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Hyperinflammation characterized by elevated proinflammatory cytokines known as 'cytokine storms' is the major cause of high severity and mortality seen in COVID‐19 patients. The pathology behind the cytokine storms is currently unknown. Increased HMGB1 levels in serum/plasma of COVID‐19 patients were reported by many studies, which positively correlated with the level of proinflammatory cytokines. Dead cells following SARS‐CoV‐2 infection might release a large amount of HMGB1 and RNA of SARS‐CoV‐2 into extracellular space. HMGB1 is a well‐known inflammatory mediator. Additionally, extracellular HMGB1 might interact with SARS‐CoV‐2 RNA because of its high capability to bind with a wide variety of molecules including nucleic acids and could trigger massive proinflammatory immune responses. This review aimed to critically explore the many possible pathways by which HMGB1‐SARS‐CoV‐2 RNA complexes mediate proinflammatory responses in COVID‐19. The contribution of these pathways to impair host immune responses against SARS‐CoV‐2 infection leading to a cytokine storm was also evaluated. Moreover, since blocking the HMGB1‐SARS‐CoV‐2 RNA interaction might have therapeutic value, some of the HMGB1 antagonists have been reviewed. The HMGB1‐ SARS‐CoV‐2 RNA complexes might trigger endocytosis via RAGE which is linked to lysosomal rupture, PRRs activation, and pyroptotic death. High levels of the proinflammatory cytokines produced might suppress many immune cells leading to uncontrolled viral infection and cell damage with more HMGB1 released. Altogether these mechanisms might initiate a proinflammatory cycle leading to a cytokine storm. HMGB1 antagonists could be considered to give benefit in alleviating cytokine storms and serve as a potential candidate for COVID‐19 therapy. [ABSTRACT FROM AUTHOR]

An outbreak of a novel coronavirus (COVID‐19 or 2019‐CoV) infection has posed significant threats to international health and the economy. Patients with COVID‐19 are at risk of cytokine storm, acute respiratory distress syndrome (ARDS), reduced blood oxygenation, mechanical ventilation, and a high death rate. Although recent studies have shown remdesivir and dexamethasone as treatment options, there is an urgent need to find a treatment to inhibit virus replication and to control the progression of the disease. Essential biometal zinc has generated a lot of excitement as one of the promising candidates to reduce the severity of COVID‐19 infection. Several published observations outlined in the review are the reasons why there is a global enthusiasm that zinc therapy could be a possible therapeutic option. However, the biggest challenge in realising the therapeutic value of zinc is lack of optimal treatment modalities such as dose, duration of zinc supplementation and the mode of delivery. In this review, we discuss the regulatory mechanism that hinges upon the bioavailability of zinc. Finally, we propose that intravenous zinc could circumvent the confounding factors affecting the bioavailability of zinc and allow zinc to achieve its therapeutic potential. If successful, due to advantages such as lack of toxicity, low cost and ease of availability, intravenous zinc could be rapidly implemented clinically. [ABSTRACT FROM AUTHOR]

During the global outbreak of COVID‐19 pandemic, "cytokine storm" conditions are regarded as the fatal step resulting in most mortality. Hemoperfusion is widely used to remove cytokines from the blood of severely ill patients to prevent uncontrolled inflammation induced by a cytokine storm. This article discoveres, for the first time, that 2D Ti3C2Tx MXene sheet demonstrates an ultrahigh removal capability for typical cytokine interleukin‐6. In particular, MXene shows a 13.4 times higher removal efficiency over traditional activated carbon absorbents. Molecular‐level investigations reveal that MXene exhibits a strong chemisorption mechanism for immobilizing cytokine interleukin‐6 molecules, which is different from activated carbon absorbents. MXene sheet also demonstrates excellent blood compatibility without any deleterious side influence on the composition of human blood. This work can open a new avenue to use MXene sheets as an ultraefficient hemoperfusion absorbent to eliminate the cytokine storm syndrome in treatment of severe COVID‐19 patients. [ABSTRACT FROM AUTHOR]