopy and biomolecular study

Ozone in Medicine. The Low-Dose Ozone Concept and Its Basic Biochemical Mechanisms of Action in Chronic Inflammatory Diseases

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