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Flavonoids against the SARS-CoV-2 induced inflammatory storm - 16/04/21

Doi : 10.1016/j.biopha.2021.111430 
Alena Liskova a, Marek Samec a, Lenka Koklesova a, Samson M. Samuel b, Kevin Zhai b, Raghad Khalid Al-Ishaq b, Mariam Abotaleb b, Vladimir Nosal c, Karol Kajo d, e, Milad Ashrafizadeh f, g, Ali Zarrabi g, Aranka Brockmueller h, Mehdi Shakibaei h, Peter Sabaka i, Ioana Mozos j, k, David Ullrich l, Robert Prosecky m, Giampiero La Rocca n, Martin Caprnda o, Dietrich Büsselberg b, Luis Rodrigo p, Peter Kruzliak q, , Peter Kubatka r,
a Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia 
b Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha, Qatar 
c Department of Neurology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia 
d Department of Pathology, St. Elizabeth Cancer Institute Hospital, Bratislava, Slovakia 
e Biomedical Research Centre, Slovak Academy of Sciences, Bratislava, Slovakia 
f Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Tuzla, Istanbul, Turkey 
g Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul, Turkey 
h Musculoskeletal Research Group and Tumor Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilian-University Munich, Munich, Germany 
i Department of Infectiology and Geographical Medicine, Faculty Medicine, Comenius University and University Hospital, Bratislava, Slovakia 
j Department of Functional Sciences, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania 
k Center for Translational Research and Systems Medicine, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania 
l Department of Leadership, Faculty of Military Leadership, University of Defence, Brno, Czech Republic 
m 2nd Department of Internal Medicine, Faculty of Medicine, Masaryk University and St. Anne's University Hospital, Brno, Czech Republic 
n Human Anatomy Section, Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo and Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy 
o 1st Department of Internal Medicine, Faculty of Medicine, Comenius University and University Hospital, Bratislava, Slovakia 
p Faculty of Medicine, University of Oviedo and Central University Hospital of Asturias (HUCA), Oviedo, Spain 
q 2nd Department of Surgery, Faculty of Medicine, Masaryk University and St. Anne's University Hospital, Brno, Czech Republic 
r Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia 

Correspondence to: 2nd Department of Surgery, Faculty of Medicine, Masaryk University and St. Anne's University Hospital, Pekarska 53, 65691 Brno, Czech Republic.2nd Department of Surgery, Faculty of Medicine, Masaryk University and St. Anne's University HospitalPekarska 53Brno65691Czech Republic⁎⁎Correspondence to: Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Mala Hora 4, 03601 Martin, Slovakia.Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in BratislavaMala Hora 4Martin03601Slovakia

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Abstract

The disease severity of COVID-19, especially in the elderly and patients with co-morbidities, is characterized by hypercytokinemia, an exaggerated immune response associated with an uncontrolled and excessive release of proinflammatory cytokine mediators (cytokine storm). Flavonoids, important secondary metabolites of plants, have long been studied as therapeutic interventions in inflammatory diseases due to their cytokine-modulatory effects. In this review, we discuss the potential role of flavonoids in the modulation of signaling pathways that are crucial for COVID-19 disease, particularly those related to inflammation and immunity. The immunomodulatory ability of flavonoids, carried out by the regulation of inflammatory mediators, the inhibition of endothelial activation, NLRP3 inflammasome, toll-like receptors (TLRs) or bromodomain containing protein 4 (BRD4), and the activation of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2), might be beneficial in regulating the cytokine storm during SARS-CoV-2 infection. Moreover, the ability of flavonoids to inhibit dipeptidyl peptidase 4 (DPP4), neutralize 3-chymotrypsin-like protease (3CLpro) or to affect gut microbiota to maintain immune response, and the dual action of angiotensin-converting enzyme 2 (ACE-2) may potentially also be applied to the exaggerated inflammatory responses induced by SARS-CoV-2. Based on the previously proven effects of flavonoids in other diseases or on the basis of newly published studies associated with COVID-19 (bioinformatics, molecular docking), it is reasonable to assume positive effects of flavonoids on inflammatory changes associated with COVID-19. This review highlights the current state of knowledge of the utility of flavonoids in the management of COVID-19 and also points to the multiple biological effects of flavonoids on signaling pathways associated with the inflammation processes that are deregulated in the pathology induced by SARS-CoV-2. The identification of agents, including naturally occurring substances such as flavonoids, represents great approach potentially utilizable in the management of COVID-19. Although not clinically investigated yet, the applicability of flavonoids against COVID-19 could be a promising strategy due to a broad spectrum of their biological activities.

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Graphical Abstract




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Highlights

Immune reaction to SARS-CoV-2 can cause uncontrolled systemic inflammatory responses (cytokine storm).
Flavonoids are potential modulators of COVID-19-related inflammatory and immune deregulations.
Network pharmacology and molecular docking show anti-inflammatory and immunomodulatory activities of flavonoids in COVID-19.
Flavonoids modulate inflammatory signaling (e.g. NLRP3 inflammasome, etc.) associated also with SARS-CoV-2.
The potential applicability of flavonoids against COVID-19 need to be evaluated in strictly defined clinical research.

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Keywords : SARS-CoV-2, COVID-19, Inflammation, Cytokine storm, Phytochemicals, Flavonoids, Immunomodulation, Anti-inflammatory effects


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© 2021  The Authors. Publicado por Elsevier Masson SAS. Todos los derechos reservados.
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