key: cord-0771786-4wpbyeds authors: Allawadhi, Prince; Khurana, Amit; Allwadhi, Sachin; Joshi, Kamaldeep; Packirisamy, Gopinath; Bharani, Kala Kumar title: Nanoceria as a possible agent for the management of COVID-19 date: 2020-09-15 journal: Nano Today DOI: 10.1016/j.nantod.2020.100982 sha: 4a1f6ec77933576b84b8bc1cbb98476c47b78e20 doc_id: 771786 cord_uid: 4wpbyeds The COVID-19 pandemic has emerged as an unprecedented global healthcare emergency and has devastated the global economy. The SARS-CoV-2 virus replicates in the host cells and is seemingly much more virulent compared to other flu viruses, as well as the SARS-CoV-1. The respiratory complications of the disease include acute respiratory distress syndrome (ARDS), cytokine storm, systemic inflammation, and pulmonary fibrosis. Nanoceria (NC) is a versatile rare earth nanoparticle with remarkable catalase and superoxide dismutase mimetic redox regenerative properties. Interestingly, NC possesses promising anti-inflammatory, antioxidant and anti-fibrotic properties making it an attractive tool to fight against the SARS-CoV-2 as well as the associated systemic complications. Until now, there is no clinically approved vaccine or drug for COVID-19, and the conquest to find a novel therapy for this global havoc is being undertaken at a warlike pace. Herein, based on preclinical evidence, we hypothesize that NC owing to its unique pharmacological properties might be an attractive preclinical candidate to win the battle over COVID-19. Further, it may be used as a prevention or treatment strategy in combination with other drugs. . . . . . TNF-α TGF-β ROS . . . . .. The COronaVIrusDiease-2019 (COVID-19) has emerged as an unprecedented global health crisis [1] . The SARS-CoV-2 virus enters the host cell through the angiotensin-converting enzyme 2 (ACE-2) receptor. Till date, more than nineteen million people have been infected with the SARS-CoV-2, and more than 0.7 million patients have succumbed to death. As of August 09, 2020, there is no approved vaccine to provide a robust clinical solution to this rapidly spreading viral disease [2] . Further, sadly it may still take up to 2 years for the pharmaceutical companies to come up with a clinically approved vaccine. hydroxychloroquine, and chloroquine have been questionable [3] [4] [5] . Further, the patients are given various medications such as steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and others for the management of systemic complications [6] . The acute respiratory distress syndrome (ARDS) is a critical complication of COVID-19. It is mediated by a complex interplay of multiple pathways like activation of nuclear factor kappalight-chain-enhancer of activated B cells (NFκB) pathway, enhanced inflammation, cytokine storm, mitogen-activated protein kinase (MAPKs) and others [7, 8] . Moreover, patients with prior chronic lung inflammation like emphysema may suffer from pulmonary fibrosis which is driven by induction of epithelial-to-mesenchymal transition (EMT) by fibrogenic growth factors like transforming growth factor beta (TGF-β) [9] [10] [11] . Nanoceria (NC) has emerged as a remarkably safe, redox regenerative, rare earth-based nanomedicine against acute and chronic inflammatory diseases owing to its unique ability to interchange between +3 and +4 oxidation states [12] [13] [14] [15] [16] [17] [18] [19] [20] . NC is postulated to be a robust antioxidant possessing catalase and superoxide dismutase mimetic activity [21, 22] . Further, NC possesses promising anti-inflammatory properties by inhibition of NFκB and MAPK pathways [23] [24] [25] . On the other side, NC has been shown to reduce fibrogenic signaling by inhibition of the TGF-β signaling pathway [26] . NC can be administered in various dosage forms, including aerosol or transdermal patches based on the condition and compliance of the patient. We hypothesized that NC could be a novel therapeutic for the management of reduce overall inflammation, can be of benefit [27] . NC is an excellent nanomedicine for combating acute inflammatory insult. It was shown to reduce severe sepsis-related mortality by inhibition of NFκB signaling and suppressed lipopolysaccharide-induced MAPK signaling [23, 28] . Manne et al., showed that NC is effective against peritonitis, proving its effective antiinflammatory activity [29] . Inflammatory cells, like neutrophils and macrophages, are the major players during the pathological response. It is well known that cytokines such as interleukin (IL)- provided protection from free radical and mechanical trauma [32] [33] [34] [35] . Owing to its regenerative potential and efficacy at low dose, NC has been pharmacologically effective against neurodegenerative diseases [36, 37] . In a stroke model, NC reduced ischemic cell death in brain slices by more than 50%, reduced the levels of nitric oxide and superoxide. The outcomes in models of ischemia and traumatic brain injury associated neuroinflammation entails that NC is a plausible candidate against chronic inflammation [38] [39] [40] . During ARDS, severe inflammation encompasses the lungs rapidly and increases mortality risk. The cyanosis of skin and short/rapid breathing are some of the important clinical features of ARDS for which patients require ventilator support. Lung images of affected patients have revealed characteristic white patches with jelly like fluid accumulation (ground glass) within the lungs, which resembles the pathological lungs after drowning [41] . Further, lung fibrosis is one of the observed complications of COVID-19 patients with prior respiratory diseases like emphysema [42, 43] . Without any respiratory support, lung fibrosis can potentially make the patients incapable of breathing [44, 45] . Physiologically, TGF-β is an important growth factor required for normal growth and development. Its excessive inhibition may have side effects like reduced apoptosis of Th17 cells, increased TNF-α expression, developmental disorders, cardiotoxicity and hyperkeratosis [46] [47] [48] . Pathologically, TGF-β induces the epithelial-tomesenchymal transition (EMT) which promotes the transformation of fibroblasts to highly mobile and secretory myofibroblasts [49] . These myofibroblasts secrete excessive extracellular J o u r n a l P r e -p r o o f matrix (ECM), resulting in scarring and fibrosis-related injuries [50, 51] . However, a large pool of scientific evidence indicates that pharmacological inhibition of excessive TGF-β can be a promising strategy for the management of fibrotic disorders. In pre-clinical studies, it has been revealed that NC can potentially attenuate fibrosis progression by inhibiting TGF-β signaling. NC was shown to effectively reduce liver fibrosis, with marked reduction in collagen deposition and EMT activation [52] . Inhibition of TGF-β by NC makes it a promising adjuvant for COVID-19 treatment therapy. Moreover, Arya et al., reported protective role of NC against hypobaric hypoxia-induced oxidative damage and inflammation via modulation of oxidative stress [53] . These findings indicate that NC could aid in lung protection in COVID-19. Figure 2 provides the rationale for the pharmacological benefits of NC for the alleviation of respiratory complications. promoting COVID-19 related systemic complications. The mechanisms which lie behind the ROS generation are macromolecular damage and impeded thiol redox circuit that result in impaired redox control and aberrant cellular signaling. Altogether these make the disease more intense. NC being a potent reactive oxygen species (ROS) scavenger, reduces pathological damage in various diseases [54] . NC can reduce lipid peroxidation, improve physiological glutathione levels, as well as elicits SOD and catalase mimetic activity which make it a potential candidate for the management of systemic complications of COVID-19 [22, 25] . to the lungs might be an excellent therapeutic approach for effective treatment. To serve this purpose, aerosol based inhalational spray is a promising approach that is not only patient compliant but also imparts quick relief for a defined time period [55] . Aerosols can deliver NC directly to the lungs and may reduce the disease severity caused by the novel coronavirus, with probable efficacy in the amelioration of ARDS related complications. While many drugs and macromolecules suffer from temperature and pressure generated through the nebulization process, this will not affect inorganic nanocrystals of NC which have a dense and robust crystal structure. Additionally, its catalytic behavior makes it effective at lower doses for a long period of time, thus it can be nebulized at very low concentration, hence preventing any change to aggregation during transportation into the alveoli. In cases, where patients are unable to administer the drug on their own, NC can be impregnated into a thin film and could be administered as transdermal patches which might provide effect for sustained and prolonged duration without any significant first-pass metabolism. Further, addition of other NSAIDs in combination with NC would serve a synergistic approach for effective COVID-19 management [56] . Figure 3 shows the mentioned routes of administration with their specific advantages. Our hypothesis provides pre-clinical rationale for the management of COVID-19 with NC. 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Pulmonary Delivery of Fenretinide: A Possible Adjuvant Treatment In COVID-19 Prince Allawadhi has completed his M.Pharmacy (Pharmacology) from He has multiple publications in international peer reviewed journals and has 2 book chapters to his credit in Thieme and Springer Nature publishing house. He is recipient of India's prestigious Rajnibhai V Patel Trust PharmInnova Best Master Thesis Award in the Pharmacology category His research interests include novel therapeutics for chronic inflammatory disorders and artificial skin substitutes for burn injury. He has authored more than thirty publications in reputed international journals. He is recipient of numerous awards like DST-DAAD Doctoral Fellowship Sachin Allwadhi has completed his B.Tech He has been a scholar throughout and has also authored multiple publications in internationally reputed journals His work and research interests include Image Processing, Neural Network, and Information Security. Dr. Joshi authored over 20 articles in international peer reviewed journals. He attended various national and international conferences and contributed research papers in their proceedings Gopinath Packirisamy is an Associate Professor in the Department of Biotechnology at Indian Institute of Technology (IIT) Roorkee, India. He earned his Ph.D. in Biotechnology from Indian Institute of Technology Guwahati, India. He did his postdoctoral research at University of Rochester Medical Center