Pomegranate has been traditionally used for thousands of years to treat various diseases. It contains powerful antioxidants and anti-inflammatory compounds that may help attenuate SARS-CoV-2 and its clinical outcomes. Specifically, pomegranate polyphenols can inhibit the three main mechanisms SARS-CoV-2 uses to enter host cells, as well as reduce viral replication, modulate the inflammatory response to prevent acute respiratory distress syndrome (ARDS), and induce apoptosis of infected cells. Due to these diverse mechanisms of action, pomegranate may be an effective natural therapy for managing COVID-19 infections and reducing mortality.

1. BY
DR. DINESH AMARASEKARA
1

2. TANGY, SOUR AND SWEET, ALL AT THE
SAME TIME, THE POMEGRANATE IS THE
TRUE HARBINGER OF THE AUTUMN
 Pomegranate has been used for thousands of years to cure a wide range of
diseases across different cultures and civilizations
 In indigenous medicine pomegranate is considered ‘a pharmacy unto itself’
 It was lauded in ancient times in the old testament of bible, the Jewish
Torah, and the Babylonian Talmud as a sacred fruit confirming power of
fertility, abundance and good luck.
2

3. 3
 Phytochemicals of pomegranates can be successfully used in controlling the various types of
carcinomas out of which some share the same biological pathways as that of SARS COV-2
 ARDS is the leading course of the death in SARS COV-2 infection which is associated with the
upregulation of proinflammatory cytokines expression which is called cytokine storm.
 Pomegranate juice and peel extracts contained 124 different types of antioxidants and
bioactive substance like polyphenols which can attenuate SARS COV-2 and its clinical outcome.

4. CHEMICAL COMPOSITION OF POMEGRANATE
4

5. HOW POLYPHENOLS OF POMEGRANATE
INTERACTS WITH SARS COV2
5

6. COVID 19 INFECTION
 Caused by SARS COV-2 virus
 Newly emerge SARS COV-2 pandemic affected more than ten million world population
 Most of the fatalities was due to multi organ failure following acute respiratory distress syndrome (ARDS).
 There were several endemics due to corona virus in the recent history
1) Severe acute respiratory distress syndrome corona virus SARS COV
2) Middle east respiratory syndrome corona virus MERS-COV
 Source of origin and exact pathogenicity SARS COV-2 is not fully understood up to the date.
6

7.  SARS COV-2 - beta corona virus
 80% mild illness
 14% lung involvement with dyspnea and hypoxia.
 5% develop ARDS, shock and multi organ dysfunction.
 Average death rate - 2.3% , can vary from 01 to 9 %.
 It has four structural proteins which are similar to other corona viruses. Spike (s), Envelop(e),
Membrane(m) and Nucleocapsid(n) proteins
7
COVID 19… Continued

8. STRUCTURE OF SARS COV-2
8

9. 9
 Spike proteins are cleavage into S1 and S2 subunits by host cell proteases
 S1 contained receptor binding domain for antigen converting enzyme 2(ACE2) to bind with host cell
leading to viral infection
 In SARS COV-2 spike proteins is cleavage into S1 and S2 subunits by the host cell protease, most
evidently by TMPRSS2 (Trance Membrane Protein Serine S2)
 Less evidently by Cathepsin and Furin
STRUCTURE OF SARS COV-2

10. POSSIBLE
CLEAVAGE
MECHANISMS
(A) STRUCTURES OF THREE COMMON HOST CELL
PROTEASES KNOWN TO ACTIVATE
CORONAVIRUS TRYPSIN , FURIN AND
CATHEPSIN L
(B) DIAGRAM OF A CORONAVIRUS LIFE CYCLE AND
THE VARIOUS HOST CELL PROTEASES KNOWN
TO CLEAVE AND ACTIVATE SOME
CORONAVIRUS S PROTEINS. INHIBITORS OF
HOST CELL PROTEASES, INCLUDING TMPRSS2,
CATHEPSINS AND FURIN, HAVE BEEN
PROPOSED AS POTENTIAL ANTIVIRAL
THERAPEUTICS FOR CORONAVIRUS
INFECTIONS
A
B
10

11. MAIN PATHOPHYSIOLOGICAL SEQUENCES OF SARS
COV-19 INFECTION
1. Rapid viral replication
2. Cytokine storm
3. Immune dysfunction
4. Oxidative stress and
5. Delayed apoptosis
 Pomegranate fruit extract may be effective in each and every step of SARS COV-2 infection and its
clinical outcome.
11

12. ELLAGITANNIN OF POMEGRANATE CAN
INHIBIT THE TMPRSS2
TMPRSS2 is essential for viral entry in to host cells. (This gene expression is up regulated in androgen
dependent prostatic cancers)
Ellagitannin of pomegranate can inhibit the TMPRSS2.
Pomegranate juice obtained by squeezing the whole fruit has the highest concentration of
ellagitannins than any commonly consumed juice.
Pomegranate extract rich in ellagitannin inhibits the viral entry.
12

13.  Furin is a serine protease which is also suggested to mediates the cleavage of the spike protein
in to S1 and S2 sub units during viral entry
 SARS COV-2 spike protein harbors a Furin cleavage site at S1/S2 boundary which is not available
in other corona viruses.
 Furin is abundant in respiratory tract. SARS COV-2 may successfully exploit Furin to activate
surface glycoproteins to its pathogenicity.
Quercetin and epigallocatechin gallate (EGCC) which are found in pomegranate can inhibit
Furin and thereby inhibit the viral entry in to the host cells.
QUERCETIN AND EPIGALLOCATECHIN GALLATE
(EGCC) INHIBITS FURIN
13

14.  CATHEPSINS Found in endosomes and lysosomes and function as degradative enzymes
 Cathepsin selectively cleave protein by cutting the peptide bonds that links specific amino acids
 It may mediate the membrane fusion function and cleavage of the spike proteins
Pomegranate peel extract shows strong inhibitory effect on cathepsin activity. Cathepsin
inhibitory properties of pomegranate fruit extract may be a potential mechanism which can be
utilize to prevent viral entry in to the host cell
POMEGRANATE PEEL EXTRACT SHOWS STRONG
INHIBITORY EFFECT ON CATHEPSIN
14

15. POMEGRANATE INHIBITS ALL 03 POSSIBLE
CLEAVAGE MECHANISMS OF SARS COV-2
15
TMPRSS2
FURIN
CATHEPSIN

16. VIRAL ENTRY
 Is mediated by binding of the spike (s) protein with cell surface angiotensin converting enzyme
2 (ACE2) receptors
 ACE2 can be found in lungs, heart, kidneys and intestine
 The highest density of ACE2 can be found in type 2 pneumocyte of alveoli
 SARS COV-2 shows twenty times more affinity to ACE2 than SARS virus
 After entering genomic RNA (RNA+) release in to host cell cytoplasm. The genomic RNA is used
to make RNA dependent RNA polymerase which regulate the production of new genomic RNA’s
16

17. VIRAL REPLICATION
17

18. ZINK BLOCK THE RNA DEPENDENT RNA
POLYMERASE
RNA Dependent RNA Polymerase (RDRP) of sars-cov-2 is essential for viral replication
Zink block the RDRP.
• Pomegranate is the second-best source of zinc behind the avocado
• Quercetin and Epigallocatechin-gallate of pomegranate fruit extract function as a zinc
ionophores to facilitate transportation of zinc across the cell membrane.
• Therefor consumption of pomegranate may reduce the viral replication.
18

19. POMEGRANATE EXTRACT DOWN REGULATES
THE VALOSIN CONTAINING PROTEIN (VCP)
EXPRESSION
 VCP Is belongs to ATPase super family. Genome-wide screen reveals VCP requirement for
coronavirus exit from endosomes. Inhibition of a VCP resulted in virus accumulation in early
endosome
 Pomegranate extract down regulates the VCP expression and thereby reduce the virus release
from endosome. Decrease in expression of VCP also reduces the effects of NF-kB induced
inflammatory cascade
20

20. LUTEOLIN AND KAEMPFEROL INDUCE
APOPTOSIS
 Delayed apoptosis
 Apoptosis is a host defense mechanism against viral replication and proliferation.
 Vires can inhibit apoptotic pathway, thereby prolong the survival of virus inside the host cells
to maximize the production of virus progeny
21

21. LUTEOLIN AND KAEMPFEROL INDUCE
APOPTOSIS
 Luteolin and Kaempferol can be found in the pomegranate. Both substances can induce
apoptosis via several mechanisms
 Increase intracellular Reactive oxygen species (ROS) levels and induce apoptosis
 Decrease the Bcl2/Bax ratio in viral infected cells promote cell death
 Trigger activation of p53
 (The p53 transcription factor prevents tumor development through induction of cell cycle arrest
and cell death by apoptosis. As many as several hundreds of genes or more are regulated by
p53. Some virus delays the apoptosis by inhibition of p53. Kaempferol and Luteolin trigger
activation of p53)
22

22. INHIBITION
ACTIVATIO
N

23. DELPHINIDIN INHIBITS INTERGRINS/PI-
3K/MAPK
 INTEGRINS Are heterogenic cell surface receptors. They are involved in cells adhesion, migration,
signaling, and angiogenesis.
 Binding spike protein with integrin heteromers activate transduction pathways involving
phosphatidylinositol-3-kinase (pi-3k) or Mitogen Activator Protein Kinase (MAPK) which promote the
viral entry
 Rgd motif of the spike protein of the SARS COV-2 shows a strong affinity to integrins, particularly
𝛼𝑣𝛽3. Rgd motif is absent in all other corona viruses. It is believed integrins may work as alternative
receptor for SARS COV-2 entry
 Delphinidin of pomegranate extract has proven to be effective in inhibition of intergrins, pi-3k and
MAPK expression. Therefore, delphinidin is a potential molecule which can prevent SARS COV-2
entry in to host cell by blockage of above-mentioned mechanism.
24

24. PUNICALAGIN OF POMEGRANATE RESTORE NK CELL
FUNCTIONS
• Total number of NK cells and Their functions are markedly depleted COVID-19 infection.
• Functions of the NK cells are exhausted with the increased expression of NKG2A.
• NKG2A is a ligand which binds to inhibitory NK cells receptor (iNKR’s) and suppress the NK cells.
PUNICALAGIN OF POMEGRANATE JUICE DOWN REGULATE EXPRESSION OF NKG2A

25. 26
HOW POLYPHENOL'S OF POMEGRANATE
INVOLVE IN ATTENUATION OF
INFLAMMATION AND PREVENT ARDS IN SARS
COV-2

26. SARS COV-2 DOWN REGULATE ACE2 AND
UPREGULATE ACE1
27
 SARS COV-2 spike protein binds to the. ACE2
which is a natural protector against lung injury.
 With the viral infection ACE2 is down regulated
and in compensation ACE 1 is up regulated.
Excess amount of angiotensin 2 production via
ACE1
 Uncontrolled angiotensin 2 cause over
stimulation of type 1a angiotensin receptors
(AGTR 1a) leading to increase vascular
permeability in the lungs witch leads to ARDS.

27. CYTOKINE STORM
 ARDS is associated with up regulation of pro inflammatory cytokines production called ‘cytokine
storm’
 Interleukin 1𝛽. Il-1, il-6, il-8, cc chemokine ligand 2 (ccl-2), cxc chemokine ligand 10 (cxcl-10),
interferon 𝛼(anti-viral substance release from the infected cells), interferon−𝛾 (anti-viral
substance release from the immune cells)’
 Initial onset of rapid viral replication causes massive epithelial and endothelial damage are
those which associate with hypercytokinemia and increase mononuclear macrophages and
neutrophil infiltration
28

28. THE MAJOR ANTHOCYANINS OF
POMEGRANATE INHIBIT NUCLEAR FACTOR
KAPPA BETA (NF-kB)
• Nuclear factor kappa beta (NF-kB) is a transcription protein complex.
• NF-κB pathway involves viral replication, delaying apoptosis and
modulating host immune response which leads to increase production
of IL-2, IL-6, IL-8, TNF-𝛼
Delphinidin, Cyanidin, Pelargonidin, the major anthocyanins of
pomegranate juice show potent inhibitory effects on NF-kB
ARDS

29. MAJOR ANTHOCYANINS OF THE POMEGRANATE
INHIBITS VASCULAR ENDOTHELIAL GROWTH
FACTOR (VEGF)
 Vascular Endothelial Growth Factor (VEGF) pays a pivotal role in
both angiogenesis and microvascular permeability in ARDS acute
lung injury (ALI)
 Major anthocyanins of the pomegranate peel have shown to
suppress VEGF via following pathways.
 Delphinidin inhibit TNF𝛼 induced VEGF receptor expression in
endothelial cells whereas ellagitannin inhibit VEGF via PIK/akt
pathway.
30

30. DELPHINIDIN VS FIBROBLAST GROWTH FACTORS (FGF)
• Fibroblast growth factors (FGF) directly corelate with morbidity and mortality in ARDS.
Delphinidin of pomegranate peel extract has proven its regulatory potentials in pathological
conditions associated with over expression of FGF in number of clinical studies.

31. VEGF/FGF
Activation of Inflammatory
markers
Activation of PIK3/AKT
Activation eNOS
Activation of
Prostaglandins (PGs)
Over-expression of VEGF
and FGF - 2
Angiogenesis
ARDS

32. ANTHOCYANINS OF POMEGRANATE
STIMULATE TISSUE INHIBITORS OF MMPS
(TIMP-2)
 Matrix metalloproteinases (MMPS) involved in degradation of extracellular matrix.
 These molecules can act independently and in coordinate manner via activation of tyrosine
regulatory pathway in development of ARDS
Anthocyanins of pomegranate stimulate tissue inhibitors of MMPS (TIMP-2) and Plasminogen
Activator Inhibitor (PAI) both of which counteract MMPS and Urokinase Plasminogen Activator UPA
33

33.  P38 Mitogen-activated protein kinase (p38 MAPK) belongs to the map kinase superfamily.
 Activation of p38 MAPK has been reportecells infected with SARS-COV
 p38 MAPK inhibitors can suppress Il-6 and TNF-𝛼 expression in monocytes and mast cells.
 p38 MAPK signaling pathway supposed to be one of the main mechanisms of acute lung
injury and ARDS
DELPHINIDIN OF POMEGRANATE EXTRACT INHIBITS p38 MAPK PATHWAY
DELPHINIDIN OF POMEGRANATE INHIBITS P38
MAPK SIGNALIN PATHWAY
34

34. Cytokine storm
SARS COV-2

35. FLAVONOIDS OF POMEGRANATE REDUCE THE
OXIDATIVE STRESS
Free radicals can attract inflammatory mediators which contribute to the inflammatory response
and tissue damage in ARDS.
• Flavonoids can interfere with different free radical forming pathways.
1. direct radical scavenging
2. nitric oxide pathway
3. xanthene oxidase pathway
It has been shown when pomegranate whole fruit extract given to the patient with acute
inflammation, it causes reduction of serum Malonaldehyde levels which is a biological marker of
oxidative stress in cell membrane injury

37. ANTHOCYANINS INHIBITS ICAM-1 AND
VCAM-1
• Upon cytokine stimulation, ICAM-1 (intra cellular adhesion molecule) and VCAM-1 (vascular cell
adhesion molecule) expression significantly upregulated in ARDS.
• ICAM‐1, and VCAM‐1 are implicated in the interactions between leukocytes and the
endothelium during the inflammatory process what is called the “adhesion cascade”.
Delphinidin, Cyanidin, Pelargonidin and their metabolites have shown strong inhibitory effects on
ICAM-1 and VCAM-1.
Gallic acid which is abundant in pomegranate peel, decrease the expression of ICAM-1 and VCAM-
1

38. OTHER MECHANISMS WHICH INVOLVE IN
ATTENUATION OF INFLAMMATION AND PREVENT
ARDS IN SARS COV-2
• COX-2 is the enzyme largely responsible for causing inflammation. Delphinidin inhibits TNF α induce
expression of COX-2.
• Delphinidin directly bind with Fyn kinase and inhibit its function. Fyn kinase
inhibitors has shown to be effective treatment in SARS.
• Punicalagin attenuate the lipopolysaccharide (LPS) induce release of NO, TNF 𝛼 and
IL6 in the setting of acute inflammation.
• Heme oxygenase 1(HO-1) activation through pi3k/akt pathway plays critical role in
protection of lungs in oxidative injury in the setting of sepsis. punicalagin shows
antioxidant activity via increasing N𝛾F2 mediated HO-1 expression and pi3k/akt
mediated HO-1 expression.

39. CONCLUSION
 Rapid viral replication, cytokine storm, immune dysfunction, oxidative stress, delayed apoptosis are
the main pathophysiological sequences of SARS COV-19 infection
 In conclusion this study provides new insight about the mechanisms by which varies types of
polyphenols of pomegranate extract works against SARS COV-2 infection and viral induce inflammatory
reaction
 We suggest further study preferably in vivo is necessary to determine whether or to what extent,
the polyphenols of pomegranate and their metabolites play roles in prevention and management of
SARS COVID 19 infection.
 With the back ground of tremendous impact of SARS COV-2 infection on global health and with the
paucity or lack of therapeutic measures, it is worth trying pomegranate juice and peel extract as a
prophylactic, anti-viral and anti-inflammatory agent based on the available knowledge as it has been
used in several systems of medicine since antient time without significant side effects. 40

40. 41
POMEGRANATE
WHOLE FRUIT IS THE HOLI FRUIT FOR

41. EAT POMEGRA DAY
KEEP COVID AWAY
POMEG IN THE MORNING
DR. DINESH’S WARNING //
POMEG AT NIGHT
KILL THE COVID OUT RIGHT
POMEG WITH BLENDED PEEL
COVID WILL INSTANT HEAL
EAT EACH DAY SEVEN DAYS A WEEK
READY ALL READY TO HEAL

42. THANK YOU!
43
Dr.Dinesh Amarasekara
Department of Urology
Sri Lanka National Hospital, Colombo.
E mail. ddnanditha@gmail.com
ddnanditha@yahoo.com
Phone No. +94716890949
Address. 420/32, ‘Sanketha’,
Walipara,Thalawathugoda,Colombo
Sri Lanka.
Zip Coad 10116