Garcinol from Garcinia indica inhibits HIV-1 reverse transcriptase-associated ribonuclease H

Article abstract of DOI:10.1002/ardp.202100123

The bioactive components of Garcinia indica, garcinol (camboginol), and isogarcinol (cambogin), are suitable drug candidates for the treatment of various human diseases. HIV-1-RNase H assay was used to study the RNase H inhibition by garcinol and isogarci

Full text of DOI:10.1002/ardp.202100123

Received: 29 March 2021
Revised: 20 April 2021
Accepted: 23 April 2021
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DOI: 10.1002/ardp.202100123
F U L L P A P E R
Garcinol from Garcinia indica inhibits HIV‐1 reverse
transcriptase‐associated ribonuclease H
Angela Corona1
Andrea Volkamer3
| Sebastian Seibt2 | David Schaller3 | Rainer Schobert2
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| Bernhard Biersack2
| Enzo Tramontano1,4
1Laboratorio di Virologia Molecolare,
Dipartimento di Scienze della Vita e
Dell'Ambiente, Universitá degli Studi di
Cagliari, Monserrato, Italy
Abstract
The bioactive components of Garcinia indica, garcinol (camboginol), and isogarcinol
(cambogin), are suitable drug candidates for the treatment of various human dis-
eases. HIV‐1‐RNase H assay was used to study the RNase H inhibition by garcinol
and isogarcinol. Docking of garcinol into the active site of the enzyme was carried
out to rationalize the difference in activities between the two compounds. Garcinol
showed higher HIV‐1‐RNase H inhibition than the known inhibitor RDS1759 and
retained full potency against the RNase H of a drug‐resistant HIV‐1 reverse tran-
scriptase form. Isogarcinol was distinctly less active than garcinol, indicating the
importance of the enolizable β‐diketone moiety of garcinol for anti‐RNase H ac-
tivity. Docking calculations confirmed these findings and suggested this moiety to be
involved in the chelation of metal ions of the active site. On the basis of its HIV‐1
reverse transcriptase‐associated RNase H inhibitory activity, garcinol is worth being
further explored concerning its potential as a cost‐effective treatment for HIV
patients.
2Organic Chemistry Laboratory, University of
Bayreuth, Bayreuth, Germany
3In Silico Toxicology and Structural
Bioinformatics, Institute of Physiology,
Charité‐Universitätsmedizin Berlin, Berlin,
Germany
4Istituto di Ricerca Genetica e Biomedica,
Consiglio Nazionale delle Ricerche (CNR),
Monserrato, Cagliari, Italy
Correspondence
Angela Corona, Laboratorio di Virologia
Molecolare, Dipartimento di Scienze della Vita
e Dell'Ambiente, Universitá degli Studi di
Cagliari, Cittadella Universitaria di
Monserrato SS554, 09042 Monserrato, Italy.
Email: angela.corona@unica.it
Bernhard Biersack, Organic Chemistry
Laboratory, University of Bayreuth,
Universitätsstrasse 30, 95440 Bayreuth,
Germany.
K E Y W O R D S
antiviral drugs, garcinol, Garcinia indica, HIV, RNase H
Email: bernhard.biersack@yahoo.com
Funding information
Regione Autonoma della Sardegna,
Grant/Award Number: RASSR17032
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1
INTRODUCTION
no effective approach to eradicate HIV‐1 integrated in latently in-
fected tissue reservoirs.[1,2] The progression of HIV infection can
Human immunodeficiency virus comprising type 1 and type 2 (HIV‐1
and HIV‐2) is a widespread virus that infected ca. 37.9 million people
(among them ca. 2.1 million children below 15 years) and resulted in
770,000 deaths worldwide in late 2018 (www.unaids.com). There is
neither vaccine for nor cure of HIV infection until today, and there is
lead to the acquired immunodeficiency syndrome (AIDS) that has
killed about 35 million people worldwide since the first known in-
fections in the 1980s (www.unaids.com). Treatment of HIV infections
is conducted through highly active antiretroviral therapy (HAART),
which mainly includes inhibitors of HIV reverse transcriptase (RT;
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2021 The Authors. Archiv der Pharmazie published by Wiley-VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft
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Arch Pharm. 2021;e2100123.
wileyonlinelibrary.com/journal/ardp
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https://doi.org/10.1002/ardp.202100123

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inhibition of its DNA polymerase subunit RDDP/RNA‐dependent
DNA polymerase), inhibitors of HIV integrase (IN), and inhibitors of
HIV protease. However, side effects of these drugs, together with
the emergence of drug resistance, have become an increasing clinical
problem.[3–5] Coinfection with other infectious diseases such as
leishmaniasis or hepatitis B (HBV) poses another threat also to
people living in underdeveloped countries.[6,7]
Considering the critical healthcare situation in poor countries
and the emergence of drug resistance, new cost‐effective drugs and
treatment options for viral infectious diseases are needed (www.
dndi.org). Natural products from tropical plants have great potential
as easily available drugs against infections and tropical diseases.[17,18]
For ages, traditional folk medicine such as Ayurveda and Traditional
Chinese Medicine have applied numerous plant‐derived drugs for the
treatment of various diseases.[19–21] Garcinia indica (the kokum tree)
is a tree growing along the sunny and fertile western coast of India.
The plum of the kokum tree is a popular sour spice in the Konkan
region and used for the preparation of local sharbats, curries, and
dishes such as “sol kadhi” known to tourists and locals alike. In ad-
dition, Ayurveda practitioners apply kokum‐based drugs for the
treatment of edema and infections.[22,23] The fruit rind of dried ko-
kum plums contains significant amounts (ca. 2.5%) of garcinol (also
called camboginol in the literature) and, to a lesser extent, its isomer
isogarcinol (cambogin), which belong to the type B polycyclic poly-
prenylated acylphloroglucinols or polyprenylated benzophenones
(Figure 1).[24,25] Both garcinol and isogarcinol showed a plethora of
biological activities against cancer, infections, and inflammatory
diseases.[26,27] The activities of garcinol against various in vivo tumor
models were thoroughly investigated and the compound was well
tolerated by laboratory animals at active doses.[28–30] In addition,
garcinol was identified as a natural histone acetyltransferase (HAT)
inhibitor and it suppressed the lysine acetylation of the influenza A
viral nucleoprotein.[31] Histone acetylation/deacetylation is also an
important process in HIV‐infected cells concerning the formation of
latent infection states. Isogarcinol and its semisynthetic derivative
LTK‐14 suppressed HIV transcription based on HAT p300
The identification of new viral drug targets can help to overcome
viral resistance mechanisms. Besides its DNA polymerase unit, the HIV
RT enzyme also harbors an RNase H domain, which, on the one hand,
degrades the RNA strand of the RNA/DNA intermediate during re-
plication in an unspecific way. On the contrary, RNase H catalyzes spe-
cific hydrolysis of RNA primers during the biosynthesis of integration‐
competent proviral DNA.[8] The active site of RNase H contains four
conserved negatively charged amino acids (DEDD motif) with two Mg2+
ions required for catalysis, that is, for hydrolysis of phosphate esters of
target RNAs. Interestingly, the Mg2+ ions could be replaced by Mn2+
,
conserving a functional enzyme, whereas the exchange for Ca2+ ions
inhibited the enzyme.[9,10] Several RNase H inhibitors have been identi-
fied over the last few years. Besides competitive inhibitors of the active
site of HIV (and of HBV) RNase H acting via coordination of the Mg2+
ions in the active site, allosteric inhibitors leading to protein destabili-
zation were described as well.[11] Various natural products such as tri-
terpenes (betulinic acid), lignans (schisandrin B), and prenylated
acylphloroglucinols were identified as RNase H inhibitors.[12–14] More-
over, the HIV‐1 RT‐associated RNase H domain displays a high degree of
conservation among naive and drug‐experienced patients, and its in-
hibition could overcome RT resistance and might pave the way to new
treatment options.[15,16]
FIGURE 1 Structures of garcinol, isogarcinol, and the reference compounds used in this study

CORONA ET AL.
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inhibition.[32,33] Given these promising preliminary findings about the
antiviral activities of garcinol and isogarcinol, we conducted further
investigations to identify new HIV targets of these natural products.
In the present report, we disclose promising results of garcinol
as a natural product to inhibit the RNase H domain of the HIV‐1
reverse transcriptase protein.
TABLE 1 Inhibitory concentrations IC50 (in µM)a of test
compounds when tested against HIV‐1 reverse transcriptase
(RT)‐associated RNase H activity and DNA polymerase (RDDP)
activity against wild‐type and drug‐resistant RTs
HIV‐1 RT
RNase H
HIV‐1 RT
RDDP
HIV‐1 RT K103N‐
K103N‐
Compound RNase H
Y181C
HIV‐1 RT RDDP Y181C
Garcinol 6.6 2.1
8.4 0.4
46.7 10.0
63.7 7.2
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RESULTS AND DISCUSSION
Isogarcinol 29.0 1.4 15.9 7.8 30.3 1.1
20.7 1.6
RDS1759
13
8.7 3.1
5.8 1.3
‐
14.6 2.3 >50
20.4 1.1 >50
‐
Garcinol and isogarcinol were tested for their HIV‐1 RT‐associated
RNase H and DNA polymerase inhibitory activities (Table 1). Their ac-
tivities were compared with the activities of RDS1759 and efavirenz as
positive controls. Garcinol showed significant inhibition of the wild‐type
HIV1‐RNase H (IC50 = 6.6 2.1 µM), comparable to our previously pub-
lished synthetic compound 13 and it was slightly more active than the
positive control RDS1759.[16,34] The activity of garcinol lies in the activity
range of other natural prenylated acylphloroglucinol compounds isolated
from Hypericum scruglii plants growing on Sardinia.[14] Isogarcinol was
found to be distinctly less active than garcinol and RDS1759. Isogarcinol
is the pyrano isomer of garcinol and it seems that the tris‐β‐diketone
moiety of garcinol is necessary for a high inhibitory activity against
RNase H. Garcinol also retained full inhibitory potency against the RNase
H function of the drug‐resistant K103N‐Y181C reverse transcriptase
form in contrast to RDS1759 and compound 13, which showed distinctly
lower activities against the mutant form than against the wild‐type en-
zyme. Although isogarcinol was also less active than garcinol against the
mutant enzyme, it is interesting to note that isogarcinol was ca. twice as
active against the mutant form as against the wild‐type form. In addition,
isogarcinol showed moderate inhibitory activities against the tested HIV‐
1 RDDP enzymes, whereas garcinol was way less active than isogarcinol.
Hence, garcinol showed considerable selectivity for the HIV1 RNase H
‐
Efavirenz
‐
0.051 0.007
0.292 0.75
Note: RDS1759, compound 13, and efavirenz were applied as positive
controls.
aCompound concentration required to reduce the HIV‐1 RT‐associated
RNase H activity or RDDP activity by 50%.
enzymes when compared with the HIV‐1 RDDP enzymes used in this
study.
To rationalize the observed difference in inhibitory efficacies of
garcinol and isogarcinol concerning the HIV‐1 RNase H enzymatic
activity, molecular docking was performed for both compounds in
the RNase H domain present in the PDB structure 4GAQ.[35] Inter-
estingly, garcinol features an enol conjugated to two carbonyl
groups, which gives rise to several keto–enol tautomers, whose de-
protonated conjugate bases are identical mesomers. To consider this,
all likely tautomers and protonation states were enumerated and
docked using functionalities from the OpenEye toolkit 2020.2.0.
The most favorable docking pose of garcinol in terms of mole-
cular interactions identified with LigandScout 4.4 involves chelation
FIGURE 2 Predicted docking pose of
garcinol in the HIV RNase H domain of the
PDB structure 4GAQ.[35] Ligand carbon atoms
are colored in orange, protein carbon atoms in
white, all oxygen atoms in red, and all nitrogen
atoms in blue. Highlighted residues (sticks) are
involved in interactions with garcinol or are
chelating the manganese ions. Interaction
types: Magenta cones—manganese binding
location, red star—negative ionizable, red
arrows—hydrogen bond acceptors, green
arrows—hydrogen bond donors, yellow
spheres—hydrophobic contact, blue spheres—
manganese ions

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CORONA ET AL.
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of the cocrystallized Mn2+ ions in the active site by the hydroxylate
and an adjacent carbonyl group (Figure 2). In addition, we observed
hydrogen bonds with ALA446, ARG448, ASN474, and ARG557, also
proven to be involved in compound 13 binding as well as hydro-
phobic contacts with ALA445 and ALA538.[16] The critical deproto-
natable hydroxyl group of garcinol involved in chelation of the Mn2+
ions is not present in isogarcinol (Figures 1 and 2). Thus, the missing
negative charge in isogarcinol may cause a weaker interaction with
the Mn2+ ions of the enzyme and, consequently, a decreased in-
hibitory activity of isogarcinol. In addition, the observed activity
difference is also reflected by the MMFF94 binding enthalpy as
calculated with LigandScout 4.4 (the lower the better), that is,
−181.50 kcal/mol for the selected docking pose of garcinol (Figure 2)
and −94.34 kcal/mol for the lowest energy docking pose of
isogarcinol.
The suspension was filtered, methanol (1 L) was added to the kokum
residue, and the suspension was stirred again at room temperature for
24 h. The suspension was filtered and the combined methanol extracts
were concentrated in vacuum. Water (1 L) was added to the con-
centrated extract and the aqueous solution was extracted with ethyl
acetate (4 × 500 ml). The organic phases were dried over Na2SO4, fil-
tered, and the filtrate was concentrated in vacuum. The obtained residue
was purified by column chromatography (silica gel 60; ethyl acetate/n‐
hexane 3:7, v/v) and recrystallized from n‐hexane. Yield: 5.5 g; yellow
solid; Rf = 0.37 (ethyl acetate/n‐hexane 3:7); 1H NMR (nuclear magnetic
resonance) (300 MHz, MeOD/1% TFA) δ 0.92 (3 H, s), 1.00 (3 H, s), 1.17
(3 H, s), 1.27 (3 H, s), 1.59 (3 H, s), 1.61 (3 H, s), 1.65 (3 H, s), 1.69 (3 H, s),
1.71 (3 H, s), 1.0–2.8 (12 H, m), 3.0–3.1 (1 H, m), 4.9–5.2 (3 H, m), 6.75 (1
H, d, J = 8.3 Hz), 7.05 (1 H, dd, J = 8.3 Hz, 2.1 Hz), and 7.26 (1 H, d,
J = 2.1 Hz); 13C NMR (75 MHz, MeOD/1% TFA) δ 18.2, 18.4, 18.8, 21.7,
23.0, 26.3, 26.6, 26.8, 27.2, 29.2, 29.4, 30.7, 40.3, 44.7, 47.2, 47.6, 50.0,
52.8, 69.6, 88.4, 115.8, 116.4, 121.3, 123.1, 124.5, 126.5, 126.7, 131.3,
134.1, 134.8, 135.6, 151.1, 152.7, 173.8, 194.4, 196.4, and 208.1.
Isogarcinol was prepared as a colorless solid upon treatment of
garcinol with diluted hydrochloric acid in toluene.[26] Garcinol (2.5 g,
4.25 mmol) was dissolved in toluene (24 ml) and concentrated HCl
(1 ml) was added. After stirring at room temperature for 15 h, the
reaction mixture was kept in a refrigerator. The precipitated solid
was collected and recrystallized from acetonitrile. Yield: 800 mg
(1.36 mmol, 32%); colorless solid; 1H NMR (300 MHz, deuterated
dimethyle sulfoxide [DMSO‐d6]) δ 0.84 (3 H, s), 0.90 (3 H, s), 1.05
(3 H, s), 1.19 (3 H, s), 1.50 (3 H, s), 1.52 (3 H, s), 1.59 (3 H, s), 1.60
(3 H, s), 1.66 (3 H, s), 0.8–2.8 (12 H, m), 2.8–2.9 (1 H, m), 4.8–5.2 (3 H,
m), 6.72 (1 H, d, J = 8.3 Hz), 6.93 (1 H, dd, J = 8.3 Hz, 2.2 Hz), and 7.13
(1 H, d, J = 2.2 Hz); 13C NMR (75 MHz, DMSO‐d6) δ 17.8, 17.9, 18.4,
21.0, 22.7, 25.6, 25.7, 26.1, 26.2, 28.3, 29.2, 30.5, 42.2, 42.7, 45.2,
45.6, 50.6, 51.1, 67.5, 86.3, 115.1, 117.4, 120.5, 121.9, 125.1, 125.3,
125.6, 132.5, 133.0, 133.2, 136.0, 151.4, 153.3, 170.9, 188.6, 198.3,
and 207.0.
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3
CONCLUSIONS
Garcinol showed a significant HIV‐1 RT‐associated RNase H in-
hibitory activity, and docking calculations suggest the relevance of
the metal ion‐chelating enolizable tris‐β‐diketone fragment of gar-
cinol, which is absent in the less active isogarcinol due to the pyran
ring closure. Thus, the antiviral activity of garcinol is worth being
further explored in ex vivo and in vivo models, with the perspective
of its formulation as a cost‐effective HIV treatment, in particular, in
cases where resistance of RT occurred. As already mentioned above,
previous in vivo studies concluded that garcinol is a safe and well‐
tolerated drug candidate.[28–30] These promising in vivo results
warrant further investigation of garcinol as a potential antiviral drug
candidate although in vitro assays with tumor cell lines revealed
considerable cytotoxicity for it and its manifold antitumor activities
are indeed well described.[28,30,36,37] Furthermore, a chemical fine‐
tuning of garcinol might improve its affinity for HIV‐1 RT‐associated
RNase H and related viral ribonucleases with Mg2+‐dependent active
sites. For instance, the exonuclease activity of coronavirus Nsp14
protein depends on Mg2+ and can be a highly relevant target for such
metal‐chelating compounds in future studies.[38] In case of oral ad-
ministration of garcinol, enteric coating formulations should be
considered, as garcinol might otherwise isomerize to the less active
isogarcinol under acidic conditions.
Analytical data of garcinol and isogarcinol correlated with pub-
lished data and the compounds were used for the following biological
studies.[32,39] The SYBYL line notation, together with selected ac-
tivity data, is provided as Supporting Information. Efavirenz was
purchased from Sigma‐Aldrich. RDS1759 and compound 13 were
kindly provided by Prof. Di Santo and Prof. Carcelli, and were pre-
pared following literature procedures.[34,40]
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4
EXPERIMENTAL
General
4.2
HIV1‐RDDP‐independent RNase H inhibition
and RDDP inhibition assays
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4.1
HIV‐1 RT‐associated RNase H inhibition and RDDP inhibition assays
were carried out as described previously.[41,42] Briefly, anti‐RNase H ac-
tivity was measured in 100 µl reaction volume containing 50 mM
Tris‐HCl buffer pH 7.8, 6 mM MgCl2, 1 mM dithiothreitol (DTT), 80 mM
KCl, and HIV‐1 RT. Reaction was started adding hybrid RNA/DNA
5ʹ‐GAUCUGAGCCUGGGAGCU‐fluorescein‐3ʹ (high‐performance liquid
chromatoghraphy [HPLC], dry, QC: Mass Check) (available from
Dried kokum plums (Garcinia indica) were purchased from Santulan
Ayurveda GmbH (Munich, imported from Maharashtra, India). Garcinol
(camboginol) was isolated from dried kokum plums as a yellow solid
according to literature procedures.[26] The dried kokum plums (500 g)
were chopped, methanol (1 L) was added to the chopped plums, and the
suspension was stirred with a KPG stirrer at room temperature for 24 h.

CORONA ET AL.
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Metabion) and 5ʹ‐dabcyl‐AGCTCCCAGGCTCAGATC‐3ʹ (HPLC, dry, QC:
Mass Check) at a final concentration of 0.25 µM. The reaction mixture
was incubated for 10 min at 37°C in a multilabel counter plate reader
Victor 3 (Model 1420‐051, Perkin Elmer), and the product was quantified
at 490/528 nm (excitation/emission wavelength). The RT‐associated
RDDP activity was measured in 30 µl volume containing 60 mM Tris‐
HCl pH 8.1, 8 mM MgCl2, 60 mM KCl, 13 mM DTT, 100 µM dTTP, 5 nM
HIV‐1 RT, and 2.5 µM poly(A)‐oligo(dT) (EnzCheck Invitrogen). The re-
action mixture was incubated for 30 min at 37°C. The enzymatic reaction
was stopped by addition of EDTA. Reaction products were detected by
picogreen addition and measured with a Victor 3 (Perkin) plate reader at
502/523 nm. All experiments were done in triplicate.
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|
4.3
Molecular modeling
A query of the protein data bank for a high‐resolution structure of the
HIV‐1 RNase H in complex with an active site inhibitor identified the
1.71 Å resolution structure 4QAG.[35,43] This structure was prepared for
docking using OESpruce and OEChem (OpenEye toolkit 2020.2.0) by
protonation at pH 7.4. OEDocking (OpenEye toolkit 2020.2.0) was used
to dock garcinol and isogarcinol into the active site of the prepared HIV
RNase H domain. SMILES notations of both compounds were taken from
PubChem,[44] reasonable tautomeric states were assigned using
OEQuacpac (OpenEye toolkit 2020.2.0), and conformations for each
tautomer were generated using the dense setting from OEOmega
(OpenEye toolkit 2020.2.0). The hybrid protocol was chosen for docking
employing the cocrystallized ligand of 4QAG to bias ligand placement,
which finally led to the generation of 20 docking poses per compound.
Afterward, docking poses were energetically minimized inside the RNase
H binding pocket using LigandScout 4.4 (license kindly provided by Prof.
G. Wolber) and the MMFF94s force field.[45,46]
[12] F. Esposito, C. Sanna, C. del Vecchio, V. Cannas, A. Venditti,
A. Corona, A. Bianco, A. M. Serrilli, L. Guarcini, C. Parolin,
M. Ballero, E. Tramontano, Pathog. Dis. 2013, 68, 116.
[13] L. Xu, N. Grandi, C. del Vecchio, D. Mandas, A. Corona, D. Piano,
F. Esposito, C. Parolin, E. Tramontano, J. Microbiol. 2015, 53, 288.
[14] C. Sanna, M. Scognamiglio, A. Fiorentino, A. Corona, V. Graziani,
A. Caredda, P. Cortis, M. Montisci, E. R. Ceresola, F. Canducci,
F. Poli, E. Tramontano, F. Esposito, PLOS One 2018, 13, e0195168.
[15] A. Schneider, A. Corona, I. Spöring, M. Jordan, B. Buchholz,
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[16] A. Corona, E. Ballana, S. Distinto, D. Rogolino, C. D. Vecchio,
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[19] B. B. Aggarwal, A. B. Kunnumakkara, Molecular Targets and Ther-
apeutic Uses of Spices: Modern Uses for Ancient Medicine, World
Scientific Publishing Co. Pte. Ltd., Singapore 2009.
ACKNOWLEDGMENTS
[20] H. Yuan, Q. Ma, L. Ye, G. Piao, Molecules 2016, 21, 559.
[21] Z. Wang, L. Yang, J. Ethnopharmacol. 2021, 270, 113896.
[22] S. Padhye, A. Ahmad, N. Oswal, F. H. Sarkar, J. Hematol. Oncol. 2009,
2, 38.
The authors thank Nadine Beck for assistance in the preparation of
garcinol and isogarcinol. Angela Corona and Enzo Tramontano were
supported by Regione Autonoma della Sardegna (RAS) (LR 07/2017,
annualità 2017) grant no. RASSR17032. Open Access funding
enabled and organized by Projekt DEAL.
[23] N. Saadat, S. V. Gupta, J. Oncol. 2012, 2012, 647206.
[24] R. Ciochina, R. B. Grossman, Chem. Rev. 2006, 106, 3963.
[25] A. M. Patel, S. B. Ezhava, I. S. Rathod, M. T. Chhabria, A. H. Patwari,
World J. Pharm. Pharmaceut. Sci. 2015, 4, 595.
[26] B. Biersack, Effects of garcinol from kokum (Garcinia indica) on the
prevention and treatment of cancer, in Critical dietary factors in
Cancer Chemotherapy (Eds: M. F. Ullah, A. Ahmad), Springer In-
ternational Publishing Switzerland, Cham, 2016.
CONFLICT OF INTERESTS
The authors declare that there are no conflicts of interests.
[27] R. Schobert, B. Biersack, Chem. Biodiv. 2019, 16, e1900366.
[28] A. Ahmad, S. H. Sarkar, A. Aboukameel, S. Ali, B. Biersack, S. Seibt,
Y. Li, B. Bao, D. Kong, S. Banerjee, R. Schobert, S. B. Padhye,
F. H. Sarkar, Carcinogenesis 2012, 33, 2450.
ORCID
Angela Corona
http://orcid.org/0000-0002-6630-8636
https://orcid.org/0000-0002-3760-580X
http://orcid.org/0000-0001-7305-346X
http://orcid.org/0000-0002-4849-0980
Andrea Volkamer
Bernhard Biersack
Enzo Tramontano
[29] S.‐H. Tu, Y.‐S. Chiou, N. Kalyanam, C.‐T. Ho, L.‐C. Chen, M.‐H. Pan,
Food Funct. 2017, 8, 1067.
[30] N. Saadat, S. Akhtar, A. Goja, N. H. Razalli, A. Geamanu, D. David,
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