POTENTIAL USES OF NATURAL PRODUCTS FROM MORINGA FOR TREATMENT OF CORONAVIRUS (COVID-19) INFECTIONS: A REVIEW OF SUPPORTING LITERATURE

©Edward H. Rau, Moringa Research Products™ Division, Sustainable Bioresources, LLC, Naalehu, Hawaii 96772-0350.

Draft 5: Last updated on December 7, 2020

1.0 INTRODUCTION

The Corona Virus Infectious Disease of 2019 (COVID-19) is an infectious disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) (WHO 2020a). The World Health Organization (WHO) declared the 2019–20 coronavirus outbreak a Public Health Emergency of International Concern (PHEIC) on 30 January 30, 2020 (WHO 2020b) and a pandemic on 11 March 2020 (WHO 2020c). As of this writing (December 6, 2020), there were in the United States of America, approximately 14,200,000 cases and 276,500 deaths; worldwide 66,000,000 confirmed cases and 1,524,000 (WHO 2020d).

Limited Drug Treatment Options for COVID-19

No U.S. Food and Drug Administration (FDA) approved drugs had demonstrated safety and efficacy in randomized controlled trials for patients with COVID-19 and there was no definite and effective treatment for COVID-19 (Sun et al. 2020). Clinical trials are underway testing multiple drug candidates with in-vitro antiviral activity against SARS-CoV-2 and/or immunomodulatory effects that may have clinical benefit (CDC 2020). On October 22, 2020 the FDA approved Veklury (remdisivir), the first treatment to receive approval (FDA 2020). Other viable therapeutic candidates will have to complete clinical trials to demonstrate their safety and effectiveness, regulatory approvals must be obtained, and then the drugs will have to be produced in large quantities and distributed for use. It is a slow, costly and problematic process.

Use of Natural Products Such as Moringa

Medicines derived from natural products may offer an alternative to the long and costly process of developing new drugs for treating COVID-19. Unfortunately, the current focus of research to develop therapeutic candidates for COVID-19 is on purified compounds of known composition for which there is prior clinical experience and a record of safety. Repurposing existing therapeutic drugs designed for other virus infections and pathologies is thought to be the most practical and expeditious approach. Purification of antiviral compounds from extracts may be viewed as too time consuming and testing of unpurified extracts from natural products such as moringa is of low priority [Bozick (2020); Frazan (2020); Tu et al. (2020)]. However, methods to screen and select herbal traditional Chinese medicines (TCM) for potential use in prevention and treatment COVID-19 have been developed. In China, TCM prescriptions are combined with modern medicines for symptomatic supportive treatment. Preliminary results showed better results than symptomatic supportive therapy alone (Ma et al. 2020 and Niu et al. 2020).

Moringa – A Long History of Medicinal Use

Several species in the plant genus Moringa have many uses in traditional medicine including treatment other viral diseases, suggesting possible applications in treatment of COVID-19 infections. Moringa has also been used since ancient times as a food and is highly nutritious. Today, there is a large and rapidly growing body of scientific literature that supports many of these uses. Review articles on the phytochemistry and pharmacology of moringa are included in the reference section below.

First Research on Moringa and COVID-19

No scientific references on the potential uses of moringa in preventing or treating coronavirus diseases such as SARS, MER and COVID-19 were found in an extensive literature search that I conducted in early April 2020. In June, a first study by Hamza et al. (2020) was published demonstrating the effectiveness of compounds from moringa in binding and inactivating the viral peptides of the SARS-CoV-2 virus. The results of this study are summarized below in the section on the antiviral activities of moringa. No additional publications on this subject were found before completion of this updated review in early December 2020 and I am not aware of any other studies in progress.

Wide Body of Evidence Supports Potential Use as a Multi-functional Therapeutic Agent

Numerous references reported properties of moringa that would appear to be potentially helpful in treating COVID-19 infections. Of the many well established medicinal and nutritional characterisitics of moringa its antiviral, anti-inflammatory, ACE inhibiting, and immunomodulating activities would appear to be most potentially useful in direct treatment of COVID-19. Drug candidates that have anti-inflammatory and potential ACE-2 blocking activities should be selected for drug development research (Li et al. 2020). Additionally, moringa is highly nutritious and its other antidiabetic, antihypertensive, antimicrobial properties could support patient resistance and recovery as an adjunct to other emerging treatment regimes. Rather than treating only one aspect of the COVID-19 disease syndrome, moringa could have multi-functional applications and be administered as a minimally processed food or nutritional supplement, minimizing the time and difficulties of obtaining approvals as a licit drug. Moringa can also be produced at low cost and is widely grown in areas of Africa, Southeast Asia and other areas where access to health care and affordable medications may be limited.

Current Use of Moringa for COVID-19 in Other Countries

Information on the potential uses of moringa for COVID-19 is beginning to emerge in the popular online media, especially that of Africa and the Philippines, and these sources cite its nutritional and immunity boosting benefits and purported virus fighting properties (Samboatyoy 2020 et al.). Examples of the publications are in the reference section. Herbalists and other sellers of moringa products are also promoting this use.

Communications recommending the use of moringa for COVID-19 will likely increase because in many areas of the world as people tend to favor use of long-established traditional medicines, particularly in times of crisis and where alternatives may not be available. For example, an herbalist in Tunisia explained that “Tunisians love everything traditional and natural: in times of panic they trust in the remedies of our ancestors. People are asking for things to prepare at home like thyme, ginger and moringa,” he said, claiming that they were “good for immunity and fighting viruses” (Anonymous 2020).

In early March 2020, the Philippines the Department of Health Secretary Francisco Duque recommended that people include moringa (known locally as malunggay) in their diet to have a stronger immune system. “Drink fruit juices rich in Vitamin C. Put malunggay in your soup,” he said in an interview relating to the coronavirus crisis (Quieta 2020). No reviews of the scientific literature were available to evaluate the veracity of such recommendations and the potential benefits of moringa in prevention or treatment of COVID-19.

2.0 RESULTS OF LITERATURE SEARCH

In early April 2020 I conducted a search of the literature on medicinal uses of moringa. No scientific references on the potential uses of moringa in preventing or treating coronavirus diseases such as the Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS) and COVID-19 were found. However, the search revealed a significant body of evidence supporting investigations of the potential use of moringa leaves and seeds for use as a direct antiviral treatment, multi-functional supportive treatment, or adjunct to other future treatment regimens for COVID-19.

Update: In June 2020 Hamza et al. published the first research on the antiviral activities of compounds present in moringa against the SARS-CoV-2 virus. This is summarized in the section below.

This evidence is presented below by subject with excerpts from abstracts of the most applicable studies. It was apparently the first compilation of information on this subject and it is a work in progress. I intend to complete this review and offer it for future publication in a scientific journal.

2.1 ANTIVIRAL ACTIVITIES OF MORINGA

2.1.1 Overview

The virus that causes COVID-19 infections (SARS-CoV-2) is an enveloped RNA virus in the family Coronaviridae. Moringa has shown evidence of antiviral activity against a wide variety of other disease-causing viruses – DNA and RNA, enveloped and non-enveloped:

Table 1. Moringa extracts have shown activity against these viruses.

AGENT	DISEASE(S)	FAMILY	TYPE	STRUCTURE
FMD	Foot and mouth disease	Picornaviridae	RNA Virus	Nonenveloped
HBV	Hepatitis B	Hepadnaviridae	DNA Virus	Enveloped
HHV-1 (HSV-1) Herpes Simplex	Oral and genital herpes, others	Herpesviridae	DNA Virus	Enveloped
HHV-4 (EBV) Epstein-Barr	Pre-malignant, and malignant diseases, others	Herpesviridae	DNA Virus	Enveloped
HIV-1 HIV-2 Human mmunodeficiency Virus	Acquired immunodeficiency syndrome (AIDS)	Retroviridae	RNA Virus	Enveloped
HCMV	Human cytomegalovirus	Herpesviridae	DNA Virus	Enveloped
Poliovirus	Poliomyelitis	Picornaviridae	RNA Virus	Enveloped

2.1.2 Epstein-Barr Virus (EBV) Carcinogenesis

Hussain et al. (2014) found that the novel active compounds from the seeds of Moringa oleifera (MO) inhibit EBV-EA (Epstein- Barr virus-early antigen).

Three known thiocarbamate (TC)- and isothiocyanate (ITC)-related compounds have been isolated from the leaves of MO as inhibitors of tumor promoter teleocidin B-4-induced Epstein-Barr virus (EBV) activation in Raji cells. Of 10 TCs and 8 synthetic ones studied, only the TC niaziminin showed considerable inhibition against EBV activation (Murikami et al. 1998).

Compounds in ethanol extracts of the seeds of MO were tested for their potential antitumor promoting activity using an in vitro assay for their inhibitory effects on Epstein-Barr virus-early antigen (EBV-EA) activation in Raji cells induced by the tumor promoter, 12-O-tetradecanoyl-phorbol-13-acetate (TPA). All of the tested compounds showed inhibitory activity against EBV-EA activation. Of these, niazimicin was found to have potent antitumor promoting activity in the two-stage carcinogenesis in mouse skin using 7,12-dimethylbenz(a)anthracene (DMBA) as initiator and TPA as tumor promoter (Guevra et al 1999).

2.1.3 Hepatitis B Virus

Moringa oleifera leaf extracts had protective effects on hepatitis B virus (HBV) genotypes C and H transiently transfected Huh7 cells (Feustel et al 2017).

Crude extracts of M. oleifera had inhibitory effects against replication of hepatitis B virus and human liver cancer cells (Waiyaput et al 2012).

2.1.4 Herpes Simplex Virus (HSV)

Moringa extracts may be possible candidates for anti-HSV-1 agents. Lipipun et al. (2003) found that the extract of M. oleifera inhibited HSV-1 plaque formation more than 50% at 100micrograms/ml in a plaque reduction assay. In mice treated at a dose of 750 mg/kg per day it significantly delayed the development of skin lesions, prolonged the mean survival times and reduced the mortality of HSV-1 infected mice as compared with a control solution (2% DMSO in distilled water). They also found that there was no significant difference between acyclovir, a most commonly used antiviral for HSV diseases, and the extracts in delaying development of skin lesions, and no significant difference between acyclovir and MO in mean survival times. Toxicity of the extract was not observed in the treated mice.

Soltan and Zaki (2009) also found that hydro-alcoholic extracts of another moringa species (Moringa peregrina) used in Egyptian traditional folk medicine had antiviral activity against HSV.

Kurokawa et al. (2016) evaluated alleviation by aqueous extracts of MO and assessed the mode of thier anti-herpetic action in a murine cutaneous herpes simplex virus type 1 (HSV-1) infection model. The extracts significantly limited the development of herpetic skin lesions and reduced virus titers in the brain on day 4 without toxicity. Their mode of action appeared to be by augmentation of delayed-type hypersensitivity (DTH), a major host defense mechanism for intradermal HSV infection. This may contribute to their efficacies against HSV-1 infection.

2.1.5 Human Immunodeficiency Virus (HIV)

Antraquinone, present in Moringa oleifera extracts, shows a high degree of antiviral activity toward HIV-1 (Barnard et al. 1992, Schinazi et al. 1990, Semple et al. 2001).

In 2013 investigators reported that MO leaf extracts showed potent and selective inhibition of the early steps in HIV-1 infectivity and that these extracts could serve as source of antiretroviral lead molecules. They also postulated that outcome of this investigation could partly explain the benefits and improvement in the quality of life claimed by people living with HIV/AIDS and their use of moringa as a supplement (Nworu, Okoye and Ezeifeka 2013).

2.1.6 Hoof and Mouth Disease (HMD)

Antiviral assays of aqueous and chloroformic extracts of M. oleifera showed potent activity against foot and mouth disease virus (Younus et al. 2016, 2017).

2.1.7 Human cytomegalovirus (HCMV)

The phytochemical anthraquinone in MO extract has antiviral activity against the human cytomegalovirus (Hamza et al. 2020).

2.1.8 Poliovirus

The anthraquinone chrysophanic acid shows in vitro antiviral activity against poliovirus (Semple et al. 2001).

2.1.9 Enteric Viruses

The SARS-CoV-2 virus has been found in untreated wastewater. While data are limited, there is no information to date that anyone has become sick with COVID-19 because of exposure to wastewater (CDC 2020d). However, there is a potential for transmission and wastewater testing for viral RNA is being used as an epidemiological tool for assessing disease prevalence and spread in defined populations (University of Sterling 2020; Quilliam et al. 2020; Nghiem eta al. 2020).

Because of their coagulant and antimicrobial properties, extracts from the seeds of MO have many applications in treatment of drinking water and wastewater (Bichi 2013). Viral contamination of drinking water from fecal sources is difficult to detect and treat effectively. However, studies by Samineni et al. (2019) found that a chitin-binding protein (MoCBP) from MO seed extracts binds selectively to viral capsid proteins, enhancing virus removal in a test sand filtration system. A ∼7 log₁₀removal of viruses was achieved. This may be applied to the design of virus removal technology for water treatment systems and suggests investigation of its potential for enhancing removal of the SARS-CoV-2 virus.

2.1.10 Plant Viruses

The anthraquinone in MO extract serves as an antiviral agent for diseases found in many plants (Kasolo et al. 2010).

2.1.11 New Study Confirms Activity Against the (SARS-CoV-2) Virus

In June 2020 Hamza et al. published the only known research on moringa and coronaviruses. For the first phase of their study they used peptide mass fingerprinting methods to find the viral peptides of SARS-COV-2, identify their novel structures and targets for inhibition. Fifteen were found. Extracts of MO were chosen for investigation as potential inhibitors because antiviral compounds are known to be present in these extracts and they have shown significant activity against viral diseases (Nkechinyere, Onyekwere and Felix 2014).

Aqueous and ethanolic extracts of flavonoids and anthraquinone from MO with known antiviral activities, and hydroxychloroquine as used for therapy in Pakistan, were used for comparative study. Using a molecular docking technique (DAS et al. 2020), the binding energies between these substances and the SARS-CoV2 peptides that were identified as targets for inhibition were measured. Kaempferol (3,4′,5,7-tetrahydroxyflavone), a flavonoid from MO, and antraquinone had high binding energies and visualization of the docked complexes of these compounds showed that they accurately fit into the hydrophobic surface of peptides, ensuring optimal attachment of drug compounds to the target peptides. These findings lead the investigators to propose that these compounds are effective inhibitors against the SARS-CoV-2 virus, that they could help the immune system to fight against COVID-19 infections, and be used in clinical trials.

2.1.12 Use in Making Other Antiviral Agents

Moringa oleifera seed extract has been used as a reducing and stabilizing agent in the synthesis of silver nanoparticles for use as a novel control tool against dengue virus (DEN-2) and its primary vector Aedes aegypti (Sujitha et al. 2015).

2.1.13 Use and Interaction with Other Antiviral Therapies

Since herbal preparations may interact with other drugs via inhibition of other metabolizing enzymes, the potential for adverse interactions with moringa and other drugs that may become available for treatment of COVID-19 must be considered. The information currently available on potential interactions with moringa is and drugs scant. Monera et al. (2008) tested the inhibitory effects of moringa leaf and root extracts on CYP3A4 hydroxylation of testosterone and found significant inhibitory effects in vitro, and stated that this finding warranted additional investigations of interactions among moringa, antiretrovirals and other drugs. In vitro studies have also indicated inhibition by moringa of cytochrome P450 A34 and 2D6 and could alter the pharmacokinetics (PK) of antiretroviral drugs metabolized by the same pathways. However, this in vitro drug interaction activity may not translate to a clinically significant effect (Monera et al. 2017). To investigate this further the researchers studied effect of moringa leaf powder on the PK of nevirapine in HIV-infected people. Co-administration of the powder at the traditional dose rate did not significantly alter the steady-state PK of the drug.

Most of the data on interactions comes from the experience of using moringa in combination with antiretroviral therapies for HIV/AIDS. In Africa, minimally processed moringa leaf and seed preparations are widely used as traditional, complementary, and alternative medicines (TCAMs) in combination with antiretroviral therapies (ART) for HIV/AIDES [Monera and Maponga 2012); Mudzviti et al. (2012); Gurumu, Teni and Tadesse (2017); Tshingi et al. (2017)].

Mudzviti et al. (2012) investigated the impact of herbal drug use on the adverse drug reaction profiles of patients on antiretroviral therapy (ART) in Zimbabwe. Nearly all (98.2%) of the patients used at least one herbal drug in combination with ART. Moringa oleifera was used by 44.1% of patients. They reported no association of moringa with adverse drug reaction profiles. Gurmu, Teni and Tadesse (2017) also found wide use of TCAM by patients on ART in Ethiopia and MO was used by 20.83% of the patients. Improvement in their conditions was reported by most (73.30%) of the patients.

In reviewing these findings, it should be noted that the capacity for ethical and regulatory reviews of herbal trials in developing countries is limited and a defined framework for these may be absent (Monera-Penduka et al. 2017).

No studies reporting adverse interactions with moringa and other antiviral drugs were found.

2.2 Antimicrobial Activity (Non-viral Agents)

Three synthetic antimicrobial peptides (AMPs) inspired on Mo-CBP₃, an antimicrobial protein from MO seeds, inhibited the growth of Candida species and pathogenic bacteria and penetrated into microbial cells, but none were hemolytic or toxic to human cells Oliviera et al. 2019).

Peptides from MO seeds mediate the sedimentation of suspended particles such as bacterial cells and have a direct bactericidal activity. Recombinant or synthetic forms of a cationic polypeptide have been shown to efficiently kill several pathogenic bacteria, including antibiotic-resistant isolates of Staphylococcus, Streptococcus, and Legionella species. Low concentrations effectively killed bacteria such as Pseudomonas aeruginosa and Streptococcus pyogenes without displaying a toxic effect on human red blood cells (Suarez et al. 2003, 2005).

Bark extracts of MO were evaluated for their antibacterial activity against four bacteria viz. Staphylococcus aureus, Citrobacter freundii, Bacillus megaterium and Pseudomonas fluorescens. All of the bark extracts, irrespective of their types, in different concentrations inhibited growth of the test pathogens to varying degrees. Staphylococcus aureus was found to be the most sensitive test organism to different extracts of MO. The investigators concluded that MO may be a potential source for treatment of infections caused by the resistant microbes (Zaffer et al. 2014).

2.3 Anti-inflammatory Activity

2.3.1 Overview of inflammatory Processes and Immune Response Deficiencies in COVID-19 Infections

The basic pathogenesis of COVID-19 primarily involves two interlinked processes: a severe lung inflammation and immune deficiency, both of which are related to an inappropriate immune response and over-production of cytokines [Wang et al. 2020; Zhang et al. 2020

Systemic Inflammation. SARS-CoV-2 virus infection can cause pulmonary and systemic inflammation, leading to multi-organ dysfunction in patients at high risk (Chen et al. 2020). This may involve the heart or liver.

Pulmonary Inflammation. Pulmonary inflammation is the most common symptom of COVID-19. When the virus infects the upper and lower respiratory tract it can cause mild or highly acute respiratory syndrome with consequent release of pro-inflammatory cytokines, including interleukin (IL)-1β and IL-6 (Conti et al. 2020). There are significant correlations between the degree of pulmonary inflammation and the main clinical symptoms and laboratory results (Wu et al. 2020). The lungs from COVID-19 pneumonia patients manifest significant pathological lesions, including the alveolar exudative inflammation and interstitial inflammation (Yao et al. 2020).

Increased inflammation is a risk factor for severe/critical COVID-19 pneumonia (Li et al. 2020). A life-threatening complication of SARS-CoV-2 infection is an acute respiratory distress syndrome (ARDS), which occurs more often in older adults, those with immune disorders and co-morbidities. Severe forms of the infection, being an indication for treatment in the intensive care unit, comprise acute lung inflammation, ARDS, sepsis and septic shock (Wujtewicz et al. 2020). Accumulated evidence suggests that a subgroup of patients with severe COVID-19 could have a dysregulation of the immune response that allows the development of viral hyperinflammation (Lagunas-Rangel 2020).

Aggravating causes of death include fulminate inflammation, lactic acid accumulation and thrombotic events (Peng et al. 2020).

Infants and young children with COVID-19 tend to have mild clinical symptoms and imaging findings not typical as those of adults. However, computed tomography examinations showed that among the 9+ children studied, 8 had pulmonary inflammation (Zhou et al. 2020).

Cardiac Inflammation. Presentation of acute myocardial inflammation in a patient with COVID-19 cardiac involvement was a complication associated with COVID-19, even without symptoms and signs of interstitial pneumonia (Inciardi et al. 2020). Myocardial injury is significantly associated with fatal outcome of COVID-19, while the prognosis of patients with underlying CVD but without myocardial injury is relatively favorable. Inflammation may be a potential mechanism for myocardial injury (GUO et al. 2020). Direct myocardial injury due to viral involvement of cardiomyocytes and the effect of systemic inflammation appear to be the most common mechanisms responsible for cardiac injury (Bansal 2020).

Liver Inflammation. Liver injury is common in non-ICU hospitalized COVID-19 patients. It may also be related to systemic inflammation (Xie et al. 2020).

2.3.2 Anti-inflammatory Activity of Moringa

Inflammation is the primary contributor to COVID-19 pathology. In recent years, a growing need to discover new compounds for the prevention and treatment of inflammatory diseases has lead researchers to investigate therapeutic agents derived from natural products as a valid option in treatment of inflammation-associated disorders (Giacoppo et al. 2017).

No other natural product has shown more evidence of anti-inflammatory activities than moringa. Multiple compounds found in the leaves, roots, flowers, pods and seeds have shown a wide range of anti-inflammatory activities and the number of publications confirming these activities has increased almost exponentially in the last several years:

Moringa oleifera is widely used as a traditional remedy for arthritis. Saleem et al. (2020) evaluated the anti-arthritic potential of methanolic and aqueous extracts from oleifera in arthritic rats. The extracts persuasively down-regulated the COX-2, PGE2, IL-1β, IL-6, NF-κB, and TNF-α, and up-regulated the mRNA expression of I-κB, IL-4, and IL-10. Histopathological evaluation showed that treatment with the extracts significantly (p < 0.05) reduced joint inflammation, pannus formation, and bone erosion in treatment groups in comparison to arthritic control.
Albasher et al. (2020) investigated the potential hepatic protective effect of MO methanolic extract (MOE) against lead-induced hepatotoxicity in adult Wistar albino rats. They found that concurrent administration of MOE had the potential to protect the liver tissues in Pb(II)-intoxicated rats by preventing oxidative stress, inflammation, and apoptosis, via attenuation of NF-κB signaling pathway.
Abdel-Daim et al. (2020) described the protective efficacy of MO ethanolic extract (MOEE) against the impact of cobalt chloride (CoCl₂) exposure on the rat kidneys. MOEE ameliorated CoCl₂-induced renal oxidative damage and inflammatory injury with the suppression of the mRNA expression pattern of pro-inflammatory cytokine-encoding genes. MO and its isolated compounds potentially have an anti-allergic activity by inhibiting both early and late phases of allergic reactions (Abd Rani et al. 2019).
Cheng et al. (2019) investigated the protective effects of moringa extract (ME) in bovine mammary epithelial cells (MAC-T) in in vitro They found that ME had beneficial effects in bovine mammary epithelial cells through its anti-inflammatory, antioxidant, and casein production properties. The study provided evidence that ME could be a good candidate for a feed supplement to decrease inflammatory responses of bovine mastitis.
Famurewa et al. (2019) investigated the potential of virgin coconut oil (VCO) and MO seed oil (MOO) on methotrexate (MTX)-induced oxidative stress-mediated cerebral neurotoxicity and inflammation in rats. The MTX-induced neurotoxic alterations were significantly abrogated by MOO and VCO supplementation via inhibition of cholinesterase, oxidative stress, and anti-inflammatory mechanisms. Supplementation of these natural food oils may be beneficial in the prevention of cerebral neurotoxic side effects in cancer patients undergoing MTX chemotherapy.
Cui et al. (2019) investigated the anti-inflammatory activity of β-sitosterol (BSS) isolated from MO. BSS dispersed well in the medium as nanoparticles with diameters of 50 ± 5 nm and suppressed the secretion of inflammatory factors from keratinocytes and macrophages induced by PGN, TNF-α, or LPS, such as TNF-α, IL-1β, IL-6, IL-8, and ROS, separately. In addition, BSS significantly reduced the expression of NLRP3, a key component of NLRP3 inflammasomes, and inhibited the activation of caspase-1.
The gastro-protective influence of moringa leaves and its extract on aspirin-induced ulcer in rats is manifested by its significant reduction in inflammatory cytokines and normalization of gastric mucosal mucin and NO level. Overall, moringa leaf powder is more efficient as an antiulcer agent than moringa extract (Mabok et al. 2019).
Moringa extract exhibited anticryptosporidial effect in buffalo intestinal tissue explants causing a significant decrease in IFN-γ, IL-12 and IL-14 levels (225, 150 and 65 pg/ml, respectively) compared with supernatants of infected non-treated ileal explant culture plate wells (Aboelsoued et al 2019).
Moringa extract significantly decreased the fecal bacterial count of novyi in both heavily and lightly infected groups. The study highlighted the potential beneficial effects of M. oleifera leaf against Fasciola (F.) gigantica and C. novyi (El Shanawany et al. 2019).
A polysaccharide named MRP-1 from the roots of oleifera has been characterized and has anti-inflammatory effects (Cui et al. 2019).
Sun et a. (2019) conducted a study to determine the effect of Moringa peregrina seed ethanolic extract (MPSE) on the viability of and NO and IL-1β production by a lipopolysaccharide (LPS)-activated macrophage (J774A.1) cell line. They found that the MPSE was not cytotoxic at 1000 μg/mL but significantly (p<0.001) inhibited NO and IL-1β production by the LPS-activated macrophage J774A.1 cells. Their findings suggested that peregrina seed extract can be used to treat and prevent inflammatory diseases through the inhibition of inflammatory mediators.
One of the anti-inflammatory constituents of moringa identified in vitro is the phytosterol β-Sitosterol (BSS), which is highly insoluble. A method to increase the solubility via the formation of nanoparticles, and nanoparticle formulation’s capacity to inhibit the signal transduction pathways of inflammation in macrophages has been reported (Liao et al. 2018).
Water-soluble MO lectin (WSMoL) promotes immunomodulation in human PBMC inducing a potential wound healing profile and, in future in vivo assays, can be evaluated as adjuvant in immunosuppressive diseases and wound repair (Coriolano et al 2018).
Moringa oleifera extract (MOE) modulates murine intestinal immunity to Hymenolepis nana resulting in reductions of both adult worms and eggs (Abdel-Latif et al. 2018).
Addition of Moringa oleifera, leaf meal to the diets of the gilthead seabream (Spartus aurata) improved markers of immune status (Mansour et al 2018).
As a folk medicine, MO is used effectively to treat inflammatory conditions and skin disease. A recent study confirmed that compounds from MO seeds suppress the expression of IL-12/IL-23 p40, IL-17A, IL-22 and IL-23 p19 in vitro, and in vivo they ameliorated psoriasis-like skin lesions, decreased IL-17A mRNA expression, and increased the expression of keratinocyte differentiation markers. This was the first report regarding the mechanism and therapeutic application of MO seeds to treat psoriasis-like lesions in vivo (Ma et al 2018).
Water-soluble MO lectin (WSMoL) is an anionic protein isolated from the seeds of the tree. Until recently, immune responses promoted by this lectin in human peripheral blood mononuclear cells (PBMC) have not been investigated. WSMoL induced the release of the cytokines TNF-α, IL-2, IL-6, IL-10 as well as nitric oxide. WSMoL promotes immunomodulation in human PBMC inducing a potential wound healing profile and, in future in vivo assays, can be evaluated as adjuvant in immunosuppressive diseases and wound repair (Coriolano et al. 2018).
Giacoppo et al. (2017a) studied the anti-inflammatory effects of a new formulation of MO -derived 4-(α-L-rhamnopyranosyloxy)benzyl isothiocyanate as a complex with alpha-cyclodextrin (moringin + α-CD) on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells, a common model used for inflammation studies. Their results showed that moringin + α-CD inhibits the production of inflammatory mediators in LPS-stimulated macrophages by down-regulation of pro-inflammatory cytokines (TNF-α and IL-1β), by preventing IκB-α phosphorylation, translocation of the nuclear factor-κB (NF-κB), and also via the suppression of Akt and p38 phosphorylation. In addition, as a consequence of upstream inhibition of the inflammatory pathway following treatment with moringin + α-CD, the modulation of the oxidative stress (results focused on the expression of iNOS and nitrotyrosine) and apoptotic pathway (Bax and Bcl-2) was demonstrated. Therefore, moringin + α-CD appears to be a new relevant helpful tool to use in clinical practice for inflammation-associated disorders.
They also investigated the efficacy of 4-(α−L-rhamnopyranosyloxy)benzyl isothiocyanate (moringin), purified from MO seeds and ready-to-use as a topical treatment in experimental autoimmune encephalomyelitis, murine model of multiple sclerosis. Western blot analysis and immunohistochemical evaluations revealed that the cream containing 2% moringin was able to counteract the inflammatory cascade by reducing the production of pro-inflammatory cytokines (interleukin-17 and interferon-γ) and in parallel by increasing the expression of anti-inflammatory cytokine (interleukin-10). Evidence from this study suggested the use of the cream for management of multiple sclerosis-induced neuropathic pain Giacoppo et al. (2017b).
Fermented MO extract (FM) decreased proinflammatory cytokine mRNA expression in the liver, epididymal adipose tissue, and quadriceps of high-fat diet fed mice (Joung et al. 2017).
Isothiocyanate-enriched moringa seed extract (MSE) displayed strong anti-inflammatory and antioxidant properties in vivo and in vitro, making them promising botanical leads for the mitigation of inflammatory-mediated chronic disorders (Jaja-Chimedza et al. 2017).
Expression of the proinflammatory cytokine IL-6 in HBV Genotypes C and H in transiently transfected Huh7 cells decreased after 24 hours of treatment with aqueous extracts of MO (Feustel et al. 2017).
A study by Almatrafi et al. (2017) demonstrated that moringa leaves may prevent hepatic steatosis by affecting gene expression related to hepatic lipids synthesis resulting in lower concentrations of cholesterol and triglycerides and reduced inflammation in the liver.
The isothiocyanate isolated from MO has shown potent anti-inflammatory activity in the treatment of murine subacute Parkinson’s disease (Giacoppo et al. 2017c).
Moringa seed extract enriched with moringa isothiocyanate-1 was effective in mitigating ulcerative colitis (UC) symptoms and reducing UC-induced colonic pathologies in mice, likely by suppressing pro-inflammatory biomarkers and increasing tight-junction proteins. It may be may be useful in prevention and treatment of ulcerative colitis (Kim et al. 2017).
Giacoppo et al. (2017) confirmed the anti-inflammatory effects of a new formulation of oleifera-derived 4-(α-L-rhamnopyranosyloxy)benzyl isothiocyanate as a complex with alpha-cyclodextrin (moringin + α-CD) on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells, a common model used for inflammation studies. Moringin + α-CD appears to be a new relevant helpful tool to use in clinical practice for inflammation-associated disorders.
Oral administration of MO leaf extract in diabetic rats showed hepatoprotective, anti-inflammatory, and lipid-lowering effects against streptozotocin-induced hepatotoxicity (Omodanisi et al. 2017a).
Methanol extracts of MO leaves contain potent phytochemical constituents that offer protective action against diabetic-induced renal damage, reactive oxygen species and inflammation (Omodanisi et a. 2017b).
Extracts from MO seed and its major isothiocyanate MIC-1 displayed strong anti-inflammatory and antioxidant properties in vivo and in vitro, making them promising botanical leads for the mitigation of inflammatory-mediated chronic disorders Jaja-Chimedza et al. 2017).
Moringa oleifera seed extract (MSE) has anti-inflammatory and antioxidant activities. Therefore, MSE, enriched with MIC-1, may be useful in prevention and treatment of ulcerative colitis (Kim et al. 2017).
Hydrolysates and peptide fractions from protein isolates of moringa seeds showed ACE-I inhibition and antidiabetic activities (González Garza et al. 2017).
A study by Tamrat et al. (2017) provided evidence supporting the traditionally claimed uses of Moringa stenopetala in pain and inflammatory diseases. The plant could be a potential source for development of new analgesic and anti-inflammatory drugs.
Fermented MO extract decreased proinflammatory cytokine mRNA expression in the liver, epididymal adipose tissue, and quadriceps of high-fat diet fed mice (Joung et al. 2017).
Leaf extract from MO has demonstrated some therapeutic effectiveness against acetaminophen -induced nephrotoxicity through enhancement of the endogenous antioxidant system and a modulatory effect on specific inflammatory cytokines in kidney tissues (Karthivashan 2016).
An ethyl acetate fraction of MO exhibited potent anti-inflammatory activity in LPS-stimulated macrophages via suppression of the NF-κB signaling pathway. (Arulselvan et al. 2016).
Moringin, an isothiocyanate obtained from myrosinase-mediated hydrolysis of the glucosinolate precursor glucomoringin present in the seeds of MO, are well known antioxidants also endowed with anti-inflammatory activity. A cannabidiol and moringin combination outperformed the single constituents that, at this dosage had only a moderate efficacy on inflammatory (Tumor necrosis factor-α, Interleukin-10) and oxidative markers (inducible nitric oxide synthase, nuclear factor erythroid 2-related factor 2, nitrotyrosine) (Rajan et al. 2016).
Moringin (GMG-ITC) present in MO inhibits signaling pathways that are upregulated in immune disorders, such as JAK/STAT and NF-κB (Michl et al. 2016).
The hydroethanolic extract from MO flowers suppresses the activation of inflammatory mediators in lipopolysaccharide-stimulated RAW 264.7 macrophages via NF-κB Pathway (Tan et al. 2015).
Galuppo et al. (2015) investigated the protective effects of 4(α-L-rhamnosyloxy)-benzyl isothiocyanate (glucomoringin isothiocyanate; GMG-ITC) obtained from glucomoringin (GMG; 4(α;-L-rhamnosyloxy)- benzyl glucosinolate), purified from MO seeds and hydrolyzed by myrosinase enzyme (β-thioglucoside glucohydrolase; E.C. 3.2.1.147) on cerebral tissue. GMG-ITC was shown to exert neuroprotective properties in preventing cerebral ischemia/reperfusion (CIR)-induced damage and the related cascade of inflammatory and oxidative mediators that exacerbate the progression of the disease in an experimental rat model.
An ethyl acetate fraction of an extract prepared from the fresh leaves of MO inhibited human macrophage cytokine production induced by cigarette smoke. It inhibited cytokines (IL-8) that promote the infiltration of neutrophils into the lungs and others (TNF, IL-6) which mediate tissue disease and damage (Kooltheat et a. 2014).
Stable, water extractable isothiocyanates from MO leaves have been found to attenuate inflammation in vitro. These were obtained from a moringa concentrate (MC) made by extracting moringa leaves with water. Naturally occurring myrosinase in the MC converted glucosinolates into more stable moringa isothocyantes. These results suggested a potential for stable and concentrated moringa isothiocyanates, delivered in a moringa leaf concentrate (MC) as a food-grade product, to alleviate low-grade inflammation associated with chronic diseases (Waterman et al. 2014).
Waterman et a. (2014) found that a moringa concentrate (MC), made by extracting fresh leaves with water, utilized naturally occurring myrosinase to convert four moringa glucosinolates into moringa isothiocyanates. The optimized MC significantly decreased gene expression and production of inflammatory markers in RAW macrophages. Their results suggested a potential for stable and concentrated moringa isothiocyanates, delivered in MC as a food-grade product, to alleviate low-grade inflammation associated with chronic diseases.
Moringa fruit extract reduces the levels of pro-inflammatory mediators including NO, IL-1β, TNF-α, and IL-6 via the inhibition of NF -κ B activation in RAW264.7 cells. These findings revealed, in part, the molecular basis underlying the anti-inflammatory properties of moringa fruit extract (lee et al. 2013).
Moringa oleifera seeds contain the lectins cmol and WSMoL. The aqueous seed extract, cmol and WSMoL (6.25 µg/mL) and diluted seed extract at 50 µg/mL exhibited anti-inflammatory activity on lipopolyssaccharide-stimulated murine macrophages by regulating the production of nitric oxide, TNF-α and IL-1β. aqueous seed extract and cmol may be cytotoxic to immune cells which may explain the immunosuppressive potential of the extract (Araújo et al. 2013).
Anti-inflammatory activity of boiled MO pod extract has been assessed by measuring pro-inflammatory mediator expression in the lipopolysaccharide-induced murine RAW264.7 macrophage cells (Muangnoi et al. 2012). Prior treatment with MO extract inhibited elevation of mRNA and the protein level of interleukine-6, tumor necrosis factor-alpha, inducible nitric oxide synthase, and cyclooxygenease-2, induced by lipopolysaccharide for 24 h in a dose-dependent manner. These results indicate that the anti-inflammatory activity from bioactive compounds present in the MO pod constituents may contribute to amelioration of the pathogenesis of inflammatory-associated chronic diseases (Muangnoi et al. 2012).
A rare aurantiamide acetate(4) and 1,3-dibenzyl urea (5) from the roots of MO have been isolated and characterized (Sashidara et al. 2009). The isolated compounds inhibited the production of TNF-alpha and IL-2; and compound 5 showed significant analgesic activities in a dose dependent manner. These findings may help in understanding the mechanism of action of this traditional plant leading to control of activated mast cells on inflammatory conditions like arthritis, for which the crude plant extract has been used (Sashidhara et al. 2009).
The efficacy of n-butanol extract of the seeds of MO (MONB) was examined against ovalbumin-induced airway inflammation in guinea pigs by Mahajan et al (2009). MONB treatment showed improvement in all parameters studied except bronchoalveolar lavage tumor necrosis factor-alpha and interleukin-4. MONB treatment demonstrated inhibition of acetylcholine-induced bronchoconstriction and airway inflammation. It possesses an antiasthmatic property through modulation of the relationship between Th1/Th2 cytokine imbalances (Mahajan et al. 2009).
Mahajan and Mehta (2008) investigated the effect of ethanolic extracts of MO seeds on ovalbumin-induced airway inflammation in guinea pigs. MOEE-treatment of sensitized hosts resulted in improvement in all parameters studies except lung lavage fluid, TNF alpha and IL-4. Moreover, MOEE-treatment also showed protection against acetylcholine-induced broncho-constriction and airway inflammation which was confirmed by histological observations. The results of this study confirm the traditional claim for the usefulness of this herb in the treatment of allergic disorders like asthma.
Glucomoringin (4(α-L-rhamnosyloxy)-benzyl glucosinolate) (GMG) from MO bioactivated with the enzyme myrosinase forms the corresponding isothiocyanate (4(α-L-rhamnosyloxy)-benzyl isothiocyanate) (GMG-ITC). Galuppo et al. (2007) assessed the effect of GMG-ITC treatment in an experimental mouse model of multiple sclerosis (MS), an inflammatory demyelinating disease. Their results clearly showed that the treatment was able to counteract the inflammatory cascade that underlies the processes leading to severe MS. This suggests that GMG-ITC could be useful as a drug for the treatment or prevention of MS, at least in association with current conventional therapy.
Mahajan, Mali and Mehta (2007) studied the anti-arthritic activity of ethanolic extract of seeds of MO (MOEE) in adjuvant-induced arthritis in adult female Wistar rats. Serum levels of Rheumatoid Factor (RF) value, TNF-alpha, IL-1, and IL-6 showed decreased levels as compared to those in the diseased control group. Treatment with MOEE also altered oxidative stress in relation to its anti-inflammatory activity. Histopathological observations showed mild or less infiltration of lymphocytes, angiogenesis and synovial lining thickening. From these results and observations, they concluded that Moringa oleifera possesses promising antiarthritic activity.

2.4 Moringa and the Major Comorbidities of COVID-19 That Worsen Prognoses

2.4.1 Overview

Findings from multiple meta-analyses of studies involving thousands of COVID-19 patients showed that the most common comorbidities were hypertension (17 ± 7, 95% CI 14-22%) and diabetes (8 ± 6, 95% CI 6-11%) [(Yang et al. (2020); (Gou et al. (2020)]. Emami et al. (2020) and Li et al. (2020) also found that hypertension was the most prevalent underlying disease in hospitalized COVID-19 cases, and the percentages of cases with hypertension and diabetes were the same as reported by the other meta-analyses within the range of statistical significance.

These conditions were most associated with the most severe cases and those with the worst prognoses:

Guo et al. (2020) found that COVID-19 patients without other comorbidities but with diabetes (n=24) were at higher risk of severe pneumonia, release of tissue injury-related enzymes, excessive uncontrolled inflammation responses and hypercoagulable state associated with dysregulation of glucose metabolism. Furthermore, serum levels of inflammation related biomarkers such as IL-6, C-reactive protein, serum ferritine and coagulation index, D-dimer, were significantly higher (p< 0.01) in diabetic patients compared with those without, suggesting that patients with diabetes are more susceptible to an inflammatory storm eventually leading to rapid deterioration of COVID-19. Their data supported the notion that diabetes should be considered as a risk factor for a rapid progression and bad prognosis of COVID-19. More intensive attention should be paid to patients with diabetes, in case of rapid deterioration.
Among different cytokines found significantly higher in patients with diabetes compared to those without, Interleukin-6 (IL-6) which is already increased in conditions of chronic inflammation, may play a more deleterious role in Covid-19 infection (Maddaloni and Buzzetti (2020).
A large proportion of patients have underlying cardiovascular disease and/or cardiac risk factors. Factors associated with CV mortality include male sex, advanced age, and presence of comorbidities including hypertension, diabetes mellitus, cardiovascular diseases, and cerebrovascular diseases (Madjid et al. 2020).

Moringa has both antidiabetic and antihypertensive activities and has been used in traditional medicine to treat both of these diseases. Recent scientific studies provide increasing evidence to support these uses.

2.4.2 Antidiabetic Activity of Moringa

Moringa isothiocyanate activates Nrf2-ARE signaling, increases expression of Nrf2 target genes, and suppresses inflammation indicating a potential role in diabetic neuropathy (Cheng et al. 2019).
The evidence for acute antihyperglycemic effects of MO extract on diabetic animal models seems to be robust, but more chronic and long-term studies are needed. In contrast, the hypoglycemic effects of MO on humans are not as clear. The scarce number of human studies, together with a diverse range of methodologies and MO doses, may explain this. In addition, evidence regarding changes in insulin levels due to MO intervention is ambiguous, both in animal and human studies (Vargas-Sánchez, Garay-Jaramillo and González-Reyes (2019).
Ahmad, Khan and Blundell (2019) reviewed the literature on the role of moringa leaves in glycemia and their physiological mechanisms. They found that moringa leaves have been shown to reduce glycemia and have the possibility to be used as a glycemic control agent in diabetes and prediabetes without causing any adverse effects. However, the studies reviewed were limited in numbers and mostly conducted in animals, in vitro and in vivo. Long‐term human studies are required to determine the hypoglycemic effect of moringa leaves, their physiological mechanisms, active ingredients, and safety.
Moringa oleifera leaf powder administered to Sprague Dawley rats with hyperglycemia induced by alloxan showed a hypoglycemic effect (Villarruel-Lopez et al. 2018).
Methanol extracts of MO leaves contain potent phytochemical constituents that offer protective action against diabetic-induced renal damage, reactive oxygen species and inflammation and could therefore play a role in reducing diabetic complications, particularly in developing countries such as in Africa where the majority cannot afford orthodox medicine (Omodanisi, Aboua and Oguntibeju 2017).
Moringa contains potent phytochemical constituents that offer protective action against diabetic-induced renal damage, reactive oxygen species (ROS) and inflammation and could therefore play a role in reducing diabetic complications, particularly in developing countries such as in Africa where the majority cannot afford orthodox medicine (Omodanisi, Aboua and Oguntibeju (2017).
Hydrolysates and peptide fractions from protein isolates of moringa seeds showed ACE- antidiabetic activities (González Garza et al. 2017).
Oral administration of MO leaf extract in diabetic rats showed hepatoprotective, anti-inflammatory, and lipid-lowering effects against streptozotocin-induced hepatotoxicity (Omodanisi et al. 2017).
Overall, the 50% MoEE at a dose of 300mg/kg showed superior antioxidant properties, weight restorative and pronounced hypoglycemic effects (Aa, Om and Ga 2017).
Antidiabetic activity of two low doses of Moringa seed powder in the diet on streptozotocin (STZ) induced diabetes male rats was investigated. Treatment ameliorated the levels of all parameters approaching the negative control values and restored the normal histology of both kidney and pancreas compared with that of the diabetic positive control group (Al-Malki and El Rabey 2015).
Moringa isocyanates are the main anti-obesity and anti-diabetic bioactives of moringa concentrate (MC), and they exert their effects by inhibiting rate-limiting steps in liver gluconeogenesis resulting in direct or indirect increase in insulin signaling and sensitivity. These conclusions suggest that MC may be an effective dietary food for the prevention and treatment of obesity and type 2 diabetes (Waterman et al. 2015).
Both the aqueous ethanol and n-butanol extracts of Moringa stenopetala leaves possess antihyperglycemic and antihyperlipidemic properties (Toma et al. 2015).

2.4.3 Antihypertensive Activity of Moringa

Moringa oleifera leaf extracts lower high blood pressure by alleviating vascular dysfunction and decreasing oxidative stress in L-NAME hypertensive rats.Aekthammarat, Pannangpetch and Tangsucharit (2019).
The study by Attakpa et al. (2017) clearly demonstrated that oleifera exerts antihypertensive effects by inhibiting the secretion of IL-2 and modulates T cell calcium signaling in hypertensive rats.
Niazicin-A, Niazimin-A, and Niaziminin-B compounds from MO ethanolic leaf extract have been reported to have potent antihypertensive activity. These compounds target and partially block the angiotensin-converting enzyme (ACE) which is one of the main regulatory enzymes of the renin-angiotensin system (RAS). Computationally, these bioactive molecules have shown better binding energy to known standard drugs which have been already known for inhibition of ACE and can further act as a pharmacophore for in vitro and in vivo studies in the development of alternative medicine (Khan et al. (2019).
Moringa stenopetala has been used in Ethiopian traditional medicine as a remedy for treatment of hypertension and diabetes. Studies have confirmed that crude extracts of the plant have antihypertensive and antihyperlipidemic activities [Mengistu et al (2012) and Geleta et al. (2016).
The hydroalcoholic extract from the leaves of Moringa peregrina have partially antihypertensive effects (Safaeian et al. 2015).
Isothiocyanate 4 and the thiocarbamate glycosides niaziminin A and B from oleifera show hypotensive activity (Faizi et al. 1994).

2.5 Angiotensin-converting Enzymes (ACE) and COVID-19

2.5.1 Overview

The Renin-angiotensin-system (RAS) can be defined as the ACE-Ang II-AT1R axis that promotes vasoconstriction, sodium retention, and other mechanisms to maintain blood pressure, as well as increased oxidative stress, fibrosis, cellular growth, and inflammation in pathological conditions.

Two host receptors were proposed for COVID-19: CD26 and the angiotensin-converting enzyme 2 (ACE2) Sargiacomo, Sotgia, and Lisanti (2020). Several studies have now confirmed that the COVID-19 virus (SARS-CoV-2) infects patients by binding of the viral S proteins to the human ACE2 receptor. These receptors are abundant in the epithelia of the lung, oral mucosa, small intestine and other tissues. ACE2 is also the same cell entry receptor enzyme as the SARS virus (SARS-CoV).

ACE2 also plays an important role as the negative regulator of the RAS (Gheblawi et al 2020). In the paper by Sun, Yang and Su (2020) it was reported that binding of COVID-19 and ACE2 can result in the exhaustion of ACE2, followed by inhibition of ACE2/Ang (1-7)/Mas receptor pathway. The resulting imbalance between ACE/Ang II/AT1R pathway and ACE2/Ang (1-7)/Mas receptor pathway in the RAS system can then lead to multi-system inflammation and severe pneumonia. Increased ACE and Ang II are poor prognostic factors for severe pneumonia in COVID-19 cases.

ACE (ACE1) inhibitors are a commonly prescribed class of blood pressure lowering medications. Conflicting recommendations about the use of these inhibitors with COVID-19 have been made but now most references to indicate such use is acceptable:

In-vitro studies are available to support the eventual role of ACE inhibitors and angiotensin receptor blockers (ARBs) in both the promotion and antagonism of COVID-19 (Iaccarino et al. 2020).
Animal studies have shown that RAS inhibitors could effectively relieve symptoms of acute severe pneumonia and respiratory failure (Sun, Yang and Su 2020). They also speculated that ACE1 and AT1R inhibitors could be used in patients with COVID-19 pneumonia under the condition of controlling blood pressure and might reduce the pulmonary inflammatory response and mortality.
Drugs with blocking activity against ACE2 can provide the basis for subsequent research and development for COVID-19 applications (Li et al. 2020).
Because the ACE2 (angiotensin-converting enzyme 2) protein is the receptor that facilitates coronavirus entry into cells, the notion has been popularized that treatment with renin-angiotensin system blockers might increase the risk of developing a severe and fatal severe acute respiratory syndrome coronavirus-2 infection. However, ACE (ACE1) inhibitors do not inhibit ACE2 because ACE and ACE2 are different enzymes. Indeed, animal data support elevated ACE2 expression as conferring potential protective pulmonary and cardiovascular effects (Danser Epstein and Batlle (2020).

2.5.2 ACE Inhibition Activity of Moringa

Two studies have shown that moringa has ACE (ACE1) inhibition activities:

Moringa oleifera seed protein isolate (ISO) and its enzymatic protein hydrolysates have ACE inhibitory properties (Arinola et al. 2018a, 2018b).
Niazicin-A, Niazimin-A, and Niaziminin-B compounds from oleifera ethanolic leaf extract target and partially block the angiotensin-converting enzyme (ACE) which is one of the main regulatory enzymes of the renin-angiotensin system (RAS) (Khan et al. (2019).

Interactions between moringa extracts and ACE2 have not been investigated. The antiviral activities of moringa against other viruses could result from binding of compounds from the plant with ACE-2 or other mechanisms. ACE1 inhibition and other hypotensive activities of moringa could be helpful to COVID-19 patients with hypertension.

2.6 Nutritional Supplementation with Antiviral Therapy

A significant proportion of HIV patients on antiretroviral therapy (ART) in the Democratic Republic of the Congo have poor nutrition and this frequently leads to therapeutic failure. Some HIV care facilities recommend supplementation with MO leaf powder to correct these nutritional deficiencies. In a single-blind randomized control trial patients receiving supplements of the leaf powder exhibited a significantly greater increase in body mass index and albumin levels than those in the control group. The investigators concluded that leaf powder supplementation may represent a readily available and effective local solution to improve the nutritional intake and nutritional status of patients undergoing ART (Tshingani et al. 2017).

2.7 Safety and Contraindications

2.7.1 Safety

Stohs and Hartman (2015) reviewed the safety and efficacy of Moringa oliefera. The leaves, seeds, bark, roots, sap, and flowers are widely used in traditional medicine, and the leaves and immature seed pods are used as food products in human nutrition. Various safety studies in animals involving aqueous leaf extracts indicate a high degree of safety. No adverse effects were reported in association with human uses.

2.7.2 Toxicity

One study found that the low concentrations of moringa seed peptides that effectively kill bacteria such as Pseudomonas aeruginosa and Streptococcus pyogenes did not have a toxic effect on human red blood cells (Suarez et al. 2005).

2.7.3 Contamination Concerns

Moringa products administered to patients should be from approved suppliers meeting food safety, quality and labeling requirements. In Zimbabwe three samples of moringa products marketed for use by HIV-infected people were tested and found to be contaminated with bacteria and fungi above the European Pharmacopeia specified limits. Escherichia coli and Salmonella species were present in all three samples. All three samples contained arsenic, nickel and cadmium. Moringa oleifera with variable labeling information and poor microbial and heavy metal quality is widely available in Zimbabwe (Monera-Penduka 2016).

2.7.3 Contraindications

No contraindications for moringa use were found in this literature search.

3.0 CONCLUSION

The information developed from this preliminary literature search suggests that moringa should be considered as a strong candidate for further investigation and development as a multifunctional treatment or dietary supplement for COVID-19 infections. Moringa’s antiviral and potent anti-inflammatory activities are probably its greatest indications for these applications. No contraindications were reported in the literature and moringa has a long history of safe uses in traditional medicine and as a highly nutritional food.

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