key: cord-0714586-fsz5z893 authors: Yi, Young-Su title: Potential benefits of ginseng against COVID-19 by targeting inflammasomes date: 2022-04-04 journal: J Ginseng Res DOI: 10.1016/j.jgr.2022.03.008 sha: 19d5d61d7417cfefdac3203d826717bebaf2ebd0 doc_id: 714586 cord_uid: fsz5z893 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogenic virus that causes coronavirus disease 2019 (COVID-19), with major symptoms including hyper-inflammation and cytokine storm, which consequently impairs the respiratory system and multiple organs, or even cause death. SARS-CoV-2 activates inflammasomes and inflammasome-mediated inflammatory signaling pathways, which are key determinants of hyperinflammation and cytokine storm in COVID-19 patients. Additionally, SARS-CoV-2 inhibits inflammasome activation to evade the host's antiviral immunity. Therefore, regulating inflammasome initiation has received increasing attention as a preventive measure in COVID-19 patients. Ginseng and its major active constituents, ginsenosides and saponins, improve the immune system and exert anti-inflammatory effects by targeting inflammasome stimulation. Therefore, this review discussed the potential preventive and therapeutic roles of ginseng in COVID-19 based on its regulatory role in inflammasome initiation and the host's antiviral immunity. inflammasome activation and subsequent pyroptosis [31] . The SARS-CoV-2 spike protein has 158 been demonstrated in vitro to interact with its molecular receptor, angiotensin-converting enzyme 159 2 (ACE2) [32, 33] , leading to the stimulation of the NLRP3 inflammasome in HSPCs and EPCs 160 [34] . 161 The regulatory role of SARS-CoV-2 in NLRP3 inflammasome activation has also been evaluated 162 in various types of cells in COVID-19 patients. The primary site of SARS-CoV-2 infection is the 163 respiratory system; therefore, the modulatory role of SARS-CoV-2 in NLRP3 inflammasome 164 initiation has been reported in lungs and airway of COVID-19 patients. SARS-CoV-2 NSP6 165 triggers pyroptotic death of lung epithelial cells in COVID-19 patients by activating the NLRP3 166 inflammasome [35] . In contrast to these results, NLRP3 inflammasome activation was inhibited The effect of SARS-CoV-2 infection has also been demonstrated in blood cells and circulating 173 monocytes of COVID-19 patients. The NLRP3 inflammasome is triggered in blood cells of 174 COVID-19 patients, leading to elevated levels of proinflammatory cytokines in serum [37] . CoV-2 also initiates the NLRP3 inflammasome in circulating monocytes of COVID-19 patients, 176 resulting in pyroptotic death of circulating monocytes and secretion of pro-inflammatory cytokines 177 from the cells [38, 39] . Interestingly, NLRP3 inflammasome activation in response to SARS-CoV-178 2 infection is associated with COVID-19 severity [39] . inflammasome-activated inflammatory signaling pathways in BV2 microglial cells [42] . A case 186 study of deceased COVID-19 patients also reported that SARS-CoV-2 nucleocapsid protein was 187 co-localized with ACE2 and NLRP3 inflammasome in the cerebral cortical tissue-resident 188 J o u r n a l P r e -p r o o f macrophages of deceased COVID-19 patients [43] , which strongly suggests the involvement of 189 NLRP3 inflammasome in SARS-CoV-2 cerebral pathogenicity. 190 Age is one of the most critical factors associated with mortality risk due to SARS-CoV-2 infection. This risk rapidly increases for people in their 60s and over 80s with serious illnesses and death 192 [44, 45] . A recent study demonstrated that age is an important factor in increasing lethality in 193 COVID-19 patients. The NLRP3 inflammasome is over-activated and the production of pro-194 inflammatory cytokines is highly increased in aged COVID-19 patients [46] . Studies explained the 195 mechanistic reason why the NLRP3 inflammasome is more activated in elderly people. Aging NLRP12 as a direct substrate of SARS-CoV-2 NSP5, resulting in its proteolysis of NLRP12 and 224 hence indicating its role in hyperinflammation [54] . Cell-based experiments also revealed that 225 NLRP12 levels were reduced in SARS-CoV-2-infected HEK293T-ACE2 cells expressing ACE2 226 [54] , suggesting that SARS-CoV-2 induces hyperinflammation by proteolytic inhibition of the 227 NLRP12 inflammasome, which is a negative regulator of inflammatory responses. The role of SARS-CoV-2 in AIM2 inflammasome activation has also been previously reported. SARS-CoV-2 activates the AIM2 inflammasome in circulating monocytes of COVID-19 patients, 230 hence inducing pyroptotic death and secreting pro-inflammatory cytokines from monocytes [38] . Table 1 . (Table 2) . In conclusion, accumulating evidence strongly suggests that ginseng and its main active 347 ingredients, ginsenosides and saponins, provide preventive and therapeutic benefits by not only 348 inhibiting inflammasome activation and consequent hyper-inflammation, but also promoting the 349 host's antiviral immunity in COVID-19 patients. J o u r n a l P r e -p r o o f Panax notoginseng Saponins Attenuate Neuroinflammation through TXNIP-601 Mediated NLRP3 Inflammasome Activation in Aging Rats Ginsenoside 604 Rg1 protects against neuronal degeneration induced by chronic dexamethasone treatment by 605 inhibiting NLRP-1 inflammasomes in mice Ginsenoside Rg1 607 protects against H2O2induced neuronal damage due to inhibition of the NLRP1 608 inflammasome signalling pathway in hippocampal neurons in vitro Fructose-arginine, a non-saponin molecule of Korean 611 Red Ginseng, attenuates AIM2 inflammasome activation Apigenin supplementation protects the development of dextran sulfate sodium-induced 614 murine experimental colitis by inhibiting canonical and non-canonical inflammasome 615 signaling pathways Epigallocatechin-3-Gallate Attenuates Microglial Inflammation and Neurotoxicity by 618 Suppressing the Activation of Canonical and Noncanonical Inflammasome via TLR4/NF-619 kappaB Pathway Scutellarin inhibits caspase-11 activation and pyroptosis in macrophages via 622 regulating PKA signaling Luteolin activates Tregs to promote IL-10 624 expression and alleviating caspase-11-dependent pyroptosis in sepsis-induced lung injury Morin alleviates aflatoxin B1-induced liver and kidney injury by inhibiting 632 heterophil extracellular traps release, oxidative stress and inflammatory responses in chicks Viburnum pichinchense methanol 635 extract exerts anti-inflammatory effects via targeting the NF-kappaB and caspase-11 non-636 canonical inflammasome pathways in macrophages Ginsenoside Rh2 Inhibited Proliferation by Inducing ROS Mediated 638 ER Stress Dependent Apoptosis in Lung Cancer Cells Role of ginsenosides, the main active components of 640 Panax ginseng, in inflammatory responses and diseases Panax ginseng: Inflammation, platelet aggregation, 642 thrombus formation, and atherosclerosis crosstalk Immuno-644 enhancement effects of Korean Red Ginseng in healthy adults: a randomized, double-blind, 645 placebo-controlled trial Stimulation of I 647 nnate Immune Function by Panax ginseng after Heat Processing SARS-CoV-2 spike protein Caco-2 SARS-CoV-2 viroporin HEK293 & A549 SARS-CoV-2 single-stranded RNA Macrophages SARS-CoV-2 nucleocapsid protein BMDMs & THP-1 SARS-CoV-2 spike protein PBMCs [30] SARS-CoV-2 spike protein HSPCs & EPCs SARS-CoV-2 spike protein HSPCs & EPCs SARS-CoV-2 NSP6 Lung epithelial cells of COVID-19 patients SARS-CoV-2 Blood cells of COVID-19 patients SARS-CoV-2 Circulating monocytes of COVID-19 patients SARS-CoV-2 Circulating monocytes of COVID-19 patients SARS-CoV-2 spike protein BV-2 SARS-CoV-2 Cerebral cortical tissues of COVID-19 patients Inhibition SARS-CoV-2 NSP1 and NSP13 Activation SARS-CoV-2 NSP5 AIM2 Activation SARS-CoV-2 Circulating monocytes of COVID-19 patients