key: cord-0843163-5n0zya8q authors: Jung, Eui-Man; Lee, Geun-Shik title: Korean Red Ginseng, a regulator of NLRP3 inflammasome, in the COVID-19 pandemic date: 2022-02-17 journal: J Ginseng Res DOI: 10.1016/j.jgr.2022.02.003 sha: 56fb24159389b4a147d919a5b10902ecbcd6d49e doc_id: 843163 cord_uid: 5n0zya8q Coronavirus disease 2019 (COVID-19) exhibits various symptoms, ranging from asymptomatic to severe pneumonia or death. The major features of patients in severe COVID-19 are the dysregulation of cytokine secretion, pneumonia, and acute lung injury. Consequently, it leads to acute respiratory distress syndrome, disseminated intravascular coagulation, multiple organ failure, and death. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of COVID-19, influences nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3 (NLRP3), the sensor of inflammasomes, directly or indirectly, culminating in the assembly of NLRP3 inflammasome and activation of inflammatory caspases, which induce the inflammatory disruption in severe COVID-19. Accordingly, the target therapeutics for inflammasome has attracted attention as a treatment for COVID-19. Korean Red Ginseng (KRG) inhibits several inflammatory responses, including the NLRP3 inflammasome signaling. This review discusses the role of KRG in the treatment and prevention of COVID-19 based on its anti-NLRP3 inflammasome efficacy. An atypical viral pneumonia was first reported in December 2019 and spread worldwide as symptoms, but approximately 10% of the infected people progress to severe pneumonia, some 48 to hypoxia and acute respiratory distress syndrome (ARDS) [1] . In these cases, mechanical 49 ventilation is required, and there is high mortality [1, 5] . Severe COVID-19 also presents 50 multiple organ failure and other disorders, such as acute kidney injury and disseminated 51 intravascular coagulation [6, 7] . The symptoms of COVID-19 are mainly respiratory diseases, 52 but cardiovascular and neurological diseases can occur, albeit at a low rate [6, 7] . 53 The severity of COVID-19 is caused by an inappropriate hyper-inflammatory response, such 54 as excessive inflammatory cytokine release [6] [7] [8] . Furthermore, the infected individual with 55 comorbidities, such as diabetes, heart disease, high blood pressure, and aging, shows a poorer 56 prognosis [7-10]. These comorbidities are tightly related to chronic and persistent activation 57 of nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain 58 containing 3 (NLRP3) inflammasomes [11, 12] . Accordingly, hyper-activation of 59 inflammasome signaling will make the symptoms of COVID-19 more severe because it can 60 amplify the inflammatory reaction in people with an excessive inflammatory response [7-10]. 61 The inflammasomes have been considered a causative factor of infectious and metabolic 62 diseases, and the research on inflammasome selective inhibiting drugs is being conducted 63 J o u r n a l P r e -p r o o f candidates that inhibit NLRP3 inflammasome activation (Fig. 2) . The role of KRG on infection. SARS-CoV-2 enters the macrophages and monocytes, and activates NLRP3 501 inflammasome through K + efflux, cytosolic Ca 2+ influx, and mitochondrial ROS production. 502 Viral E protein stimulates K + efflux and cytosolic Ca 2+ influx. ORF3a increases K + efflux and 503 mitochondrial ROS production. ORF3a also interacts with ASC leading to assembly NLRP3 504 inflammasome. The viral S protein disrupts the mitochondrial integrity, resulting in ROS 505 generation, and binds with the NLRP3 protein leading to inflammasome assembly. E protein 506 and ORF3a upregulate the NLRP3 and IL-1 transcripts through NF-B signaling. KRG and 507 ginsenosides attenuate the activation of caspase-1 (Casp1) and the formation of ASC 508 pyroptosome through the inhibition of NLRP3 inflammasome assembly. A Novel Coronavirus from Patients with Pneumonia in China Coronaviridae Study Group of the International Committee on Taxonomy of V. 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