Abstract: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 … Show more
“…Even if the effects observed may, to some extent, share similarities with the impact of dexamethasone (Horby et al , 2020 ) and tocilizumab (anti‐IL‐6) (Rossotti et al , 2020 ) on COVID‐19, IVM action is steady and strong in the golden hamsters and is not expected to block the effectors of inflammation but rather to dampen its initiation. Interestingly, the activation of nuclear factor erythroid 2‐related transcription factor (Nrf2) via low‐dose radiotherapy (LDRT) treatment has been proposed to cause a shift from M1 to M2 macrophages and a blockade of NLRP3 inflammasomes (Calabrese et al , 2021 ) and to be potentially beneficial on the lungs of COVID‐19 patients. Along the same line, we noticed via our RNA‐seq analyses that IVM treatment increased the gene expression of Nrf2 (or Nfe2l2) in the lungs of female hamsters and slightly in males (Dataset EV1 ), which gives additional evidence of the broad and upstream activity of IVM during SARS‐CoV‐2 infection.…”
The devastating pandemic due to SARS‐CoV‐2 and the emergence of antigenic variants that jeopardize the efficacy of current vaccines create an urgent need for a comprehensive understanding of the pathophysiology of COVID‐19, including the contribution of inflammation to disease. It also warrants for the search of immunomodulatory drugs that could improve disease outcome. Here, we show that standard doses of ivermectin (IVM), an anti‐parasitic drug with potential immunomodulatory activities through the cholinergic anti‐inflammatory pathway, prevent clinical deterioration, reduce olfactory deficit, and limit the inflammation of the upper and lower respiratory tracts in SARS‐CoV‐2‐infected hamsters. Whereas it has no effect on viral load in the airways of infected animals, transcriptomic analyses of infected lungs reveal that IVM dampens type I interferon responses and modulates several other inflammatory pathways. In particular, IVM dramatically reduces the Il‐6/Il‐10 ratio in lung tissue and promotes macrophage M2 polarization, which might account for the more favorable clinical presentation of IVM‐treated animals. Altogether, this study supports the use of immunomodulatory drugs such as IVM, to improve the clinical condition of SARS‐CoV‐2‐infected patients.
“…Even if the effects observed may, to some extent, share similarities with the impact of dexamethasone (Horby et al , 2020 ) and tocilizumab (anti‐IL‐6) (Rossotti et al , 2020 ) on COVID‐19, IVM action is steady and strong in the golden hamsters and is not expected to block the effectors of inflammation but rather to dampen its initiation. Interestingly, the activation of nuclear factor erythroid 2‐related transcription factor (Nrf2) via low‐dose radiotherapy (LDRT) treatment has been proposed to cause a shift from M1 to M2 macrophages and a blockade of NLRP3 inflammasomes (Calabrese et al , 2021 ) and to be potentially beneficial on the lungs of COVID‐19 patients. Along the same line, we noticed via our RNA‐seq analyses that IVM treatment increased the gene expression of Nrf2 (or Nfe2l2) in the lungs of female hamsters and slightly in males (Dataset EV1 ), which gives additional evidence of the broad and upstream activity of IVM during SARS‐CoV‐2 infection.…”
The devastating pandemic due to SARS‐CoV‐2 and the emergence of antigenic variants that jeopardize the efficacy of current vaccines create an urgent need for a comprehensive understanding of the pathophysiology of COVID‐19, including the contribution of inflammation to disease. It also warrants for the search of immunomodulatory drugs that could improve disease outcome. Here, we show that standard doses of ivermectin (IVM), an anti‐parasitic drug with potential immunomodulatory activities through the cholinergic anti‐inflammatory pathway, prevent clinical deterioration, reduce olfactory deficit, and limit the inflammation of the upper and lower respiratory tracts in SARS‐CoV‐2‐infected hamsters. Whereas it has no effect on viral load in the airways of infected animals, transcriptomic analyses of infected lungs reveal that IVM dampens type I interferon responses and modulates several other inflammatory pathways. In particular, IVM dramatically reduces the Il‐6/Il‐10 ratio in lung tissue and promotes macrophage M2 polarization, which might account for the more favorable clinical presentation of IVM‐treated animals. Altogether, this study supports the use of immunomodulatory drugs such as IVM, to improve the clinical condition of SARS‐CoV‐2‐infected patients.
“…Nrf2 can be also activated in other ways. Recently, the possible beneficial outcomes of COVID-19 pneumonia by activating the Nrf2 pathway via chemical and ionizing radiation were analysed by Calabrese et al [ 159 ], while Martínez-Sánchez et al verified the potential of ozone therapy [ 154 ].…”
Section: Nrf2 Activation As a Strategy For Covid-19 Treatmentmentioning
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known transcription factor best recognised as one of the main regulators of the oxidative stress response. Beyond playing a crucial role in cell defence by transactivating cytoprotective genes encoding antioxidant and detoxifying enzymes, Nrf2 is also implicated in a wide network regulating anti-inflammatory response and metabolic reprogramming. Such a broad spectrum of actions renders the factor a key regulator of cell fate and a strategic player in the control of cell transformation and response to viral infections. The Nrf2 protective roles in normal cells account for its anti-tumour and anti-viral functions. However, Nrf2 overstimulation often occurs in tumour cells and a complex correlation of Nrf2 with cancer initiation and progression has been widely described. Therefore, if on one hand, Nrf2 has a dual role in cancer, on the other hand, the factor seems to display a univocal function in preventing inflammation and cytokine storm that occur under viral infections, specifically in coronavirus disease 19 (COVID-19). In such a variegate context, the present review aims to dissect the roles of Nrf2 in both cancer and COVID-19, two widespread diseases that represent a cause of major concern today. In particular, the review describes the molecular aspects of Nrf2 signalling in both pathological situations and the most recent findings about the advantages of Nrf2 inhibition or activation as possible strategies for cancer and COVID-19 treatment respectively.
“…The Nrf2-induced antioxidant response drives immunological reactions toward an anti-inflammatory M2 phenotype. Activation of Nrf2 is dose dependent and displays features of a biphasic (hormetic) response (Calabrese et al 2021 ).…”
Section: Ldrt Application—role Of Nrf-2—timing Is Keymentioning
confidence: 99%
“… Fig. 1 LDRT induced Nrf2 activation and its effect on SARS-CoV-2 (including variants) induced pneumonitis (adapted from Calabrese et al 2021 ) …”
Section: Ldrt Application—role Of Nrf-2—timing Is Keymentioning
Coronavirus variants are gaining strongholds throughout the globe. Despite early signals that SARS-CoV-2 coronavirus case numbers are easing up in the United States and during the middle of a (not so easy) vaccination roll out, the country has passed a grim landmark of 600,000 deaths. We contend that these numbers would have been much lower if the medical community undertook serious investigations into the potential of low doses of radiation (LDRT) as a mainstream treatment modality for COVID-19 pneumonia. LDRT has been posited to manifest anti-infectious and anti-inflammatory properties at doses of 0.3–1.0 Gy via the activation of the Nrf-2 pathway. Although some researchers are conducting well-designed clinical trials on the potential of LDRT, the deep-rooted, blind, and flawed acceptance of the Linear No-Threshold (LNT) model for ionizing radiation has led to sidelining of this promising therapy and thus unimaginable numbers of deaths in the United States.
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