key: cord-0907321-is336owo
authors: Ratha, Sachitra K.; Renuka, Nirmal; Rawat, Ismail; Bux, Faizal
title: Prospectives of algae derived nutraceuticals as supplements for combating COVID-19 and human coronavirus diseases
date: 2020-11-21
journal: Nutrition
DOI: 10.1016/j.nut.2020.111089
sha: 013a2a45f448f6ad3d9d57c85e32263dc1b723a1
doc_id: 907321
cord_uid: is336owo

The outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) that has created huge trepidation worldwide, has a mortality rate of 0.5-1% which is growing incessantly. There are currently no therapies and/or vaccines that may help to abate this viral disease but the use of masks and social distancing can limit the spread. Boosting immunity has been a simple way to resist viral infection and limit fatalities. In this context, the use of nutraceuticals appears to be a potential panacea. The ability of algae-based nutraceuticals, mainly Spirulina for boosting immunity against viral diseases has already been reported clinically. Spirulina-based nutraceuticals boost the adaptive and innate immunity, and bioactive compounds such as ACE inhibitor peptides, phycobiliproteins, sulfated polysaccharides, and calcium-spirulan can serve as antiviral agents. The presence of these molecules indicates its potential role in resisting infection and the COVID-19 disease progression. This review focuses on the potential role of algal nutraceuticals as immune boosters for combating human coronavirus and other viral diseases. The potential use of Spirulina-based nutraceuticals for combating COVID-19, its mechanism, and future directions have also been discussed.

Since the beginning of the 21 st century, humankind has suffered from betacoronaviruses (CoVs) diseases such as severe acute respiratory syndrome coronavirus (SARS-CoV), middle-east respiratory syndrome (MERS-CoV), and SARS-CoV2 [1] . The recent outbreak of COVID-19 caused by SARS-CoV2 has created panic around the world, because of its higher rate of infection and comorbidity combined with the unavailability of standard therapies and/or vaccines [2] . CoVs are single-stranded positive-sense encapsulated RNA viruses that have membrane augmented with glycoprotein spikes. These viruses attack the lower respiratory system of the host and affect the lungs leading to acute respiratory distress causing pneumonia and later leading to failure of multiple organs such as the heart, kidney, liver, and central nervous system [2] [3] [4] .

SARS-CoV2 uses angiotensin converting enzyme 2 (ACE2) cellular receptor for entry into the host cell through binding of its spike (S) protein followed by S protein priming using the serine protease TMPRSS2 [5] . SARS-CoV 2 contains four structural proteins viz. spike (S), nucleocapsid (N), membrane (M), and envelop (E) that may act as antigens. These antigens may induce neutralizing antibodies in the human body and increase CD 4+ / CD 8+ T-cell responses. These mechanisms of action serve as the basis for the treatment regimens used for this disease. At present, no specific or clinically proved therapies/ vaccines are available, and therefore the outbreak requires an urgent response from the scientific community for new developments in this area. According to WHO, the development of a vaccine for COVID-19 might take more than 18 months, because of the multiple steps required to ensure its effectiveness and safety. A study conducted by Gordon et al., [6] identified 67 druggable host proteins targeted by 69 existing FDA-approved drugs [6] . However, at present only a few 4 potential therapies viz. favipiravir, remdesivir, lopinavir, and hydroxychloroquine (or chloroquine) are reported to be at the final stage of human testing [7] .

The elderly and people with underlying medical conditions such as chronic lung disease, diabetes, kidney and liver diseases, obesity, immunocompromised people (cancer, immune deficiencies), and smokers are at high risk [8] . The use of immune-boosting nutraceuticals has the potential to help to combat and control coronavirus infections through the activation of immune response and alleviating the oxidative stress [9] [10] [11] [12] . To date, many types of nutraceuticals, which are derived from natural resources such as animals, plants, marine organisms, and microorganisms, have been reported and are in use. Algae comprising prokaryotic cyanobacteria and other eukaryotic forms are rich bioresource of bioactive compounds of nutraceutical and therapeutic importance [13] [14] [15] [16] [17] . The use of cyanobacterium Spirulina based nutraceuticals is well explored in in-vitro and clinical studies and is commercially available. Spirulina-based nutraceuticals have been reported to boost innate and adaptive immunity [18] [19] [20] , and possess antiviral properties against different enveloped viral infections such as human immunodeficiency virus (HIV) and herpes simplex virus (HSV) [21] [22] [23] [24] . This review discusses the potential therapeutic role of algae-based, Spirulina nutraceuticals in addressing the SARS-CoV and related viral infections.

Compounds that induce the innate and adaptive immune responses are generally used to prevent and fight against various pathogenic infections. Algae derived bioactive compounds are well reported for their antimicrobial, anti-inflammatory, immunostimulatory, and immunomodulatory properties that can be potentially used as immune boosters and/or 5 therapeutic agents for controlling pathogen attack and disease prevention in humans [15, 19, 25] . Cyanobacterium Spirulina is commercially produced for human consumption and is typically used as a health food supplement due to its high protein content, lipids, vitamins, essential amino acids, minerals, photosynthetic pigments, and biologically active substances including phycocyanin, chlorophyll, and β-carotene.

The use of Spirulina spp. has been found to improve the immune function and disease resistance in animals and humans [20, 26] . A study on human subjects by Selmi et al. [26] demonstrated the use of Spirulina supplements in ameliorating anemia and immunosenescence in senior citizens diagnosed with anemia (˂13 g dl -1 and ˂12 g dl -1 of hemoglobin in male and female individuals respectively for previous 12 months) [26] . Both and eye tissues in healthy animal models [27] . Tested algae Spirulina platensis and Botryococcus braunii were isolates from India, while microalga Haematococcus pluvialis was an isolate from Germany. Algal biomass grown under controlled conditions in standard growth media was suspended in olive oil for 15 days and administered to the rats with equal carotenoid concentration [27] . The administration of microalgal biomass helped to restore 6 enzyme activity and prevent lipid peroxidation through scavenging free radicals and hydroxy radicals in living cells in the rat model. A significant (p ≤ 0.05) increase in the activity of antioxidant enzymes viz. catalase, superoxide dismutase, and peroxidase in plasma and liver was reported after the repeated dose of algae biomass in rats, indicating their potential role in food, pharmaceutical, and nutraceutical applications [27] .

Spirulina supplements and/or extracts are believed to potentiate the immune system, which may help to fight and suppress different viral infections [20] . Soluble extracts of Spirulina have been found to enhance natural killer (NK) cell function, macrophage phagocytic activity, and red blood cells antibody response in in-vitro studies and trials on different animals and humans [20] . Interferon gamma (IFN-γ) cytokine plays an important role in innate and adaptive immunity in humans and is a primary activator of macrophages as well as a stimulator of natural killer (NK) cells and neutrophils [28] . Administration of Spirulina could enhance the non-specific preventive measures, such as activation of CD 4+ cells which further enhance the production of interferon gamma (IFN-γ) in humans, for the prevention of viral infection [29] . Hirahashi et al. [20] evaluated the potential of condensed soluble extracts of S. platensis grown under outdoor open tanks in alkaline conditions as immune potentiator in human subjects. Hot water extracts of S. platensis were prepared by autoclaving (1 h, 120 °C) biomass, and pH was adjusted to 4.0 using citric acid. The water-soluble fraction was separated via centrifugation and condensed soluble extracts were orally administered to healthy male volunteers aged 40-65 [20] . They demonstrated the immune potentiating ability of S. platensis and its mechanism through the analysis of blood cells with pre-and post oral consumption of hot water extracts in the selected human subjects [20] . The administration of S. platensis extracts increased the production of (IFN-γ) (representative of NK function) in more than 50% of tested individuals in IL-12/IL-18 dependent manner. They suggested that the oral administration of Spirulina in humans could aid signaling responses via Toll-like 7 receptors (TLR) and NK-mediated IFN-γ production. Bacille Calmette-Guerin-cell wall skeleton (BCG-CWS) is a strong immune adjuvant for various immune therapies and acts as a ligand for Toll-like receptors (TLR) 2 and 4 to raise the maturation stage of monocytes/macrophages [30] . In-vitro study on the addition of BCG-CWS to the fresh human peripheral blood mononuclear cells PBMC or monocytes (expressing TLR2/4) augmented the potent production of IL-12p40 in immune-competent cells taken postadministration of S. platensis extracts as compared to pre-administration [20] . Therefore, oral uptake of S. platensis could be involved in the signaling responses through TLR in blood cells in humans and improve immunity [20] .

Inflammation plays an imperative role in innate immunity and depending upon the amount of inflammation caused, it may lead to various chronic disorders. Betacoronavirus infection results in the activation of monocytes, macrophages, and dendritic cells followed by secretion of IL-6 and other inflammatory cytokines [1] . Acute respiratory distress syndrome (ARDS) in severe cases of coronavirus infections is generally a result of cytokine release syndrome (CRS) and secondary hemophagocytic lymphohistiocytosis [1, 31] . CRS and cytokine interleukin-6 (IL-6) driven elevated serum C-reactive protein (CRP) are common with COVID-19 patients. This has led to urgent clinical research on the use of therapies for suppressing CRS [1, 32] . The host immune system recognizes pathogen-associated molecular patterns through pattern recognition receptors. The recognition of coronavirus-associated molecular patterns by the host immune system is mainly mediated by the use of various pattern recognition factors such as toll-like receptor (TLR), NOD-like receptor (NLR), etc. [33] . The NLRP3 inflammasome activation plays an important role in the innate immune response to pathogenic infections in macrophages including COVID-19 [34, 35] . Spirulina extracts (SE) are found to prevent the 8 activation of NLRP3 inflammasome through the inhibition of extracellular signal-regulated kinases (ERK) signaling [18] . Chei patients is also highly essential due to side effects related to the drug toxicity. Spirulina and its extracts have been proved to play multiple roles as immune boosters, anti-inflammatory, antioxidant, antiapoptotic, and immune stimulatory agents. In this scenario, the application of Spirulina biomass and/or its active ingredients may provide promising protection against drugs induced hepatotoxicity and immunosuppression. Khafaga and Sayed studied the effect of oral feeding of Spirulina platensis powder (DXN Company, Kedah, Malaysia) at 500 mg kg -1 bwt in adult male Wistar albino rats against the effect of the cytotoxic drug, methotrexate [36] . Methotrexate (MTX) caused a reduction in leukocyte counts, hepatic antioxidant enzymes, reduced glutathione, glutathione peroxidase, catalase, superoxide dismutase; serum 9 immunoglobulins, IgA, IgM, and IgM level. Spirulina intake helped in ameliorating the methotrexate toxicity through the restoration of liver enzymes, and a significant reduction in pro-inflammatory cytokines and lipid peroxidation products. In summary, Spirulina has the potential to enhance the immune components and reduce the physio-biochemical stress and therefore could be used as a supplement along with the treatments, or for prevention of COVID-19 infection and related symptoms.

In addition to immune-boosting agents, algae are potential resources for biologically active compounds having anti-inflammatory and antiviral properties, and have been said to enhance the immune system and treat immune disorders related to coronavirus and other viral infections [15, 16, 19] . There has been much research done on the antiviral properties of algal extracts in-vitro, however, studies on practical implications are still underway and need to be explored at demonstration scale.

The mechanism of infection by SARS-CoV2 includes attachment of the viral glycosylated spike (S) protein to the angiotensin-converting enzyme 2 (ACE2) protein of the host human cells followed by the use of serine protease TMPRSS2 for S protein priming. [2] Severe coronavirus (SARS-CoV) infections generally lead to the down-regulation of ACE2 and more severe lung injury [37, 38] . Angiotensin-converting enzyme (ACE) enhances the generation of angiotensin II (AngII) from angiotensin I (AngI), which induces acute lung injury via stimulating the Ang II type 1 receptor (AT1R), whereas ACE2 and AngII type 2 10 receptor (AT2R) negatively regulate this pathway and are protective [37, 39] . Upon SARS-CoV2 infection, once the defensive immune system is impaired, propagation of virus leads to tissue damage in organs with ACE2 receptors and induces innate inflammation mediated by pro-inflammatory macrophages and granulocytes. At this stage, greater effort is required in suppressing inflammation and managing life-threatening symptoms.

Generally, angiotensin-converting enzyme inhibitors (ACE-Is), which inhibit the reninangiotensin-aldosterone system (RAAS), are used as protective gear for the treatment of severe coronavirus infections [38, 40, 41] . ACE-Is help to treat lung/organ injury via enhancing ACE2 activity. However, the use of ACE-Is for the treatment of COVID-19 is still under critical debate especially in cases with medical conditions such as hypertension, heart diseases, and diabetes [42] . In general, the medication for the treatment of these conditions increases the expression of ACE2. It was suspected that increased expression of ACE2 receptors would lead to an increased risk of SARS-CoV2 infection since the virus uses ACE2 receptors for entry into the host; however, this concept is not yet clinically proven. Moreover, the use of ACE-Is is clinically proven for the treatment of severe SARS-CoV infections.

According to Kuster et al., [38] there is no current data available to show the relationship between ACE2 activity and mortality related to SARS-CoV2 [38] . The most common lethality in coronavirus infections and COVID-19 is associated with the underlying lung injury due to the downregulation of ACE2 [38, 43] . Therefore, the use of ACE-Is is continued for the treatment of multiple organ injury in severe cases of coronavirus infections [38, [44] [45] [46] .

Spirulina is a natural bioresource of ACE inhibitory peptides of therapeutic value that could be explored for their potential in the treatment of severe symptoms (lung injury) and inflammation related to the betacoronavirus infections including COVID-19. Spirulina 11 extracts have been reported to possess anti-inflammatory properties and its potential use in humans and mechanism as an anti-inflammatory agent has been demonstrated successfully [18] . Moreover, Spirulina nutraceuticals and derived ACE inhibitory peptides have been well demonstrated for boosting immune response, reduction in cytokine related inflammation, and enhancing ACE2 activity in in-vitro, in-vivo, and in-silico studies on model animal organisms and humans in different diseases [18, [47] [48] [49] [50] . Heo et al., [49] investigated the potential of ACE inhibitory peptide from hydrolyzed Spirulina sp. protein in inhibiting ACE activity in human endothelial cells. In their study, Spirulina sp. biomass was hydrolyzed using gastrointestinal enzymes to obtain hydrolysate. Different sizes of peptides were obtained by molecular weight fractionation of the hydrolysates. ACE inhibitory peptides were purified using ion-exchange chromatography followed by reversed-phase high-performance liquid chromatography [49] . MD simulation revealed the formation of 5.76 ± 1.50 and 2.58 ± 0.83 pairs of H-bonds by purified peptides with ACE and Ang II respectively, indicating their potential to make dead-end complex through the formation of enzyme-inhibitor and enzymesubstrate-inhibitor complexes and inhibiting ACE catalytic activity [49] . They also revealed that application of ACE inhibitory peptide (at 250 μM concentration) decreased the Ang IIinduced production of nitric oxide and reactive oxygen species and downregulated the expression of inducible nitric oxide synthase (iNOS) and endothelin-1 (ET-1) and blocked the activation of mitogen-activated protein kinase (p38) in EA.hy926 endothelial cells. McCarty and DiNicolantonio, [9] postulated the possible use of nutraceuticals capable of inhibiting NOX2 production, promoting clearance of hydrogen peroxide, or aiding the restoration of the native structure of Cys98 in TLR7, might help in boosting the TLR7-mediated induction of type 1 interferon (innate immunity response) and antiviral antibodies. Thus, in this perspective, the use of algae-derived ACE inhibitory peptides seems to be a potential option 12 that might play multiple roles as ACE inhibitors, immune boosters, and treating vascular dysfunction in human viral diseases including COVID-19.

He et al. found that the ACE inhibitory peptides viz. Ile-Gln-Pro (IQP) and Val-Glu-Pro (VEP) derived from Spirulina platensis (synthesized by SP Biomart Ltd., Beijing, China) could be absorbed intact via. Caco-2 cell monolayers and expected to have high bioavailability [51] . The transport of both peptides was energy-dependent and involved an apical-to-basolateral flux mediated by P-glycoprotein for the transport of VEP. Zheng et al. [50] also reported that oral administration (10 mg -1 kg -1 day -1 for 6 weeks) of Spirulina platensis derived bioactive peptides IQP, VEP, as well as biomass hydrolysates, exhibit ACE inhibiting activity, and could improve blood pressure in hypertensive rats [50] . They found that there was a significant reduction (p˂0.05) in the ACE mRNA levels by 76.8, 68.6, and 87.7% in IQP, VEP, and biomass hydrolysates supplemented groups as compared to the control respectively. This was achieved by modulating the expression of local kidney renin angiotensin system (RAS) components via downregulating the angiotensin-converting enzyme (ACE), angiotensin II (Ang II) and angiotensin type-1 receptor (AT 1), while upregulating ACE2, Ang (1-7), Mas and AT 2.

Additionally, peptic (SP) and tryptic (ST) protein hydrolysates of Spirulina platensis were also reported to inhibit the activity of peptidyl-peptidase IV (DPP-IV) (IC 50 -3.4 and 0.1 mg mL -1 ) and ACE (IC 50 -3.0 and 0.28 mg mL -1 ) in an in-vitro study and cellular assays in Caco-2 cells respectively [47] . Aiello et al. found that S. platensis peptic and tryptic hydrolysates were able to decrease the ACE activity in-vitro (measuring the formation of HA from HHL, a mimic substrate for Ang I) in a dose-dependent manner with IC 50 values of 0.1 ± 0.04 mg 13 mL -1 and 0.28 ± 0.03 mg mL -1 respectively. Similarly, both the hydrolysates were able to inhibit ACE activity in cellular assays in Caco-2 cells with IC 50 values of 2.7 ± 0.3 mg mL -1 and 2.8 ± 0.9 mg mL -1 respectively. Anekthanakul et al. [48] developed a -SpirPep‖ platform to assist in silico-based bioactive peptides discovery of bioactive compounds from Spirulina.

They showed that peptides derived from Spirulina were mainly involved in the ACE inhibitory activity. They reported two new ACE substrate binding sites (R124 and S219) along with binding sites residues (D121, E123, S516, and S517) from natural ACE inhibitory peptides (angiotensin II and bradykinin-potentiating peptides) through which -SpirPep1‖ indirectly bound to ACE. Natural ACE inhibitory peptides from Spirulina have great potential in ACE inhibition and enhancing ACE2 activity [48] .

ACE-Is are generally used for enhancing ACE2 activity for the treatment of tissue injury in various organs in severe cases of coronavirus infection. Since, different studies have shown potential applications of Spirulina derived ACE inhibitory peptides as an anti-inflammatory and antioxidative agent via enhancing ACE2 activity and reducing cytokine related inflammation [18, [47] [48] [49] [50] . Therefore, based on these studies, it can be postulated that supplementation of Spirulina derived ACE inhibitory peptides may play a potential therapeutic or subsidiary role in the alleviation and treatment of oxidative stress, cytokine release syndrome, and tissue injury in SARS-CoV2 and other coronavirus infections through the regulation of ACE2 activity (Fig. 1) . However, it is too early to assess the potentiality of these Spirulina derived compounds in SARS-CoV2 infection, which needs to be reconnoitered with basic and clinical research. 14 Novel sulfated polysaccharides from different algal resources are reported to exhibit antiviral properties and are of therapeutic use against different viral infections [23] . Novel sulfated polysaccharide derived from different species of Spirulina designated as calcium-spirulan (Ca-SP) was found to possess distinct antiviral activity against different enveloped viruses including Herpes simplex virus type 1, human cytomegalovirus, measles virus, mumps virus, influenza A virus, and HIV-1 in different human cell lines [21, 22, 52] . Hayashi et al. [21] revealed the main mechanism of antiviral activity of Ca-SP derived from Spirulina platensis is found to be involved in the inhibition of viral replication, via selective inhibition of penetration of the virus into the host cell. The main components of Ca-SP were calcium, sulfate, glucuronic acid, galacturonic acid, glucose, xylose, galactose, fructose, mannose, ribose, and rhamnose. They suggested that the main antiviral activity of the Ca-SP might be exhibited due to the molecular conformation through the chelation of Ca-ion with sulfate groups. In another study conducted by Hayashi et al. [52] evaluated the antiviral potential of Ca-SP derived from Spirulina platensis against human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus type 1 (HSV-1) as compared to standard dextran sulfate (DS).

Mice treated intravenously with Ca-SP isolated from S. platensis showed increased serum concentration of 1000 µg mL -1 after 30 min of administration, which gradually decreased.

Serum samples from Ca-SP administrated mice showed long-lasting antiviral activity against HIV-1 and HSV-1 even after 24 h of administration. This was significantly higher as compared to the representative sulfated polysaccharide DS [52] .

Phycobiliproteins are a group of water-soluble proteins that possess antioxidant, antiinflammatory, and antimicrobial properties [53] . Water-soluble extracts of Spirulina are generally rich in phycobiliproteins, which also exhibit antiviral properties. A study conducted by Chen et al. [29] reported that cold water extract of Spirulina (Arthrospira platensis, Far II, which further binds to AT1R receptors and induces acute tissue injury. While, ACE2 hydrolyses Ang II to Ang (1-7) peptide that acts on the Mas receptor (MasR) and protect from tissue injury. It can be postulated that supplementation of Spirulina nutraceuticals in SARS-CoV2 infection may help to upregulate the ACE2 activity and downregulate ACE activity that may further assist to overcome CRS and aid in tissue protection and repair. Abbreviations: SARS-CoV2: severe acute respiratory syndrome coronavirus 2; ACE: angiotensin converting enzyme 1, ACE2: angiotensin converting enzyme 2, Ang I: angiotensin I, Ang 1-9: angiotensin 1-9 peptide, Ang II: angiotensin II, Ang 1-7:

Cytokine release syndrome in severe COVID-19

research and development on therapeutic agents and vaccines for COVID-19 and related human coronavirus diseases

Neutralizing antibodies against SARS-CoV-2 and other human coronaviruses

A rampage through the body

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

The COVID-19 vaccine development landscape

People who are at higher risk for severe illness

Nutraceuticals have potential for boosting the type 1 interferon response to RNA viruses including influenza and coronavirus

Nutritional recommendations for COVID-19 quarantine

Early nutritional supplementation in non-critically ill patients hospitalized for the 2019 novel coronavirus disease (COVID-19): Rationale and feasibility of a shared pragmatic protocol

Nutrition support in the time of SARS-CoV-2 (COVID-19)

Seaweed and human health

Lipidlowering nutraceuticals in clinical practice: position paper from an International Lipid Expert Panel

Hypolipidemic, antioxidant, and antiinflammatory activities of microalgae Spirulina

New insights into the biodiversity and applications of cyanobacteria (blue-green algae)-Prospects and challenges

Extraction and characterisation of analytical grade C-phycocyanin from Euhalothece sp

Spirulina maxima extract prevents activation of the NLRP3 inflammasome by inhibiting ERK signaling

Preventive or therapeutic composition for viral infectious disease

Activation of the human innate immune system by Spirulina: augmentation of interferon production and NK cytotoxicity by oral administration of hot water extract of Spirulina platensis

Calcium spirulan, an inhibitor of enveloped virus replication, from a blue-green alga Spirulina platensis

Antiviral activity of Spirulina maxima against herpes simplex virus type 2

Bioactivity and applications of sulphated polysaccharides from marine microalgae

Anti-HIV Activity of extracts and compounds from algae and cyanobacteria

The antioxidant, immunomodulatory, and anti-inflammatory activities of Spirulina: an overview

The effects of Spirulina on anemia and immune function in senior citizens

In vivo bioavailability and antioxidant activity of carotenoids from microalgal biomass -A repeated dose study

Metabolic Regulation of Natural Killer Cell IFN-γ Production

Well-tolerated Spirulina extract inhibits influenza virus replication and reduces virus-induced mortality

Immune adjuvant therapy using Bacillus Calmette-Guérin cell wall skeleton (BCG-CWS) in advanced malignancies: A phase 1 study of safety and immunogenicity assessments

COVID-19 infection: the perspectives on immune responses

COVID-19: Melatonin as a potential adjuvant treatment

Coronavirus infections and immune responses

The diagnostic and predictive role of NLR, d-NLR and PLR in COVID-19 patients

SARS-CoV-2 and COVID-19: The most important research questions

Spirulina ameliorates methotrexate hepatotoxicity via antioxidant, immune stimulation, and proinflammatory cytokines and apoptotic proteins modulation

Angiotensin-converting enzyme 2 protects from severe acute lung failure

SARS-CoV2: should inhibitors of the renin-angiotensin system be withdrawn in patients with COVID-19?

Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target

Novel inhibitors of severe acute respiratory syndrome coronavirus entry that act by three distinct mechanisms

Angiotensin-converting enzyme 2 (ACE2) in disease pathogenesis

Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?

A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury

Angiotensin and the Coronavirus. Science and Translation medicine

Outcomes in Patients with COVID-19 Infection Taking ACEI/ARB

Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19

Chemical and biological characterization of spirulina protein hydrolysates: Focus on ACE and DPP-IV activities modulation

Natural ACE inhibitory peptides discovery from Spirulina (Arthrospira platensis) strain C1

A heptameric peptide purified from Spirulina sp. gastrointestinal hydrolysate inhibits angiotensin I-converting enzyme-and angiotensin II-induced vascular dysfunction in human endothelial cells

Effects of IQP, VEP and Spirulina platensis hydrolysates on the local kidney renin angiotensin system in spontaneously hypertensive rats

Transport of ACE Inhibitory Peptides Ile-Gln-Pro and Val-Glu-Pro Derived from Spirulina platensis Across Caco-2

A Natural Sulfated Polysaccharide, Calcium Spirulan, Isolated from Spirulina platensis: In Vitro and ex Vivo Evaluation of Anti-Herpes Simplex Virus and Anti-Human Immunodeficiency Virus Activities

Phycobiliproteins from cyanobacteria: Chemistry and biotechnological applications

Spirulina Platensis Exposure Enhances Macrophage Phagocytic Function in Cats

AT1R: angiotensin II type 1 receptor, CRS: cytokine release syndrome, ROS: reactive oxygen species

The authors hereby acknowledge the National Research Foundation (UID 84166), Republic of South Africa, and Durban University of Technology for providing financial assistance.

No conflict of interest to declare.