CME INDIA Presentation by Dr N K Singh.

Eat Annar to beat Corona: One recent story has generated interest in using Pomegranate peel extract (POM Ex) in prevention of COVID infection and needs consideration.

”Legend: King Tut was fond of pomegranates, and so were the ancient Persians. They surely enjoyed the fruit in its natural form — not processed into pomegranate extract pills.”

एक अनार सौ बीमार – Ek  Annar sau Bimar

• Pomegranates have been grown for centuries in India, Asia, the Mediterranean, and the tropical parts of Africa. The Punica Granatum, commonly known as ‘the pomegranate’, comes with its own line of rich history and is truly one of the world’s most ancient of foods. The pomegranate is a superfood (rich in antioxidants) native to the East and can be found mentioned in historical documents as far back as 4000 B.C.
• In ancient times, pomegranates represented fertility, and the fruit has been depicted many times in art throughout history. 
• A few centuries ago, the fruit was brought over to North America.
• Pomegranate juice is a polyphenol-rich fruit juice with high antioxidant capacity.
• Pomegranate juice has been shown to exert significant antiatherogenic, antioxidant, antihypertensive, and anti-inflammatory effects.
• It also decreases lipid peroxidation in patients with type 2 diabetes.
• It decreases systolic blood pressure and serum angiotensin converting enzyme activity in hypertensive patients.

Superfood pomegranate

• Its juice has three times as many antioxidants as other antioxidant-rich beverages, such as green tea and red wine.
• This fruit is rich in bioactive compounds such as ellagitannins and anthocyanins content, which are protective toward degenerative diseases.
• Pomegranate fruit, because of its high nutritive value, health benefits, and antioxidant bioactive compounds, is considered a food medicine.
• Pomegranate has been considerably used in herbal medicine for flu and infections of the upper respiratory tract.
• All parts of the pomegranate fruit, i.e., peel and seeds, considered as waste products, can be processed for immense health benefits.
• Currently, most of the studies attributing health benefits to pomegranates have been conducted on the fruit.
• It includes its arils, peel, and seeds in beverage forms (juice and wines) and as extracts.
• By far, the most abundant phytochemicals present in the pomegranate fruit (arils and peels) are polyphenols, while the seeds contain fatty acids and triglycerides
• Pomegranate peel extracts are particularly rich with phytobiotics such as hydrolysable tannins (ellagitannin, punicalagin, punicalin, gallic and ellagic acid), flavonoids, anthocyanins and other phenols. These polyphenols possess a wide range of biologic properties including anti-inflammatory, antioxidant, hypoglycemic, lipid-lowering, antihypertensive or antimicrobial effects

The current study is exciting

• It has targeted four major ellagitannins: Punicalin, ellagic acid, gallic acid and punicalin to understand its role in COVID infection.
• The researchers tested binding affinities of these on four protein targets:
  1. Camostat.
  2. Lopinavir.
  3. Umifenovir.
  4. Pomegranate peel extracts.
• The four proteins target:
  1. SARS-CoV-2 spike glycoprotein.
  2. Furin.
  3. ACE-2. 
  4. Transmembrane serine protease 2 (TMPRSS2).

What we know about Virus Entry

• The structure of SARS-CoV-2 virus is well determined and the virus itself is composed of four main structural proteins such as spike (S) glycoprotein, small envelope (E) glycoprotein, membrane (M) glycoprotein and nucleocapsid (N) protein.
• The S glycoprotein, which is incorporated into the viral envelope, is crucial for virus binding to a specific receptor and fusion with target host cells.
• It has already been well established that SARS-CoV-2 virus enters the cells of the respiratory system by interacting with angiotensin-converting enzyme 2 (ACE2) as its specific receptor.
• One of these is the enzyme transmembrane serine protease 2 (TMPRSS2) which is, together with ACE2, required for SARS-CoV-2 cell entry.
• Both of these enzymes are highly expressed on the surface of the epithelial cells of the respiratory system, and after the fusion the TMPRSS2 will cleave the S glycoprotein.
• However, it has become evident that the S glycoprotein is activated by a two-step process requiring another enzyme, furin.
• It is clear that in addition to the ACE2, the furin/TMPRSS2 coexistence is a crucial human host factor for the SARS-CoV-2 infection, and these proteases are potential therapeutic targets for the coronavirus infection.
• Different substances, like camostat mesylate as a TMPRSS2 inhibitor, as well as several furin inhibitors, could potentially attenuate or block the virus entry process

Evidence so far

• Several studies have reported the inhibitory effect of pomegranate extracts on the influenza virus, herpes virus, poxviruses and human immunodeficiency virus .
• In a computational study the pomegranate ligand molecules, namely the punicalagin, punicalin and ellagic acid, showed a strong interaction with the catalytic and substrate binding residues of the hepatitis C virus (HCV) NS3/4A protease.
• Recent in vitro studies have shown that the antiviral effect of pomegranate peel extracts (PoPEx) on influenza virus is associated with the inhibition of viral absorption and RNA transcription  

What study reveals

• In a new study, published as “Computational study of pomegranate peel extract polyphenols as potential inhibitors of SARS-CoV-2 virus internalization” in Mol Cell Biochem (2020) some exciting scenarios hava emerged.
• The S glycoprotein, ACE2, furin and TMPRSS2 were selected as known key proteins for SARS-CoV-2 virus internalization and as relevant therapy targets.
• Researchers used the crystal structures of furin and ACE2 in a complex with the S glycoprotein 
• Constituents of pomegranate peel extracts such as punicalagin and punicalin show significant potential in interacting with the selected protein targets.
• This could prevent viral entry into the host cell.
• Punicalagin and punicalin formed the most stable complexes with the protein targets.
• It also showed intensive interactions with TMPRSS2 amino acid residues.

How they took it

The powdered pomegranate extract (Dermogranate^®) employed in this study was provided by Medinutrex (Catania, Italy).

How they made extract

1. The extract was prepared from dried and grinded pomegranate fruits.
2. Then it was mixed with hydroalcoholic solutions (food grade).
3. Next, it was filtered.
4. The filtrate was further concentrated and spray-dried to obtain the standardized extract.
5. The Dermogranate extract’s chemical composition: total polyphenols (16%), punicalagins (8%), ellagic acid, and derivatives (8%).

What we see as waste is extraordinary nutrient

• It tempts from this study to use peels of this unique fruit. We can preserve it and make it dry in 3 to 5 days. Then we can use a grinder to powder it.
• No standard study exists to scientifically recommend that how much extract is useful to a particular disorder.
• However, animal safety studies and some human studies are available with commercially available extract and juice.
• Many herbal companies sell it for various disorders.
• But numerous scientific studies are available with pomegranate in inflammatory disorders, cardio-metabolic disorders, various cancers, erectile disorder etc.

CME INDIA Learning Points

• Although it has not been definitively established whether high values of viral load correspond to more severe symptoms, the virus entry process represents a crucial step in the SARS-CoV-2 infection and research activities seek to identify specific binders that would be able to block the viral entry proteins.
• In the protein structure, sites with certain physicochemical and spatial characteristics are a prerequisite for a stable interaction between proteins and ligands.
• Non-polar amino acid ratios for selected ACE2, furin and TMPRSS2 pockets were lower than for the second ranged predicted pockets in the present study. The best drug score (0.84) was revealed for TMPRSS2. Recent studies confirmed the DogSiteScorer capability to identify pocket active sites at the newly determined SARS-CoV-2 crystal structures.
• The results described in the present study highlight the potential inhibitory activity of POM Ex polyphenols against the SARS-CoV-2 internalization process.
• PMPEx constituents, i.e., punicalagin and punicalin are promising candidates for further anti-SARS-CoV-2 in vitro studies.
• Being the ingredients of a natural product that is used as food, these candidates also have a confirmed safety profile.
• Pomegranate polyphenol extracts, up to 1400 mg appear to be safe, though most of the clinical trials that have shown significant beneficial effects with pomegranate juice have been made commercially or carefully extracted under controlled laboratory settings by the researchers.
• Pomegranate is one among the highly explored and appreciated fruits on account of its promising health-promoting and disease-preventing properties.
• Pomegranate fruit and its key components including rind, seed, and membranous network have been evidently reported as carriers of a wide range of bioactive compounds including ellagitannins, hydroxycinnamic acids, hydroxybenzoic acids, flavons, flavonol-3-ols, anthocyanidins, anthocyanins, and conjugated and nonconjugated fatty acids, phytosterols, vitamins, and minerals.
• Findings of the research carried out in the last two decades manifest fruit, flower, seeds, and peel of pomegranate as natural strategy to treat microbiological and parasitic pathogenesis and to act as a chemo-preventive and therapeutic approach against inflammatory and infectious chronic ailments.
• In current perspective, there is no hesitation to recommend to take one pomegranates fruit daily and collect its peel to make extract.

CME INDIA Tail Piece

• Pomegranate extract – effective in reducing mRNA expression levels of Adiponectin, IL-6, FAS, and in upregulating IL-10.
• Studies suggest that pomegranate and other bioactive compounds present in its juice show anti-inflammatory effects in vitro, and that the mechanisms involved appear to be related to inactivation of NF-κB signaling.
• Several lines of experimental and clinical evidence have shown that pomegranate intake helps in lowering blood pressure (BP) through different mechanisms.
• There is evidence that pomegranate has a putative anticancerogenic effect in prostate cancer and can safely be used in high doses.
• Pomegranate juice, rich in polyphenols, can reduce postprandial blood glucose spikes when consumed with bread as a digestible carbohydrate source.
• The effect of the juice is comparable to the nonabsorbed drug acarbose, which is administered to diabetic patients to limit postprandial glucose excursions. It has been shown that pomegranate polyphenols, when present in a beverage but not a supplement, can reduce the acute postprandial glycemic response of bread, and we propose that this is primarily because of the ability of punicalagin to inhibit α-amylase.
• Pomegranate polyphenol microbial metabolites may modulate sugar metabolism after the acute postprandial period.

Further Reading:

1. Suručić, R., Tubić, B., Stojiljković, M.P. et al. Computational study of pomegranate peel extract polyphenols as potential inhibitors of SARS-CoV-2 virus internalization. Mol Cell Biochem (2020). https://doi.org/10.1007/s11010-020-03981-7
2. Asimina Kerimi, Hilda Nyambe-Silavwe, Julia S Gauer, Francisco A Tomás-Barberán, Gary Williamson, Pomegranate juice, but not an extract, confers a lower glycemic response on a high–glycemic index food: randomized, crossover, controlled trials in healthy subjects, The American Journal of Clinical Nutrition, Volume 106, Issue 6, December 2017, Pages 1384–1393
3. Pomegranate juice: A heart-healthy fruit juiceFebruary 2009.Nutrition Reviews 67(1):49-56DOI: 10.1111/j.1753-4887.2008.00133.x

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