https://orcid.org/0000-0003-3517-8135
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Abstract
Severe imbalance in iron metabolism among SARS-CoV-2 infected patients is prominent in every symptomatic (mild, moderate to severe) clinical phase of COVID-19. Phase-I – Hypoxia correlates with reduced O2 transport by erythrocytes, overexpression of HIF-1α, altered mitochondrial bioenergetics with host metabolic reprogramming (HMR). Phase-II – Hyperferritinemia results from an increased iron overload, which triggers a fulminant proinflammatory response – the acute cytokine release syndrome (CRS). Elevated cytokine levels (i.e. IL6, TNFα and CRP) strongly correlates with altered ferritin/TF ratios in COVID-19 patients. Phase-III – Thromboembolism is consequential to erythrocyte dysfunction with heme release, increased prothrombin time and elevated D-dimers, cumulatively linked to severe coagulopathies with life-threatening outcomes such as ARDS, and multi-organ failure. Taken together, Fe-R-H dysregulation is implicated in every symptomatic phase of COVID-19. Fe-R-H regulators such as lactoferrin (LF), hemoxygenase-1 (HO-1), erythropoietin (EPO) and hepcidin modulators are innate bio-replenishments that sequester iron, neutralize iron-mediated free radicals, reduce oxidative stress, and improve host defense by optimizing iron metabolism. Due to its pivotal role in ‘cytokine storm’, ferroptosis is a potential intervention target. Ferroptosis inhibitors such as ferrostatin-1, liproxstatin-1, quercetin, and melatonin could prevent mitochondrial lipid peroxidation, up-regulate antioxidant/GSH levels and abrogate iron overload-induced apoptosis through activation of Nrf2 and HO-1 signaling pathways. Iron chelators such as heparin, deferoxamine, caffeic acid, curcumin, α-lipoic acid, and phytic acid could protect against ferroptosis and restore mitochondrial function, iron-redox potential, and rebalance Fe-R-H status. Therefore, Fe-R-H restoration is a host biomarker-driven potential combat strategy for an effective clinical and post-recovery management of COVID-19.
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The authors declare no conflicts of interest. The authors alone are responsible for the content and writing of the article.
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Notes on contributors
Sreus A.G. Naidu
Dr. Sreus A.G. Naidu has earned Doctorate in Pharmacy and MS in Regulatory Science from the University of Southern California. Sreus has over 15 years of experience working at N-terminus Research Laboratory based in California, which specializes in the isolation, purification, and activation of bioactive molecules. He is co-inventor on multiple patents with applications in human nutrition and animal healthcare.
Roger A. Clemens
Professor Roger A. Clemens is Associate Director of the Regulatory Science program and Adjunct Professor of Pharmacology and Pharmaceutical Sciences within the USC School of Pharmacy. Dr. Clemens was the Director of Analytical Research at USC for 5 years, and the Scientific Advisor for Nestlé USA for more than 21 years. He has published more than 50 original manuscripts in nutrition and food science, participated in more than 200 invited domestic and international lectures, and served as an expert panel member for the food industry, scientific organizations, trade associations and regulatory agencies in the United States and Canada.
A. Satyanarayan Naidu
Professor A Satyanarayan Naidu is the Director of N-terminus Research Laboratory in California, USA. After receiving PhD in Medical Microbiology (1985) from the Osmania University in India, Dr. Naidu served the Directorate of Public Health Services (DPHS), the Government of A.P., India and the World Health Organization (WHO) Surveillance program. He performed post-doctoral research at the Medical University of Pécs, Hungary and the Biomedical Center-Uppsala, Sweden. Dr. Naidu joined the faculty at the Lund University; Sweden (1988-1992), the University of North Carolina at Chapel Hill, USA (1993-1997). He was appointed as the Director at the Center for Antimicrobial Research, California State University-Pomona, USA (1998-2000). Dr. Naidu’s discoveries on Staphylococcal toxic shock syndrome (TSS) and E. coli hemolytic uremic syndrome (HUS) have garnered international recognition. He was principal investigator for several NIH grants, published more than 100 peer-reviewed research publications, written over 30 book chapters, and authored 4 reference volumes in the field of medical sciences. He holds 24 core patents, and his technology transfers in biomedical technology reach worldwide. Dr. Naidu is an elected fellow of the Royal Society for Medicine, the Linnean Society of London, the American College of Nutrition, and the International Society for the Study of Vulvovaginal Disease.