key: cord-0682102-canec2lt authors: Kritis, Panagiotis; Karampela, Irene; Kokoris, Styliani; Dalamaga, Maria title: The combination of bromelain and curcumin as an immune-boosting nutraceutical in the prevention of severe COVID-19 date: 2020-11-13 journal: Metabol Open DOI: 10.1016/j.metop.2020.100066 sha: 3610cbfaeb225e7d1c62beb8e7b5e0b49b6af80f doc_id: 682102 cord_uid: canec2lt The coronavirus disease 2019 (COVID-19) pandemic is still ongoing, while no treatment has been proved effective. COVID-19 pathophysiology involves the activation of three main pathways: the inflammatory, the coagulation and the bradykinin cascades. Here, we highlight for the first time the joint potential therapeutic role of bromelain and curcumin, two well-known nutraceuticals, in the prevention of severe COVID-19. Bromelain (a cysteine protease isolated from the pineapple stem) and curcumin (a natural phenol found in turmeric) exert important immunomodulatory actions interfering in the crucial steps of COVID-19 pathophysiology. Their anti-inflammatory properties include inhibition of transcription factors and subsequent downregulation of proinflammatory mediators. They also present fibrinolytic and anticoagulant properties. Additionally, bromelain inhibits cyclooxygenase and modulates prostaglandins and thromboxane, affecting both inflammation and coagulation, and also hydrolyzes bradykinin. Interestingly, curcumin has been shown in in silico studies to prevent entry of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into cells as well as viral replication, while a recent experimental study has demonstrated that bromelain may also inhibit viral entry into cells. Notably, bromelain substantially increases the absorption of curcumin after oral administration. To the best of our knowledge, this is the first report highlighting the significance of bromelain and, most importantly, the potential preventive value of the synergistic effects of bromelain and curcumin against severe COVID-19. The coronavirus disease 2019 (COVID-19) pandemic is still ongoing, while no treatment has been proved effective. COVID-19 pathophysiology involves the activation of three main pathways: the inflammatory, the coagulation and the bradykinin cascades. Here, we highlight for the first time the joint potential therapeutic role of bromelain and curcumin, two well-known nutraceuticals, in the prevention of severe COVID-19. Bromelain (a cysteine protease isolated from the pineapple stem) and curcumin (a natural phenol found in turmeric) exert important immunomodulatory actions interfering in the crucial steps of COVID-19 pathophysiology. Their antiinflammatory properties include inhibition of transcription factors and subsequent downregulation of proinflammatory mediators. They also present fibrinolytic and anticoagulant properties. Additionally, bromelain inhibits cyclooxygenase and modulates prostaglandins and thromboxane, affecting both inflammation and coagulation, and also hydrolyzes bradykinin. Interestingly, curcumin has been shown in in silico studies to prevent entry of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into cells as well as viral replication, while a recent experimental study has demonstrated that bromelain may also inhibit viral entry into cells. Notably, bromelain substantially increases the absorption of curcumin after oral administration. To the best of our knowledge, this is the first report highlighting the significance of bromelain and, most importantly, the potential preventive value of the synergistic effects of bromelain and curcumin against severe COVID-19. [4, 6] . Additionally, curcumin inhibits ACE modulating angiotensin II synthesis and downregulating inflammation, while it also promotes fibrinolysis and the anticoagulation process [4, 6, 7] (Fig. 1) . The antiviral actions of curcumin against multiple viruses (influenza and hepatitis viruses, herpes viruses, human papilloma virus, human immunodeficiency virus, severe acute respiratory syndrome coronavirus and other coronaviruses), bacteria and fungi have been established by experimental evidence [8] . Remarkably, recent evidence from in silico studies has demonstrated that curcumin prevents SARS-CoV-2 entry to cells by blocking the viral binding sites and the cell ligands (spike protein, ACE-2 receptors and basigin), downregulating trans-membrane serine protease 2 (TMPRSS-2), and by interfering with viral replication through the interaction with various viral proteins [4] . However, the minimal absorption of curcumin following oral administration presents a major limitation in its bioavailability [6] . Bromelain is a cysteine protease, isolated from the pineapple stem (Ananas comosus) [9] . Traditionally, it has been used for its anti-inflammatory and healing effects in cases of arthritis and injury, while it has been approved in Europe for the debridement of Importantly, bromelain exerts dose-dependent anticoagulant effects: 1) downregulation of PGE-2 and thromboxane A2 (TXA2), thus leading to relative excess of prostacyclin; 2) promotion of fibrinolysis by stimulating the conversion of plasminogen to plasmin and prevention of platelet aggregation; 3) hydrolysis of bradykinin and reduction of kininogen and bradykinin levels in serum and tissues, improving inflammation and edema as shown in animal studies [15] . Notably, the latter action supports a potential role of bromelain in alleviating COVID-19 symptoms such as cough, fever and pain, and the more serious implications of inflammation, thrombosis and edema (Fig. 1) . The effect of bromelain on PGE-2 inhibition exceeds that of prednisone and aspirin, presenting very low toxicity and no major side effects [12, 16] . Clinical studies have demonstrated multiple beneficial effects of bromelain in trauma, ischemic injury, hypertension, atherosclerosis, inflammatory bowel disease, arthritis, and sinusitis as well as antibacterial and antifungal properties [5] . Interestingly, a recent experimental study demonstrated that bromelain inhibits infection of VeroE6 cells by SARS-CoV-2 by blocking the virus binding and entry to cells through downregulation of ACE-2 and TMPRSS2 expression, and cleavage of the SARS-CoV-2 spike protein, presenting a novel promising therapeutic option that warrants further investigation [17] . Due to its proteolytic action, bromelain is absorbed directly when administered orally, while it substantially promotes the absorption of curcumin enhancing its bioavailability, and making this a perfect combination of immune-boosting nutraceuticals with synergistic anti-inflammatory and anticoagulant actions [12, 16] . To the best of our knowledge, this is the first report highlighting the significance of bromelain and, most importantly, the potential value of the synergistic effects of bromelain and curcumin against COVID-19. The hypothesis that this combination of nutraceuticals may prove useful for the protection against SARS-Co-V-2 infection warrants clinical investigation. Noteworthy, the favorable safety profile of this nutraceutical combination makes a compelling case for their use in the general population with potentially important implications in preventing severe COVID-19. The authors have no conflicts of interest to declare that are relevant to the content of this article. None J o u r n a l P r e -p r o o f Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review Understanding the Pathophysiology of COVID-19: Could the Contact System Be the Key? Curcumin, a traditional spice component, can hold the promise against COVID-19? 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An update Bromelain Inhibits SARS-CoV-2 Infection in VeroE6 Cells Bromelain (B) and curcumin (C) exert multiple immunomodulatory actions interfering in the crucial steps of COVID-19 pathophysiology ACE-2, angiotensin-converting enzyme 2 receptor; COVID-19, coronavirus disease 19; NF-κB, nuclear factor kappa B; PG; prostaglandin; SARS-CoV; severe acute respiratory syndrome coronavirus; STAT-3, signal transducer and activator of transcription 3