Role of ACE2-Ang (1-7)-Mas axis in post-COVID-19 complications and its dietary modulation.

Severe acute respiratory syndrome-coronavirus-2 (COVID-19) virus uses Angiotensin-Converting Enzyme 2 (ACE2) as a gateway for their entry into the human body. The ACE2 with cleaved products have emerged as major contributing factors to multiple physiological functions and pathogenic complications leading to the clinical consequences of the COVID-19 infection Decreased ACE2 expression restricts the viral entry into the human cells and reduces the viral load. COVID-19 infection reduces the ACE2 expression and induces post-COVID-19 complications like pneumonia and lung injury. The modulation of the ACE2-Ang (1-7)-Mas (AAM) axis is also being explored as a modality to treat post-COVID-19 complications. Evidence indicates that specific food components may modulate the AAM axis. The variations in the susceptibility to COVID-19 infection and the post-COVID its complications are being correlated with varied dietary habits. Some of the food substances have emerged to have supportive roles in treating post-COVID-19 complications and are being considered as adjuvants to the COVID-19 therapy. It is possible that some of their active ingredients may emerge as the direct treatment for the COVID-19.

Introduction

After having experienced the first wave of COVID-19, the second wave has posed unprecedented challenges of the variants of the SARC-CoV-2 virus and post-COVID-19 disease complications [1]. Although much has been understood regarding SARS-CoV-2 transmission, the pathophysiology of COVID-19 still remains to be thoroughly understood [2]. The global data indicates that the majority of the COVID-19 patients experience mild to moderate symptoms. However, only a small portion of the patient population progresses up to critical illness [3]. A considerable number of patients, including those with mild symptoms of COVID-19, experience certain symptoms of post-COVID-19 complications after their initial recovery [4]. Several such short- and long-term complications like pulmonary fibrosis [5], mental disorders [6, 7], and retinopathy [8] are being extensively reported.

The severity of COVID-19 infection and associated mortality rate vary considerably across different populations and countries. The probable factors contributing to such variations include seasonal, environmental, or nutritional differences [9, 10]. It has been speculated that certain dietary habits predominant in the Asian countries might have contributed to lesser severity and low death rates compared to those of the European and American countries [10]. Recently, Rodriguez and Pierce [11] reviewed the impact the nutritional status in COVID-19 and suggested a possibility that food habits can modulate infectious disease and the inflammatory processes associated with it positively or negatively by altering the immune system during COVID-19. Although inconclusive the impact of vitamin D and zinc status in COVID-19 patients regarding viral transmission and its clinical symptoms has distinctly emerged in various studies. It has been concluded by Rodriguez and Pierce [11] that those nutritional interventions may have effects on the incidence of COVID-19 infection and mortality rates [11]. Other factors responsible for these variations in the severity and mortality rate include obesity, old age, diabetes, and cardiovascular diseases [12]. ACE2 protein can be found in two forms, membrane ACE2 (mACE2) and soluble (sACE2). Important, the soluble form of ACE2 is also active and it has been reported that SARS-CoV2 can be blocked by the recombinant soluble ACE2, which might represent a therapeutic option; in this respect, a pilot trial (NCT04335136) has been launched. Gender differences have also been reported in relation to the ACE2 expression. Males to have a higher level of tissue ACE2 [14], while serum activities seem to be higher in females [13, 14]. Further, there are evidences that show that ACE2 expression is age dependent [15].

Certain food items reduce the Angiotensin-converting enzyme (ACE) activity and exert antioxidant effects. However, the COVID-19 virus uses ACE2 as a gateway to human cells, and there is a need to explore if any food components affect the expression and effects of ACE2. Diet-dependent variations in the ACE2 expressions may provide insights into the variations in the COVID-19 severity, complications, and related death rates [10]. Recently our group reported several phytoconstituents interacting with the ACE2, which may contribute to the treatment of COVID-19 [16]. Similarly, it is proposed that certain food components may be useful in the treatment of COVID-19 [17]. The COVID-19 pathogenesis and its complications are based on the immune-inflammatory cascade, cytokine storm, pneumonia, and genetic predispositions [18-20]. The differences in the ACE2 expressions have been reported between different countries, and these correlate with genetic variations [21, 22]. Many food components are reported to be useful for the treatment of COVID-19, and these may act through altering ACE2 expression and its activity. Even the expression and activity of ACE2 change rapidly in response to certain food items [23-28] Hence, it can be speculated that the dietary habits and dietary components may affect a person’s susceptibility to COVID-19 infection and the severity of the post-COVID-19 complications. Through this review, we have tried to explore whether any food components alter the ACE2 levels and thereby may have a role in the treatment of COVID-19 and its consequences.

COVID-19 virus enters the host cell infection by binding virus-specific ‘S’ spikes to the human ACE-2 [19]. Ang-II mediates its actions via AT1 and AT2 receptors, whereas Ang (1–7) acts via MAS1 protooncogene GPCR receptors (Fig. 1). The entry in the body occurs by endosome formation through transmembrane protease serine 2 (TMPRSS2). After the entry of the virus inside the cell, viral polyproteins are synthesized that encode for the replicase-transcriptase complex. The virus then synthesizes RNA via its RNA-dependent RNA polymerase (RdRp) and subsequently structural proteins of the new viruses are formed and after assembly viral particles are released [20]. Because of high virus titer, strong cytokine surge and inflammatory response are induced in lungs and other organs, where ACE2 is highly expressed, leading to high morbidity and mortality.

Fig. 1

Role of ACE2-Ang (1–7)-Mas axis in the physiology and pathophysiology

In the human body, alveolar epithelial type II cells mainly express ACE2 (almost 83% of type II cells) and serve as a reservoir for viral invasion [29]. Apart from these cells, other cells expressing ACE2 include the heart, kidney, endothelium, brain, and intestine [30, 31]. The expression of ACE2 has also been noted at different anatomical sites like oral and nasal mucosa, nasopharynx, stomach, skin, lymph nodes, thymus, bone marrow, spleen, and liver [30-33]. New SARS-CoV-2 variants more frequently affect the intestinal mucosa. The expression of ACE2 is of great significance in the susceptibility of the patient to infection and severity of the post-COVID-19 complications. Higher ACE2 expression provides more sites of entry and hence facilitates the COVID-19 infection [34, 35]. The COVID-19 higher viral load induces more severe COVID-19 symptoms and increases the mortality rate [36, 37]. The occurrence and severity of COVID-19 are more in the older patients; however, it is noteworthy that the ACE2 expression is reduced with the older age [38]. Apart from old age, male gender and hypertension also strongly correlate with the severity of COVID-19 [39, 40]. Conversely, higher ACE2 expression as such is observed in younger age, female gender, normotensive state, and even Asian smokers. These populations suffer less from the COVID-19 and its consequences. Additionally, the immunocompromised patients are not necessarily at higher risk of COVID-19 infection. Considering the strong affinity of the COVID-19 virus to ACE2 and its contagiousness, it has been thought that the levels of ACE2 expression may not significantly alter either the rates of initial infection or the viral clearance [41]. However, more recent reports confirm the vital role of ACE2 in the pathogenesis and consequences of COVID-19 in clinical studies (http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=48763&EncHid=&userName=Remedium).

The physiological role of ACE2, Angiotensin (1–7) and its receptor – MAS1 protooncogene GPCR is depicted in Fig. 1. Apart from these roles, alterations in the expression of ACE2 plays a crucial role in the pathogenesis of COVID-19 infection and its consequences. Overexpression of human ACE2 enhances disease severity in a mouse model of COVID-19 infection, demonstrating that the viral entry into cells is a critical step. It has also been found that ACE2 level varies as per demographic area and diet as well. ACE2 downregulation by COVID-19 may reduce the further viral entry into cells, thereby limiting viral spread. However, such reduction of ACE2 expression may lead to the development of post-COVID-19 complications. The COVID-19 infection consequently reduces the ACE-2 expression. Such reduction in the ACE2 is considered to be responsible for the post-COVID-19 complications like acute lung injury rather than the COVID-19 viral load or cytotoxic actions of this virus. Therefore, increasing ACE2 expression would most likely help to prevent secondary fibrotic changes following COVID-19 pneumonia along with other consequences [41]. The role of altered activity of ACE2-Ang (1–7)-Mas axis is represented in the Fig. 2.

Fig. 2

Role of ACE2 in COVID-19 complications

Pulmonary complications

ACE2 and transmembrane serine protease-2 (TMPRSS2) are the two receptors present in the respiratory tract's epithelial cells, which support the spread of viral infections. The ACE2 expression is increased in the lungs of COVID-19 patients suffering from other comorbidities [42]. On the other hand, cardiopulmonary diseases are associated with a decreased ACE2 activity [43]. The role of ACE in cardiopulmonary diseases has been substantiated through multiple preclinical and clinical studies. A cohort study in 576 hypertensive patients has concluded that Angiotensin-converting enzyme inhibitors (ACEIs) increase the increased risk of pneumonia [44]. Ang-II receptor blockers (ARBs) and ACE inhibitors also increase ACE2 in the heart and brain [45]. Chronic administration of ACE inhibitors increases ACE2 expression in pneumocytes [46]. Such observations prove a direct relationship between the cardiopulmonary diseases, their treatment with ACEIs/ARBs, and susceptibility to the COVID-19 infections. It has been recently found that administration of RAAS inhibitors worsens the symptoms of COVID-19 while increasing the expression of ACE 2 in the lungs [46]. However, the ACEIs/ARBs were not found to possess any therapeutic advantages in reducing the COVID-19 infection, its progression or consequences [47]. Reports are stating that cytokine storm leads to an increased ACE2 expression in the lungs [48]. The COVID-19 patients suffer more from cellular exudates in the small airways and alveoli [49, 50].

Extra pulmonary complications

Renal complications

ACE-2 is expressed in podocytes and proximal straight tubular cells. Hence, SARS-CoV-2 could directly infect the human kidney and induce cytopathic effects in renal cells, contributing to AKI and the spread of the virus in the body [51]. Renal dysfunction could result from both direct coronavirus infection and the cytokine storm due to abnormal host immune response [52]. The COVID-19 patients with severe symptoms may develop various levels of renal damage and even AKI. Such occurrence of kidney damage has been reported in multiple clinical studies. As per an estimate by Guan et al., the AKI incidence in the COVID-19 patients is only 0.5% [53]. However, a recent study on 59 SARS-CoV-2 patients has reported massive albuminuria in 20 patients on the first days of the admission and proteinuria in 37 patients during their hospitalization [54]. This study further noted that 35.5% patients developed AKI, and 12.3% of them succumbed to death [55]. Still, the incidence of AKI in SARS-CoV-2infection is lower than in SARS and MERS [56]. ACE-2 is the main binding site for SARS-CoV-2, and it is expressed in lung tissue and other vital organs, including the kidneys.

COVID-19 may induce renal impairment through direct viral infection via ACE-2 binding. It is plausible that the higher renal tropism of COVID-19 due to increased affinity of the S1 domain for ACE-2 worsens virus-induced cytopathic changes and disruption of the RAS homeostasis [57]. The expression level of ACE-2 in the kidneys is crucial in the pathogenesis and progression of renal dysfunction in several diseases [58]. Decreased ACE-2 expression and activity were implicated in different acute and chronic kidney disease models. It was associated with the loss of RAS homeostasis and worsened pathological changes in renal parenchyma [59]. Even in the archived renal biopsy samples of diabetics, a decreased expression of ACE2 messenger RNA was evident [60].

Cardiovascular complications

ACE2 is localized to the endothelial and smooth muscle cells of intramyocardial vessels and cardiac myocytes [61]. ACE2 internalization by COVID-19 may potentially result in the loss of ACE2 at the cell surface and voids a key pathway for the cell to degrade Ang-II and generate the Ang-(1–7). Possible pathophysiology of SARS-CoV-2–related to myocarditis is proposed by Siripanthong et al. [62]. In patients with Cardiovascular diseases (CVD), the loss of ACE2 by COVID-19-induced internalization may exacerbate acute and chronic CVD [63]. Myocardial damage, inflammatory cell infiltration, oedema of the myocardium, fibrosis and cardiac muscle atrophy are reported in the COVID-19 [64]. Acute myocardial injury and associated increased risk of mortality is a routine finding in the patients with COVID-19 [65]. Activation of AAM axis induces relaxation of coronary vessels, reduces oxidative stress, suppresses myocardial remodelling, and improves post-ischemic cardiac work [66]. According to recent studies, a majority of patients with severe COVID-19 also have hypertension [67, 68]. An increased activity of RAAS might pre-exist in these individuals irrespective of the infection. The downregulation of ACE2 with a concomitant increase in Ang-II in COVID-19 patients leads to RAAS over-activation. Further, the reduced protection of Ang (1–7) may worsen cardiac injuries. Higher ACE2 expression contributes to heart injury even though it slows the disease progresses [69].

Central nervous system-related complications

ACE2 predominantly expresses in the glial cells and contributes to the neural regulation of multiple physiological functions, including neurogenesis, metabolic activities, and stress response [33, 70]. The neurological symptoms reported in the COVID-19 patients include fatigue, memory loss, disturbance in sleep, and dyspnoea [71]. As per the Center for Disease Control and Prevention (CDC) report, almost 35% of the mild COVID-19 cases continue to suffer from post-COIVD-19 symptoms [72]. The most persistent post-COVID-19 symptoms that may last for more than six weeks include fatigue (92%), memory ad attention disturbances (74%), headache (65%), weakness (68%), and dizziness (64%) [71]. Other symptoms like fatigue and dyspnoea affecting patients' quality of life have been reported by others [73, 74].

Gastrointestinal tract (GIT)-related complications

The intestine is more vulnerable to COVID-19 infections [64]. A significant occurrence of GIT symptoms like anorexia, nausea-vomiting, diarrhea, and abdominal pain have been commonly reported in COVID-19 patients (84.85). In addition, the ACE2 receptors are highly expressed in the colonic tissue [75] and feces [76] of COVID-19 patients. All such findings suggest that the abundance of ACE2 in the gut contributes to the pathogenesis of post-COVID-19 GIT complications.

Hepatic complications

ACE2 is expressed in both liver cells and bile duct cells, contributing to the liver damage associated with COVID-19 infection [77]. It is evident that many patients with COVID-19 have an increased Serum glutamate pyruvate transaminase (SGPT) and Serum glutamate oxaloacetate transaminase (SGOT) levels [78, 79]. Even the autopsies of COVID-19 patients have revealed cellular infiltration, fatty depositions, and necrosis in the liver [64]. Different detection techniques including single-cell RNA-seq analysis and immunohistochemistry have revealed that only cholangiocytes were positive for ACE2 expression whereas hepatocytes, the endothelial lining of sinusoids, and Kupffer cells were negative for ACE2 [80-82]. In congruence with this, certain COVID-19 patients had elevated levels of Gamma-glutamyltranspeptidase (GGT) reflecting the cholangiocyte damage [83]. Overall, these findings suggest that the acute hepatic injury may be due to the drug treatment given in COVID-19 rather than the infection itself. Further investigations are warranted to determine the role of ACE2 in the COVID-19-induced cholangiocyte [69].

Skin-related complications

The skin cutaneous manifestations of COVID-19 include itching, reddening, rashes and chickenpox-like vesicles. In the COVID-19 patients, the cutaneous symptoms like chilblain-like lesions are most commonly reported [84]. Similarly, certain other symptoms like necrosis, maculopapular rash, vesicular lesions, and livedoid lesions have also been identified in COVID patients. The chilblain-like lesions were frequent in less-severe COVID-19 whereas the livedoid/ necrotic lesions were common in the severe COVID-19 [85].

Food and herbals affecting ACE2

The factors contributing to the variations in the susceptibility to COVID-19 and its consequences also include dietary habits [10]. The impact of certain food items on the ACE activity is well-reported. Considering the role of ACE2 in COVID-19, a meticulous exploration of the food items and their components on the ACE2 activity. Such food items may prove to be important adjuvants to the treatment of COVID-19 [86].

Following are some of the chemical constituents from the food items that can be considered for the prevention and treatment of post-COVID-19 complication:

Terpenes

Carvacrol (C10H14O)

Carvacrol (C10H14O), is a phenolic monoterpenoid found in the essential oils of plant origin [87, 88]. It is safe for consumption and approved by the US-FDA and Council of Europe for its use in food, confectionery, and alcoholic beverages [89]. In a mice model of autoimmune encephalomyelitis, carvacrol reduces pro-inflammatory mediators (IL-6, IL-17, and IFN-γ), and increases anti-inflammatory cytokines (IL-4, IL-10, and TGF-β) [90]. The in-silico studies have shown that carvacrol has an affinity for the receptor-binding domain of S protein of COVID-19 and can inhibit the binding of the virus to ACE2. It may also inhibit the replication and maturation of the COVID-19 virus [91, 92]. The capability of carvacrol to avoid ACE2 binding of the virus, antiviral properties, and antibacterial properties further strengthen its candidature as an important adjuvant to the treatment of COVID-19 infections [89]. It possesses drug-like physicochemical and pharmacokinetic properties; however, detailed investigations on its efficacy and safety are warranted to prove its usefulness as a therapeutic intervention in treating COVID-19 infection and its consequences [93].

Lemon oil

Lemon oil biologically obtained from Citrus limon. ACE2 expression is significantly down-regulated in human colorectal adenocarcinoma (HT-29) cells by applying lemon oil [94]. D-limonene, the main component of lemon oil, inhibits the production of IL-2, IL-4, IL-13, IFN-γ, and TNF-α from CD3+CD4+ T cells and IL-2, TNF-α, and IFN-γ in CD3+CD8+T cells [95]. The immunomodulatory, antiviral, and anti-inflammatory effects of limonene might also prove beneficial against COVID-19 [96]. The in silico evaluations of limonene indicate its potential to inhibit the ACE2 [97]. These predictions have been substantiated through cell culture studies. Limonene decreased the ACE-2 expression HT-29 cell line [94]. Thus, the lemon oil and its components may prove valuable natural anti-COVID-19 compounds to be added to the therapeutic arsenal [94].

Geranium oil

This volatile oil is obtained derived from Pelargonium graveolens leaves [98]. It is widely used in perfumery, cosmetics and aromatherapy. Geranium oil possesses immunomodulatory properties and us considered to cleanses the lymphatic system. Clinically this oil is used in treating GIT ailments and urolithiasis. Geranium oil significantly down-regulated the expression of ACE-2 while producing moderate cytotoxic effects in Human colorectal adenocarcinoma (HT-29) cells. GC–MS analysis of Geranium oil indicated 22 compounds, out of which citronellol and geraniol had the highest concentration. Further investigations demonstrated the decreased expression of ACE-2 in HT-29 cells upon treatment with citronella and geraniol. Out of 22 compounds in geranium oil including geraniol, citronellol, and neryl acetate as the major compounds which downregulate the ACE2 expression in epithelial cells [94].

Polyphenols

Resveratrol

Resveratrol, a polyphenol is exhaustively reported for potential protective effect against a number of conditions like respiratory illness, cancer, and cardiovascular disease [99]. Miyazaki et al. reported that resveratrol, through activation of SIRT1, down-regulated the expression of AT1R in the aorta of C57/B6 mice [100]. In another study, resveratrol suppressed AngII-mediated fibrosis by inducing SIRT1-mediated manganese superoxide dismutase (Mn-SOD) in TO-2 hamsters [101]. Also, resveratrol is reported to increase the expression of ACE2, AT2R, and MasR and decrease the pro-fibrotic protein expression in Ang-II actuated Vascular smooth muscle cells (VSMCs) [102]. In SD rats, resveratrol increased the expression of ACE2, AT2R, and MAS in the liver, which might have a role in preventing Non-alcoholic fatty liver disease (NAFLD) [103]. It has been observed that upon feeding Ang (1–7) and resveratrol along with a high-fat diet to male FVB/N mice, both increased the expression of ACE2 and SIRT1 [104]. In another study, Moran et al. provided evidence that resveratrol induced the expression of ACE2 in apolipoprotein-deficient mice (ApoE-/-Ace2-/y) on account of SIRT1[105]. Few computation studies have reported a considerable affinity of resveratrol with S1: ACE2 complex and postulated about the probable potential of resveratrol in preventing the entry of COVID 19 into the host cells [106, 107].

Curcumin

A polyphenol from the rhizome of turmeric (Curcuma longa) is known to possess significant antiviral potential [108]. Already, curcumin has been proved to impede the growth of SARS-coronavirus [109], and the genomic semblance of SARS-CoV-2 with MERS coronavirus [110] and SARS-coronavirus (> 80%) collectively imply the prospect of the efficacy of curcumin against COVID-19. Administration of curcumin is associated with decreased expression of the AT1 receptor and elevated expression of both the AT2 receptor and ACE2 in male SD rats. These findings also indicated that curcumin modulated the myocardial fibrosis via ACE2 and reduced the expression of TGF-beta1 [111]. An in-silico investigation projected that curcumin interacts with several amino acids (Ala 348, Asn 394, Glu402, His 378, His 401, and Tyr385) of ACE2 that are involved in the binding of ACE2 with the S1 subunit of SARS-CoV-2[107]. This might have significant implications on the entry of SARS-Cov2 inside host cells. SARS-CoV-2 preferentially infects and propagates alveolar type II cells that are the precursor of gas exchanging [112], and curcumin has reportedly protected alveolar type II cells of the inflammatory lung [113]. It could be assumed that curcumin has the potential to be effective against SARS Cov-2 but, its limited oral bioavailability is a snag in its handiness. However, it can be managed with the help of novel drug delivery systems [114]. Curcumin possesses significant antioxidant and anti-inflammatory potentials [115] and can reduce the pulmonary fibrosis [116], hence it has a promising role in treating COVID-19.

Ginger

Ginger is widely popular because of its ethnomedicinal and condimental uses. The 6-gingerol inhibited the AngII induced AT1 receptor activation in HEK293/Gα15/AT1 cells. Sini decoction, formulation ginger, and other herbal drugs significantly improved acute inflammatory lung injury by reducing ACE and AT1R expression and ACE2/Ang (1–7)/Mas axis modulation [117]. In silico studies have disclosed that gingerol has a strong binding affinity with RBD domain S protein of SARS-CoV-2, and interaction of gingerol with RNA-dependent RNA polymerase RdRp was comparable with remdesivir [118].

The phytoconstituents having a binding affinity towards spike protein include 10-paradol, 8-paradol, scopoletin, 10-shogaol, 8-gingerol, and 10-gingerol. Administration of nasal purge of ginger oil may be considered for in vitro studies as well as clinical trials for minimizing the severity and transmission of COVID-19. The in silico evaluation has revealed that the components of ginger interact with the active sites of the receptor-binding domain of COVID-19 spike protein and ACE-2 to exert antiviral effects against COVID-19 [119].

Flavonoids

Quercetin

Quercetin exists in diet as glycosides and rutinosides [120]. A recent study using supercomputer-based in silico drug-docking has revealed that quercetin inhibits interaction between ACE-2 and COVID-19 virus spike protein [121]. It might exert protection against COVID-19, particularly its antioxidant, anti-inflammatory [122], and antiviral properties [123]. Quercetin modulates several key elements such as PI-3 kinase, RNA-dependent RNA polymerase, reverse transcriptase, TNF, TLR3, HA2 subunit of glycoprotein hemagglutinin, glycoprotein D. that are crucial for the replication and packaging of viruses [124].

An in-vitro study proved that quercetin (IC50 4.48 μM) and its metabolites inhibited recombinant human (rh) ACE2 activity at physiologically relevant concentrations [120]. A Tibetan remedy called Tsantan Sumtang, quercetin is one of the constituents that significantly reduced chronic hypoxia-induced right ventricular tissue remodeling and fibrosis through up regulation of the ACE2-Ang1-7-Mas axis [125]. Quercetin inhibited the Akt activation, up-regulated Fas and caveolin 1 expression, and hindered the advancement of bleomycin-induced pulmonary fibrosis in aged mice [126]. In another study, sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate lyase (S1PL) pathway inhibition by quercetin prevented the progress of pulmonary fibrosis [127].

Vitamins

Vitamin A

A metabolite of vitamin A- All-trans retinoic acid (atRA) is biologically active. A study performed by Zhong et al. demonstrated that chronic all-trans retinoic acid (atRA) induces expressions of ACE2 at both gene and protein level thereby reducing the blood pressure and myocardial damage in spontaneously hypertensive rats. This indicates the possibility of using atRA in the potential prevention and treatment of hypertension [128]. All-trans retinoic acid up-regulates the ACE2 expression in the heart and kidney, ensuing the reduced blood pressure and attenuated cardiomyocyte injury in spontaneously hypertensive rats [128]. The well-reported role of Vitamin A in preventing the fibrosis of the lungs and liver [129, 130] indicates its possible role in treating post-COVID-19 complications [131].

Vitamin C

Vitamin C or ascorbic acid is involved in enzymatic processes, antioxidative defense, and collagen synthesis [132]. It stimulates the INF formation, induces lymphocyte multiplication and stimulates the phagocytic capacity of neutrophils [133]. One of the first clinical trials on the efficacy of vitamin C in COVID-19 patients (n = 148) who received 24 g per day for 7 days had a decreased need for ventilation, needed lesser vasopressor therapy, and had reduced organ failure. Patients receiving this dose needed less ICU length of stay and had a reduced mortality. High-dose intravenous vitamin C as well as additional bolus doses had been used to treat moderate to severe cases of COVID-19 in China. In critically ill patients, additional bolus doses of vitamin C were needed [134]. Though ineffective in preventing the COVID-19 infection, vitamin C decreased the period of the disease, reduced the duration of indoor confinement, and ameliorated symptoms [135].

Vitamin D

A meta-analysis by Martineau et al. deduced that daily or weekly administration of vitamin D protects from the risk of acute respiratory tract infection [136]. Even in preclinical findings, vitamin D protected rats from the lipopolysaccharide-induced lung injury by decreasing ACE expression, reducing Ang-II production, and up-regulating the expression of ACE2 [137]. Likewise, vitamin D receptor gene knocked down mice exhibited severe acute lung injury and had higher mortality in the lipopolysaccharide-induced sepsis model [138]. Vitamin D also blocked the RAAS cascade by reducing the expression of renin [139]. Retrospective investigations have revealed that the serum levels of vitamin D were significantly lower in COVID-19 patients, correlated with critical pulmonary symptoms, a longer period of infection, and a higher death risk in COVID-19 patients [140]. Further, a randomized, double-blind pilot study has proved that a large dose of Calcifediol in COVID-19 patients significantly decreased the severity of the diseases and mitigated the need for intensive care [141]. It is also speculated that old age is associated with reduced vitamin D levels, and this population mostly suffers from the COVID-19.

Organosulphur compounds

Garlic

The Organic sulfur compounds (OSCs) are the principle bioactive constituents of garlic and account for garlic’s pungent odor and pharmacological effects [142]. To date, a little over thirty OSCs have been identified in garlic and categorized into two groups, L-cysteine sulfoxides and γ-glutamyl-l-cysteine peptides [143]. Amongst the OSCs, allicin (S-allyl-l-cysteine sulfoxide) is plentiful in both fresh and dry garlic. It transforms to allicin(diallylthiosulfinate), having antiviral activity, antioxidant, anti-inflammatory, immunomodulatory, and other pharmacological properties [144, 145].

A few randomized clinical studies have investigated the effect of garlic extract on viral infections and immunity. These studies concluded that the administration of garlic extract is associated with a reduction in the severity of cold and flu symptoms and decreased duration of viral infection [144, 146]. Recent computational studies have indicated that allicin-derived OSCs may inhibit the Mpro of SARS-CoV-2 through hydrogen bonding [147]. The allyl disulfide and allyl trisulfide present in the garlic essential oil is predicted to strongly inhibit the ACE2 protein expression as well as proteases of SARS-CoV-2 [148]. In addition, garlic and its OSCs have immune-boosting properties. OSCs decrease the stimulation of pro-inflammatory cytokines, the signature hallmark of SARS-CoV-2, via down-regulation of the leptin-mediated pathway [149]. Thus, garlic essential oil is an important component of food containing natural antivirus agents and may be considered in the treatment of COVID-19.

Proteins/peptides

Rapeseed proteins

Rapeseed is a common name for the plant Brassica oleifera. Several studies have reported the antiviral, antioxidant [150], and ACE inhibiting [151] properties of the peptides and proteins of rapeseed. Oral administration of rapeseed peptide, namely LY, RALP, and GHS, to spontaneously hypertensive rats for 5 weeks decreased the systolic blood pressure. Furthermore, it reduced the expression of ACE and renin in the myocardium. Also, myocardial expression of ACE2, Ang (1–7), and Mas receptors were up-regulated by these peptides at the gene and protein levels. Moreover, LY reduced the expression of Ang-II in cardiac tissue [151]. These findings indicate the advantages of rapeseed proteins in reducing the post-COVID-19 complications.

Linoleic acid (LA)

Polyunsaturated fatty acids (PUFA) are essential for the architecture and functionality of cell membrane and various biological processes, including cell signaling, synthesis of key inflammatory mediators (prostaglandins, leukotrienes, protectins, resolvins, etc.), and regulation of gene expression [152]. A metabolomic profiling study done on sera of COVID-19 patients observed the dysregulated lipid metabolism after SARS-CoV-2 [153]. Another study on Human coronavirus 229E (HCoV-229E) infected cells observed a significant elevation in linoleic acid and arachidonic acid. However, the growth of the HCov-229E virus was significantly suppressed by exogenous supplementation of LA or AA, and similar results were obtained with MERS-CoV [154]. Studies on SARS-CoV-2 S glycoprotein reported that S trimer apo S cryo-EM structures have about 60–75% open conformation with one of the RBD rotated up for ACE2 binding preferentially [155]. In contrast, the binding of linoleic acid with S trimer stabilized the closed conformation by the lockdown of hydrophilic anchor and compaction of RBD trimer resulting in reorganization of receptor-binding motif needed for ACE2 interaction. Therefore, the LA-binding pocket on S protein is a potential target for synthesizing small molecules that could stabilize the closed conformation of S protein and interfere with ACE2 [156].

Broccoli

Broccoli produces sulforaphane (Isothiocyanates) from glucoraphanin in response to stress. The stimulation of the Nrf2 signaling pathway by sulforaphane aids the transcription factor interaction with Antioxidant response elements (AREs). Consequently, it up-regulates the transcription of a group of genes associated with cell protection through antioxidant defense and cellular detoxification [157]. Sulforaphane is an activator of Nrf2 and has been proved to block the effects of Ang-II-mediated via ROS [158]. Further, sulforaphane is reported to produce anti-inflammatory effects by inhibiting the JNK/AP-1/NF-κB pathway. Therefore, sulforaphane and other nutraceuticals may be recommended to have therapeutic relevance against COVID-19 [159].

Liquorice

Liquorice contains saponins, flavonoids, and coumarins. The characteristic yellow color and sweet aromatic flavor are because of flavonoids and glycyrrhizin, respectively. Glycyrrhizin (GL) is a triterpenoid saponin obtained as calcium, potassium, and ammonium salts of 18β-glycyrrhizic acid (glycyrrhizic or glycyrrhizic acid and a glycoside of Glycyrrhetinic acid [GA]). Both GL and GA exert antiviral effects against the SARS-coronavirus in in vitro studies. GL administration in Vero cells infected with patient plasma samples resulted in a significant reduction in virus absorption and replication rate [160]. Chen et al. reported a similar result of GL in the Vero-E6 cell line, but encouraging outcomes were not observed in the fRhK4 cell line [161]. Given the circumstances, another important fact is the role of serine protease TMPRSS2 along with ACE2 in infecting the cells with the virus [162]. TMPRSS2 is of considerable importance in both influenza and coronavirus infections [163]. Intriguingly, GA regulated the expression of TMPRSS2 via mineralocorticoid receptor [164], which may describe the wide-range antiviral effects of GL [165]. Another significant property of GL and GA is the immunomodulation by inhibition of Toll-like Receptor-4 (TLR4). TLR4 is associated with endotoxin storm as a consequence of the suppression of the AAM axis [164].

The Traditional Chinese Medicine, Sini decoction contains three herbs, namely aconite (Aconitumcarmichaelii), licorice (Glycyrrhizaglabra), and ginger rhizome (Zingiber officinale). Reportedly, Sini decoction produced a significant reduction in E. coli-induced acute lung injury through a decrease in inflammatory mediators in lung tissue, and it also down-regulated the expression of ACE and AngII type 1 receptor (AT1R). Further, Sini decoction stimulated the AAM axis [117]. Additionally, liquorice extract has been reported to stimulate the release of interferon-1ß in upper and lower respiratory tract cells, which might be important in protecting against inflammation induced by COVID-19 [166]. Therefore, liquorice might reduce the ACE2 expression in the lung and still be able to decrease lung inflammation.

White button mushroom (WBM)

Reportedly, White button mushroom (WBM), commonly consumed in Asia–Pacific, Europe and US, inhibited dihydrotestosterone (DHT)-mediated Androgen receptor (AR) activation. TMPRSS2 is reportedly induced by androgen in prostate cancer. Wang et al., proved that WBM interferes with AR mediated TMPRSS2 expression and reduces the concentration of pro-inflammatory cytokines in serum [167].

Non-vegetarian components of food

Egg ovotransferrin‐derived ACE inhibitory peptide IRW

Recent in silico modeling studies have projected IRW (Ile-Arg-Try), an egg white protein ovotransferrin, as a novel ACE inhibitory tripeptide [168]. IRW possesses anti‐inflammatory, antioxidant, and modulatory effects on the TNF-mediated expression of cytokines and adhesion molecules through suppression of NF-κB in endothelial cells [169]. RPYL (a lactoferrin‐derived peptide) was reported to inhibit Ang II-induced vasoconstriction in the rabbit carotid artery [169]. Also, IRW significantly upregulated the expression of ACE2 and decreased the pro-inflammatory mediators in the kidney tissue of SHR [170]. Such reports highlight the importance of these bioactive peptides in the treatment of COVID-19 [171].

Tuna protein-derived peptides

Tuna (Katsuwonus pelamis) is a common component of human diets. Tuna protein hydrolysates have multiple etiological activities including ACE inhibition [172]. Tuna skeletal myosin heavy chain protein contains an antiviral peptide EEAGGATAAQIEM (E-M). Molecular docking simulation demonstrated that Gly143 and Gln189 of this protein might play an important role in the interactions of peptide E-M and SARS Cov -2 protein Mpro. The peptide E-M can block SARS-CoV-2 attachment to host cells by interfering with the interaction of COVID-19 virus with receptor ACE2. All these findings indicate that tuna may contribute significantly as an adjuvant to COVID-19 treatment [173]. The role of various food components and their chemical constituents is summarized in Table 1.

Table 1

Impact of food components on the ACE2-Ang (1–7)-MAS axis (AAM) and their applications in the treatment of post-COVID-19 complications

Food component	Active ingredients	Effect on COVID-19	References
Terpenes
Thyme and oregano	Carvacrol	Interference of ACE2 receptors in the host	Kulkarni [92], Kumar [91]
Lemon oil	Limonene	Downregulated ACE2 expression in epithelial cells and Stoppage of SARS-CoV-2/COVID-19 entry into the human body	Abdelli [97]
Geranium oil	Citronellol, geraniol, and neryl acetate	Prevention of the invasion of SARS-CoV-2/COVID-19 into the human body	Senthil Kumar [94]
Polyphenols
Resveratrol	Resveratrol	increase the expression of ACE2, AT2R and MASR	Kim [102]
Turmeric	Curcumin	Inhibition of binding of spike glycoprotein to ACE2 receptors	Mason [112]
Zinger	10-paradol, 8-paradol, scopoletin, 10-shogaol, 8-gingerol, 10-gingerol	Reduction of viral load. Decreased shedding of COVID-19 virus in the nasal passages	Haridas [119]
Flavanoid
Dill, fennel leaf, onion, oregano, chili pepper	Quercetin	Binding to S protein & inhibition of rhACE2 activity	Sargiacomo [121]
Vitamins
Beef liver, cod liver oil, sweet potatoes, carrots, black-eyed peas, spinach, broccoli	Vitamin A	Upregulation of ACE2 receptor	Zhong [128]
Citrus fruits	Vitamin C	Prevention of the development of “cytokine storm” decreased the period of infection, reduced the duration of indoor confinement, and ameliorated symptoms	Hoang [135]
Vitamin D	Calcitriol	Increase in the ACE2 level	Xu [137]
Organosulphur compounds
Garlic	Allyldisulfide and allyltrisulfide	Strongly inhibit the ACE2 protein expression and COVID-19 proteases	Thuy [148]
Proteins/Peptides
Rapeseed protein	LY, RALP, and GHS	Increased ACE2 expression, angiotensin-(1–7) and Mas receptor levels	Rong He [151]
Vegetarian food components
Essential free fatty acid (FFA)	Linoleic acid (LA)	SARS-cov-2 spike (S) glycoprotein receptor-binding domains (rbds) bind tightly and specifically with essential free fatty acid (FFA) linoleic acid (LA) in three composite binding pockets	Christine Toelzer [156]
Broccoli	Sulforaphane	anti-inflammatory effects by inhibiting JNK/AP-1/NF-κB pathway	Horowitz [159]
Liquorice	Glycyrrhizin	reduces the ACE2 expression in the lung and still be able to decrease lung inflammation	Feng [166]
Non-vegetarian food components
Egg ovotransferrin‐derived ACE inhibitory peptide	IRW	Increase in ACE2 and decrease in pro-inflammatory genes expression	Majumder [171]
Tuna	Peptides and selenonein	Blockade of COVID-19 viral attachment to host cells though ACE2 binding	Zhipeng Yu [173]

Conclusion

The ACE2-Ang (1–7)-MAS axis has emerged as an important mediator of the post-COVID-19 complications. The disparity of the susceptibility to COVID-19 infection and to the post-Covid complication is now being correlated not only to the genetic constitution but also to the dietary habits. The ACE2-Ang (1–7)-MAS axis plays a cardinal role in the pathogenesis of COVID-19 and its complications. The viral entry into human body depends on the ACE2 expression levels. Whereas, reduced ACE2 expression is related to post-COVID-19 complications. Many foods and their components interact with the main pathway through which COVID-19 enters human body and induce post-COVID-19 complications. This review proposes that such food components can be considered as adjuvants to the COVID-19 therapy.