COVID-19 and low-dose radiation therapy.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of the coronavirus disease 2019 (COVID-19), has caused more than 179 million infections and 3.8 million deaths worldwide. Global health authorities working on the COVID-19 outbreak continue to explore methods to reduce the rate of its transmission to healthy individuals. Treatment protocols thus far have focused on social distancing and masking, treatment with antivirals early in infection, and steroids to reduce the inflammatory response. An alternative approach is therapy with low dose radiation (LDR), which has several advantages compared to the current drugs and medicines. To date more than 10 case reports and pilot clinical trial preliminary outcome are available from different countries. These reports cover a wide range of patient conditions and LDR treatment strategies. Although one report showed the failure to observe the improvement of COVID-19 patients after LDR therapy, the majority showed some clinical improvement, and demonstrated the safety of LDR for COVID-19 patients, particularly with 0.5 â€‹Gy. This review aims to summarize the potential rationales and mechanisms of LDR therapy for COVID-19 patients, and its current clinical status and potential use.

Low-Dose Radiation Therapy (LDRT) against Cancer and Inflammatory or Degenerative Diseases: Three Parallel Stories with a Common Molecular Mechanism Involving the Nucleoshuttling of the ATM Protein?

Very early after their discovery, X-rays were used in multiple medical applications, such as treatments against cancer, inflammation and pain. Because of technological constraints, such applications involved X-ray doses lower than 1 Gy per session. Progressively, notably in oncology, the dose per session increased. However, the approach of delivering less than 1 Gy per session, now called low-dose radiation therapy (LDRT), was preserved and is still applied in very specific cases. More recently, LDRT has also been applied in some trials to protect against lung inflammation after COVID-19 infection or to treat degenerative syndromes such as Alzheimer's disease. LDRT illustrates well the discontinuity of the dose-response curve and the counterintuitive observation that a low dose may produce a biological effect higher than a certain higher dose. Even if further investigations are needed to document and optimize LDRT, the apparent paradox of some radiobiological effects specific to low dose may be explained by the same mechanistic model based on the radiation-induced nucleoshuttling of the ATM kinase, a protein involved in various stress response pathways.

Understanding Long COVID; Mitochondrial Health and Adaptation-Old Pathways, New Problems.

Many people infected with the SARS-CoV-2 suffer long-term symptoms, such as "brain fog", fatigue and clotting problems. Explanations for "long COVID" include immune imbalance, incomplete viral clearance and potentially, mitochondrial dysfunction. As conditions with sub-optimal mitochondrial function are associated with initial severity of the disease, their prior health could be key in resistance to long COVID and recovery. The SARs virus redirects host metabolism towards replication; in response, the host can metabolically react to control the virus. Resolution is normally achieved after viral clearance as the initial stress activates a hormetic negative feedback mechanism. It is therefore possible that, in some individuals with prior sub-optimal mitochondrial function, the virus can "tip" the host into a chronic inflammatory cycle. This might explain the main symptoms, including platelet dysfunction. Long COVID could thus be described as a virally induced chronic and self-perpetuating metabolically imbalanced non-resolving state characterised by mitochondrial dysfunction, where reactive oxygen species continually drive inflammation and a shift towards glycolysis. This would suggest that a sufferer's metabolism needs to be "tipped" back using a stimulus, such as physical activity, calorie restriction, or chemical compounds that mimic these by enhancing mitochondrial function, perhaps in combination with inhibitors that quell the inflammatory response.

Neuroinflammation and Neurodegeneration of the Central Nervous System from Air Pollutants: A Scoping Review.

In this scoping review, we provide a selective mapping of the global literature on the effects of air pollution on the life-span development of the central nervous system. Our synthesis first defines developmental neurotoxicants and the model effects of particulate matter. We then discuss air pollution as a test bench for neurotoxicants, including animal models, the framework of systemic inflammation in all affected organs of the body, and the cascade effects on the developing brain, with the most prevalent neurological structural and functional outcomes. Specifically, we focus on evidence on magnetic resonance imaging and neurodegenerative diseases, and the links between neuronal apoptosis and inflammation. There is evidence of a developmental continuity of outcomes and effects that can be observed from utero to aging due to severe or significant exposure to neurotoxicants. These substances alter the normal trajectory of neurological aging in a propulsive way towards a significantly higher rate of acceleration than what is expected if our atmosphere were less polluted. The major aggravating role of this neurodegenerative process is linked with the complex action of neuroinflammation. However, most recent evidence learned from research on the effects of COVID-19 lockdowns around the world suggests that a short-term drastic improvement in the air we breathe is still possible. Moreover, the study of mitohormesis and vitagenes is an emerging area of research interest in anti-inflammatory and antidegenerative therapeutics, which may have enormous promise in combatting the deleterious effects of air pollution through pharmacological and dietary interventions.

The hormetic and hermetic role of IL-6.

Interleukin-6 is a pleiotropic cytokine regulating different tissues and organs in diverse and sometimes discrepant ways. The dual and sometime hermetic nature of IL-6 action has been highlighted in several contexts and can be explained by the concept of hormesis, in which beneficial or toxic effects can be induced by the same molecule depending on the intensity, persistence, and nature of the stimulation. According with hormesis, a low and/or controlled IL-6 release is associated with anti-inflammatory, antioxidant, and pro-myogenic actions, whereas increased systemic levels of IL-6 can induce pro-inflammatory, pro-oxidant and pro-fibrotic responses. However, many aspects regarding the multifaceted action of IL-6 and the complex nature of its signal transduction remains to be fully elucidated. In this review we collect mechanistic insight into the molecular networks contributing to normal or pathologic changes during advancing age and in chronic diseases. We point out the involvement of IL-6 deregulation in aging-related diseases, dissecting the hormetic action of this key mediator in different tissues, with a special focus on skeletal muscle. Since IL-6 can act as an enhancer of detrimental factor associated with both aging and pathologic conditions, such as chronic inflammation and oxidative stress, this cytokine could represent a "Gerokine", a determinant of the switch from physiologic aging to age-related diseases.

Low-dose radiation effects

The Earth was highly radioactive four billion years ago when life emerged. Even today, all humans are bombarded by 20,000 radiation strikes each second. Although high radiation doses are hazardous, organisms have evolved not only to tolerate lower-dose radiation but also to benefit by it (hormesis). Hormesis is prevailing in all species in various respects. An example is that hibakusha (Japanese A-bomb survivors) have longer lifespans and have lower risk of cancer, on average. Many microbes thrive in deep subsurface regions by consuming radiation as a source of nutrition. Low-dose radiation (LDR) is effective at treating severely affected COVID-19 patients, but the invalid linear no-threshold model (LNT) hinders the full beneficial use of LDR.

Disinfectant-induced hormesis: An unknown environmental threat of the application of disinfectants to prevent SARS-CoV-2 infection during the COVID-19 pandemic?

Massive additional quantities of disinfectants have been applied during the COVID-19 pandemic as infection preventive and control measures. While the application of disinfectants plays a key role in preventing the spread of SARS-CoV-2 infection, the effects of disinfectants applied during the ongoing pandemic on non-target organisms remain unknown. Here we collated evidence from multiple studies showing that chemicals used for major disinfectant products can induce hormesis in various organisms, such as plants, animal cells, and microorganisms, when applied singly or in mixtures, suggesting potential ecological risks at sub-threshold doses that are normally considered safe. Among other effects, sub-threshold doses of disinfectant chemicals can enhance the proliferation and pathogenicity of pathogenic microbes, enhancing the development and spread of drug resistance. We opine that hormesis should be considered when evaluating the effects and risks of such disinfectants, especially since the linear-no-threshold (LNT) and threshold dose-response models cannot identify or predict their effects.

Radio-frequency (RF) room temperature plasma treatment of sweet basil seeds (Ocimum basilicum L.) for germination potential enhancement by immaculation.

Ocimum basilicum L. is an antiviral and immunity boosting medicinal plant and culinary herb. Potential use of sweet basils in COVID 19 prevention and management is making its demand rise. This study is aimed at germination potential enhancement of sweet basil seeds. Reported study is evidenced with scientific data of radio-frequency cold plasma treatment using Ar + O2 feed gas. O. basilicum seeds, placed inside the rotating glass bottle, were directly exposed to RF (13.56 MHz) plasma produced in Ar + O2 feed gas. Seed treatment was done using RF source power (60 W, 150 W, 240 W), process pressure (0.2 mbar, 0.4 mbar, 0.6 mbar), and treatment time (5 min, 10 min, 15 min) at different combinations. Results show that, the most efficient treatment provide up to ∼89 % of the germination percentage which is an enhancement by 32.3 % from the control. SEM images revealed slight shrinkage in the seed size with eroded appearance over the seed. Enhancement of lipid peroxidation, show that oxidation of seed coat may propagate internally. Water imbibition analysis, of the treated seeds, was carried out for 2-12 hours. Further analysis of seed weight, on every one hour, after soaking shows enhanced water absorption capability except the treatment at 240 W, 0.6 mbar and 15 min. Plasma treatment enhanced carbohydrate content and protein content which is reported to be due to increased primary metabolism. Whereas, increased activity of secondary metabolism results in the enhancement of enzymatic (catalase) and non-enzymatic antioxidants (proline). Vital growth parameters, such as SVI I and SVI II, got amplified by 37 % and 133 % respectively after treatment. Ameliorative effects of plasma treatment are found highly significant with a positive and significant correlation value (p < 0.01) between germination percentages, SVI I, SVI II, carbohydrate, protein and proline show their interrelationship. Ar + O2 plasma treatment is found to bring forth significant changes in the O. basilicum seeds which eventually enhanced the germination potential and it could be a very promising technology for the medicinal crop.

Homeostatic control of redox status and health.

Research on oxidants and electrophiles has shifted from focusing on damage to biomolecules to the more fine-grained physiological arena. Redox transitions as excursions from a steady-state redox set point are continually ongoing in maintenance of redox balance. Current excitement on these topics results from the fact that recent research provided mechanistic insight, which gives rise to more concrete and differentiated questions. This Commentary focuses on redox eustress and the feedback restoration of steady state as concepts in active maintenance of physiological health, with brief discussion of redox stress response to viral infection, exemplified by COVID-19.

Nrf2 activation putatively mediates clinical benefits of low-dose radiotherapy in COVID-19 pneumonia and acute respiratory distress syndrome (ARDS): Novel mechanistic considerations.

Novel mechanistic insights are discussed herein that link a single, nontoxic, low-dose radiotherapy (LDRT) treatment (0.5-1.0 Gy) to (1) beneficial subcellular effects mediated by the activation of nuclear factor erythroid 2-related transcription factor (Nrf2) and to (2) favorable clinical outcomes for COVID-19 pneumonia patients displaying symptoms of acute respiratory distress syndrome (ARDS). We posit that the favorable clinical outcomes following LDRT result from potent Nrf2-mediated antioxidant responses that rebalance the oxidatively skewed redox states of immunological cells, driving them toward anti-inflammatory phenotypes. Activation of Nrf2 by ionizing radiation is highly dose dependent and conforms to the features of a biphasic (hormetic) dose-response. At the cellular and subcellular levels, hormetic doses of <1.0 Gy induce polarization shifts in the predominant population of lung macrophages, from an M1 pro-inflammatory to an M2 anti-inflammatory phenotype. Together, the Nrf2-mediated antioxidant responses and the subsequent shifts to anti-inflammatory phenotypes have the capacity to suppress cytokine storms, resolve inflammation, promote tissue repair, and prevent COVID-19-related mortality. Given these mechanistic considerations-and the historical clinical success of LDRT early in the 20th century-we opine that LDRT should be regarded as safe and effective for use at almost any stage of COVID-19 infection. In theory, however, optimal life-saving potential is thought to occur when LDRT is applied prior to the cytokine storms and before the patients are placed on mechanical oxygen ventilators. The administration of LDRT either as an intervention of last resort or too early in the disease progression may be far less effective in saving the lives of ARDS patients.

The geroscience agenda: Toxic stress, hormetic stress, and the rate of aging.

Geroscience offers a counterpoint to the challenged pursuit of curing diseases of aging, by focusing on slowing the biological aging process for extended healthspan earlier in life. Remarkable progress has led this field toward animal trials and the next challenge lies with translation to humans. There is an emerging number of small human trials that can take advantage of new models integrating behavioral and social factors. Understanding dynamic aging mechanisms, given the powerful social determinants of aging (Crimmins, 2020) and human variability and environmental contexts (Moffitt, 2020), will be critical. Behavioral and social factors are intrinsic to aging. Toxic stressors broadly defined can lead to stress-acceleration of aging, either directly impacting aging processes or by shaping poor behavioral health, and underlie the socioeconomic disparities of aging. In contrast, hormetic stressors, acute intermittent stressors of moderate intensity, can produce stress resilience, the ability for quick recovery and possibly rejuvenation of cells and tissues. Although health research usually examines static biomarkers, aging is reflected in dynamic ability to recover from challenges pointing to new interventions and targets for examining mechanisms. A fuller model incorporating stress resilience provides innovative biobehavioral interventions, both for bolstering response to challenges, such as COVID-19, and for improving healthspan.

Chloroquine commonly induces hormetic dose responses.

The use of chloroquine in the treatment of COVID-19 has received considerable attention. The recent intense focus on this application of chloroquine stimulated an investigation into the effects of chloroquine at low doses on highly biologically-diverse models and whether it may induce hormetic-biphasic dose response effects. The assessment revealed that hormetic effects have been commonly induced by chloroquine, affecting numerous cell types, including tumor cell lines (e.g. human breast and colon) and non-tumor cell lines, enhancing viral replication, sperm motility, various behavioral endpoints as well as decreasing risks of convulsions, and enhancing a spectrum of neuroprotective responses within a preconditioning experimental framework. These diverse and complex findings indicate that hormetic dose responses commonly occur with chloroquine treatment with a range of biological models and endpoints. These findings have implications concerning study design features including the number and spacing of doses, and suggest a range of possible clinical concerns and opportunities depending on the endpoint considered.

Low dose radiation therapy as a potential life saving treatment for COVID-19-induced acute respiratory distress syndrome (ARDS).

The new coronavirus COVID-19 disease caused by SARS-CoV-2 was declared a global public health emergency by WHO on Jan 30, 2020. Despite massive efforts from various governmental, health and medical organizations, the disease continues to spread globally with increasing fatality rates. Several experimental drugs have been approved by FDA with unknown efficacy and potential adverse effects. The exponentially spreading pandemic of COVID-19 deserves prime public health attention to evaluate yet unexplored arenas of management. We opine that one of these treatment options is low dose radiation therapy for severe and most critical cases. There is evidence in literature that low dose radiation induces an anti-inflammatory phenotype that can potentially afford therapeutic benefit against COVID-19-related complications that are associated with significant morbidity and mortality. Herein, we review the effects and putative mechanisms of low dose radiation that may be viable, useful and of value in counter-acting the acute inflammatory state induced by critical stage COVID-19.