antioxidants

Editorial
Ionizing Radiation, Antioxidant Response and Oxidative
Damage: Radiomodulators
Elena Obrador 1, * and Alegría Montoro 2

1 Elena Obrador Department of Physiology, Faculty of Medicine and Odontology, University of Valencia,
46010 Valencia, Spain
2 Alegría Montoro, Radiation Protection Service, University and Polytechnic Hospital La Fe,
46021 Valencia, Spain; almonpas@hotmail.com
* Correspondence: elena.obrador@uv.es

Ionizing radiation (IR) is the energy released by atoms in the form of electromagnetic
waves (e.g., X or gamma rays) or particle radiation (alpha, beta, electrons, protons, neutrons,
mesons, prions, and heavy ions) with sufficient energy to ionize atoms or molecules [1].
IR induces DNA breaks leading to direct molecular damages or even cell death, whereas
in the case of cell survival, it can lead to carcinogenesis or other abnormalities [2,3]. The
highly reactive free radicals formed by the radiolysis of water (superoxide anion (O2 •− ),
hydroxyl radical (•OH), hydrated electron (e− (aq) ), and hydrogen peroxide (H2 O2 )) and
the subsequent oxidative stress are the main cause of most of the molecular (DNA, lipids,
proteins, etc.) damages [1,4]. In turn, cells injured by IR are responsible for inducing
radiation bystander effects (RIBEs) in non-exposed tissues, manifested by changes including
(but not limited to) gene expression alterations, chromosomal aberrations, micronuclei
formation, secretion of miRNAs and or exosomes, and cell death/proliferation and/or
transformation. In that sense, overproduced reactive oxygen species (ROS) and reactive
nitrogen species (RNS) are considered initiators, whereas nitric oxide, the transforming
growth factor beta (TGF-β), and other inflammatory cytokines are considered effectors
involved in RIBE [5].
Radiation-induced biological effects are determined by the type of radiation, dose
rate and total dose received, fractionation and protraction, penetration capacity, linear
Citation: Obrador, E.; Montoro, A. energy transfer, cell or tissue affected, and time of exposure [6]. The survival response
Ionizing Radiation, Antioxidant can be modulated by different factors, e.g., DNA repair mechanisms, antioxidant defences,
Response and Oxidative Damage: intrinsic radiosensibility of tissues, inflammatory response, RIBE, health condition, and/or
Radiomodulators. Antioxidants 2023, the administration of radiomodulators. Radiomodulators include radioprotectors, radiomit-
12, 1219. https://doi.org/10.3390/ igators, and molecules with radiosensitizing properties. The first ones reduce or prevent
antiox12061219
the damage induced by IR (generally acting as chelators of free radicals, antioxidants, . . . ),
Received: 16 May 2023 but to be effective, they must be administered before or at the same time as exposure [2].
Revised: 16 May 2023 In contrast, radiomitigators help to recover or attenuate radio-induced damages even
Accepted: 31 May 2023 when they are administered after radiation exposition [3,7], which represents an important
Published: 5 June 2023 strategic advantage. Mechanisms involved in the radiomitigating activity include the
restoration of the cellular antioxidant defence mechanisms, the prevention of excessive
inflammatory responses, and/or the repair of damaged tissues [5]. Finally, radiosensitizers
can increase radio-induced damage in cells or tissues, and their use is mainly focused on
Copyright: © 2023 by the authors.
cancer treatment, where it is especially important to induce cytotoxicity in the cancer cells
Licensee MDPI, Basel, Switzerland.
without affecting healthy tissues [8–10].
This article is an open access article
Nuclear technology is becoming widely used in many diverse fields, i.e., industry,
distributed under the terms and
medicine, military, and basic research. Although a few years ago, exposure to IR was
conditions of the Creative Commons
restricted to accidents at nuclear power plants or terrorist attacks, nowadays, the risk is
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
increased by the improper and careless management of IR in the radiographic industry
4.0/).
and in radiation oncology [11]. Moreover, IR exposure is unavoidable in the case of cancer

Antioxidants 2023, 12, 1219. https://doi.org/10.3390/antiox12061219 https://www.mdpi.com/journal/antioxidants

patients undergoing radiotherapy, and it will also be unavoidable for future aerospace ship
crews [12]. All this raises the inexorable need to develop strategies that may allow rapid
interventions to prevent or reduce radiation-induced damages. Significant advances have
been made in public health and the clinical planning intended to prevent or improve the
response to an accidental exposure [5]. However, despite the strong economic and scientific
efforts over recent decades, at present, clinical biomarkers of radiation-induced damage
and drugs that can effectively protect against lethal IRs are still an unmet need.
Overall, this Special Issue provides the readers with an understanding of the lat-
est advancements in the bioefficacy and/or mechanisms of action of several promising
radiomodulators [2,3,5,7,9,10,13–16], the capacity of hyperthermia to increase cancer treat-
ment efficacy [17], a new clinical model to evaluate the radio-induced damages [15,18], and
novel IR biomarker technologies [19,20].
N-acetyl-5-methoxytryptamine (melatonin), often referred to as a “sleep hormone”, is
produced by the pineal gland. Its free radical scavenger and antioxidant actions contribute
to reducing nitric oxide formation, which facilitates the decrease in the inflammatory
response after IR exposition [5]. According to the experiments concerning whole body
irradiation, melatonin administered both before and after IR exposure increased the sur-
vival rate of examined animals, reduced symptoms of acute irradiation syndrome, and
improved radio-induced oxidative stress and histopathological damages [21]. Animal
studies have confirmed that melatonin can also alleviate radiation-induced cell death
via inhibition of proapoptotic genes (e.g., Bax) and upregulation of antiapoptotic genes
(e.g., Bcl-2) [22]. The radioprotective and radiomitigating efficacy of melatonin was con-
firmed by Abdullaev et al. in tissues (brain and spleen) that exhibit different proliferative
activity and radiosensitivity [2].
Peroxiredoxins are capable of reducing a wide range of inorganic and organic per-
oxides. Novoselova et al. show that peroxiredoxin 6 treatment normalized p53 and
NF-κB/p65 expression, p21 levels, DNA repair-associated genes, TLR expression, pro-
inflammatory cytokine production (TNF-α and IL-6), and apoptosis in irradiated 3T3 cells
cultures. Moreover, the IR-induced suppression of the Nrf2 activity (a key regulator of
the antioxidant cellular response) could be restored by peroxiredoxin 6, even when it was
administered after radiation exposure [3].
Wagle et al. evidenced that supplemented ferulic acid attenuates the total body
irradiation-mediated bone marrow damages, stem cell senescence, and hematopoietic injury
by enhancing the antioxidant defence. Thus pointing out its potential as a radioprotective
countermeasure [13].
Lactoferrin is a multifunctional glycoprotein present in mammalian secretory fluids
and in neutrophil granules. The study of Kopaeva et al. provided evidence for the ra-
diomitigating potential of human Lactoferrin on mice subjected to sublethal irradiation.
Their results show that treated mice increased their survival from 28% to 78%, attenuated
weight loss, normalized their behaviour, and also increased the leukocyte account, serum
homeostasis parameters, and structural organization of the spleen [7].
Pelvic irradiation-induced mucositis secondarily leads to changes in the composition
of microbiota and reduces its diversity, all factors that contribute to radiation enteropa-
thy [23,24]. Microbiome dysbiosis contributes to the overexpression of proinflammatory
cytokines and weakens the function of the intestinal epithelial barrier [24]. Typical symp-
toms of gastrointestinal radiation injury, including vomiting, anorexia, abdominal pain,
and diarrhoea, can seriously affects patients’ quality of life after or during radiotherapy
treatment [25,26]. Limiting the intestinal irradiation dose and using a lower fractionated
dose helps to relieve symptoms, but compromises and reduces the anti-tumour efficacy
of the treatment [27]. Probiotics can attenuate radiation-derived enteritis side effects by
restoring microbiota, regulating the immune system, downregulating proinflammatory
cytokines, regulating apoptosis, and reversing ecological dysregulation [28,29]. Thus, the
development of probiotic therapy to prevent the radiotherapy-induced diarrhoea is a hot
topic, but with contradictory efficacy according to several recent studies [30–32]. Although
Antioxidants 2023, 12, 1219 3 of 6

some studies have proposed that Lactobacillus rhamnosus supplementation is efficacious for
preventing radio-induced enteritis [33,34], Segers et al.’s results [14] evidence that, although
supplementation with Limnospira indica PCC 8005 or Lacticaseibacillus rhamnosus GG ATCC
prevented radio-induced dysbiosis, probiotic administration did not preserve the intestinal
protective barrier or did not have significant immunomodulatory effects.
Radiotherapy failure and poor tumour prognosis are primarily attributed to radioresis-
tance. In 1924, Otto Warburg observed that tumours consumed large quantities of glucose
while secreting high levels of lactate, irrespective of the tissue oxygen concentration [35].
Since then, this “aerobic glycolysis” has been shown to benefit tumour growth by providing
intermediates needed to maintain high rates of cellular division. Moreover, the link between
glucose metabolism and redox stress is relevant for the cancer radiation response. Bian
et al. present an interesting review exposing the mechanisms involved in mitochondrial
metabolism and cancer radioresistance, targeting mitochondrial signalling pathways to
reverse radiation insensitivity [36].
Planarians are invertebrate flatworms with stem cells constantly replacing old, dam-
aged, or dying cells. Combined with new genomic technologies, the planarian sensitivity to
IR provides an outstanding tool for the evaluation of potential radioprotective agents [18].
In this, Tsarkova et al.’s study on the planarian model confirms the antioxidant properties
of Tameron against X-ray-induced and menadione-induced oxidative stress [15].
In cancer therapeutics, the development of radiosensitizers would represent a great
advance, especially if treatment can also exert radioprotective effects on healthy tissues.
Pacifico et al. evidence that a polyphenol-rich Olea europaea L. cv. Caiazzana Leaf extract
mitigates radiation-induced DNA damage in normal cell lines, whereas it exacerbates
radiation damage in cancer cells [9].
The prognosis of patients diagnosed with pancreatic cancer remains dismal, with a
less than 3% survival at 5 years [37]. At supraphysiologic levels, ascorbate (vitamin C)
acts as a pro-oxidant, donating electrons to form H2 O2 and, thereby, causing selective
cytotoxicity and oxidative stress in pancreatic cancer cells [38,39]. Thus, pharmacological
ascorbate has potential as a radiosensitizer at the same time that several studies evidence
its radioprotective potential in normal tissues [40]. During recent years, Auranofin has
garnered interest for its anticancer potential, although its mechanisms of action are not
completely elucidated. Steers et al. review the mechanism and effectiveness of auranofin
alone and in combination with ascorbate and IR, in the treatment of pancreatic cancer [10].
Applying focused hyperthermia (HT), the temperature of the affected area is raised to
around 40–45 ◦ C using different methods, i.e., microwave, radiofrequency, ultrasound, or
infrared radiations. In cancer therapy, a specific area is exposed to high temperatures to
kill cancer cells or make them more sensitive to other cancer treatments, such as chemo
and/or radiotherapy [17,41,42]. The tumour microenvironment is characterized by nutrient
deprivation, limited oxygenation, and highly acidic conditions, properties associated with
low effects on the tumour response to radiation [42]. HT increases tumour perfusion
and re-oxygenation, drug uptake, and ROS production, inhibits the repair of radiation-
induced damage, and induces cancer cell apoptosis [43,44]. In addition to the various
thermoradiobiological effects, it has recently been shown that HT has immunostimulatory
effects involving the innate and adaptive immune systems, thereby inducing systemic
anti-tumour immune responses [45]. Kwon et al. review the latest advances regarding
the efficacy of HT in the treatment of cancer and its possible synergistic effects with
radiotherapy [17].
Sagkrioti et al. developed a database termed RadBioBase, which includes compre-
hensive transcriptomes of mammalian cells across healthy and non-healthy tissues when
responding to a range of radiation types and doses. Their results evidence that the effects
of high linear energy transfer (LET) radiation on cell transcriptomes significantly differ
from those caused by low LET and, importantly, are consistent with immunomodulation,
inflammation, oxidative stress responses, and cell death. The transcriptome changes also
depend on the dose, since low doses up to 0.5 Gy mainly involve cytokine cascades, while
Antioxidants 2023, 12, 1219 4 of 6

higher doses are mainly linked to ROS metabolism. Overall, their results suggest that differ-
ent radiation types and doses can trigger distinct cell-intrinsic and cell-extrinsic pathways,
which may facilitate manipulation to improving radiotherapy efficiency and reducing
systemic toxicities [19].
The serum proteomic and oxidative modification profiling in mice exposed to total
body X-Irradiation evidenced a dose-dependent and oxidation-related response involving
six different serum proteins (angiotensinogen, odorant-binding protein 1a, serine protease
inhibitor A3K, serum paraoxonase/arylesterase 1, prothrombin, and the epidermal growth
factor receptor). Consequently, Yamaguchi et al. suggest the possible application of these
changes as novel biomarkers to validate the radiation dose [20].
Electron radiation is widely used to ensure the microbiological safety of food and
drugs. One of the most important advantages of this method is that it is carried out
at low temperatures, which is important for heat-sensitive products. Many brands of
nutraceuticals containing resveratrol are available, and Rosiak et al. show that, far from
endangering the biological properties of resveratrol, electron beam radiation (even at a
dose of 25 kGy) can increase the antioxidant properties of resveratrol [16].
Finally, Obrador et al. discuss the best choices for triage, dose assessment, and victim
classification in the case of large-scale atomic or radiological events. Furthermore, our
review focuses on the available medical countermeasures (radioprotectors, radiomitiga-
tors, radionuclide scavengers) that can implement the response to an accidental radiation
exposure or can help to increase survival in cancer patients [5].
As a whole, these 11 research [2,3,7,9,13–16,18–20] and 4 review articles [5,10,17,36]
from leading experts bring to the field exciting discussions on different aspects, new
findings, and new perspectives, thus making this Special Issue an essential read for anyone
interested in the impact of radiation exposure on human health.

Funding: This work was supported by the Project CPP2021-8817 funded by the MCIN/AEI/10.13039/
501100011033/ and the European Union NextGenerationEU/PRTR.
Conflicts of Interest: The authors declare no conflict of interest.

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