Year by year, the characterization of the biological activity of natural products is becoming more competitive and complex, with the involvement in this research area of experts belonging to different scientific fields, including chemistry, biochemistry, molecular biology, immunology and bioinformatics. These fields are becoming of great interest for several high-impact scientific journals, including eCAM. The available literature in general, and a survey of reviews and original articles recently published, establishes that natural products, including extracts from medicinal plants and essential oils, retain interesting therapeutic activities, including antitumor, antiviral, anti-inflammatory, pro-apoptotic and differentiating properties. In this commentary, we focus attention on interest in networks based on complementary activation and comparative evaluation of different experimental strategies applied to the discovery and characterization of bioactive natural products. A representative flow chart is shown in the paper

Gambari, Roberto

Evidence-Based Complementary and Alternative Medicine

English

PubMed

Roberto Gambari

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Hindawi Publishing Corporation
Evidence-Based Complementary and Alternative Medicine
Volume 2011, Article ID 383290, 4 pages
doi:10.1093/ecam/nep096
Commentary
Predictive Analyses of Biological Effects of
Natural Products: From Plant Extracts to Biomolecular
Laboratory and Computer Modeling
Roberto Gambari
Department of Biochemistry and Molecular Biology, Section of Molecular Biology, Via Fossato di Mortara, 74, 44100 Ferrara, Italy
Correspondence should be addressed to Roberto Gambari, gam@unife.it
Received 25 January 2009; Accepted 25 June 2009
Copyright © 2011 Roberto Gambari. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Year by year, the characterization of the biological activity of natural products is becomingmore competitive and complex, with the
involvement in this research area of experts belonging to diﬀerent scientific fields, including chemistry, biochemistry, molecular
biology, immunology and bioinformatics. These fields are becoming of great interest for several high-impact scientific journals,
including eCAM. The available literature in general, and a survey of reviews and original articles recently published, establishes
that natural products, including extracts frommedicinal plants and essential oils, retain interesting therapeutic activities, including
antitumor, antiviral, anti-inflammatory, pro-apoptotic and diﬀerentiating properties. In this commentary, we focus attention on
interest in networks based on complementary activation and comparative evaluation of diﬀerent experimental strategies applied
to the discovery and characterization of bioactive natural products. A representative flow chart is shown in the paper.
1. Plant Extracts Exhibit Biological
Properties Relevant for Alternative
Treatments of Human Diseases
A first level of screening that is followed by many research
groups allows the identification of plant extracts and essen-
tial oils exhibiting relevant biomedical eﬀects (action I of
the flow chart shown in Figure 1) [1–8]. A careful review
of the conclusions in available literature reveals that several
plant extracts exhibit activity against herpes simplex virus
[4]. On the other hand, several plant extracts stimulate
expression of diﬀerentiation-related functions of great value
for developing drugs against important genetic diseases [9].
A complementary approach focusing on mechanism(s)
of action instead of bio-medical eﬀects identifies possible
molecular targets of plant extracts (action II of Figure 1).
Lampronti et al. [10] were able to demonstrate that extracts
from medicinal plants diﬀerentially inhibit molecular inter-
actions between nuclear factor κB (NF-κB) and target DNA.
The finding of activity against a transcription factor (TF)
stimulated experiments on eﬀects of single plant extracts or
essential oils on biological functions depending on this TF.
NF-κB is deeply involved in inflammatory processes, as well
as antiapoptotic properties. Hence, plant extracts inhibiting
NF-κB (for instance, extracts from Emblica oﬃcinalis) deeply
modify the production of inflammation-related proteins
induced in bronchial cell lines by Pseudomona aeruginosa
(PAO) infection [11]. Nicolis et al. [11] demonstrated that
extracts from E. oﬃcinalis strongly inhibited the PAO-
dependent expression of the neutrophil chemokines IL-8,
GRO-α and GRO-γ, of the Inter-Cellular Adhesion Molecule
1 (ICAM-1) and of the pro-inflammatory cytokine IL-
6, when tested in human IB3-1 bronchial epithelial cells
exposed to the P. aeruginosa laboratory strain PAO1. This
finding might be relevant for treatment of the inflammatory
process of cystic fibrosis (CF) [12]. In fact, the most
important cause of morbidity and mortality in CF patients
is the lung pathology characterized by chronic infection and
inflammation sustained mainly by P. aeruginosa.
Penolazzi et al. [13] demonstrated that E. oﬃcinalis
extracts induce apoptosis of primary osteoclasts (OCs), as a
possible treatment of osteoporosis and rheumatoid arthritis.
In this study, the eﬀects of extracts from E. oﬃcinalis
on diﬀerentiation and survival of human primary OC
cultures obtained from peripheral blood were determined
by tartrate acid-resistant acid phosphatase positivity and
2 Evidence-Based Complementary and Alternative Medicine
colorimetric studies based on 3-(4,5-Dimethylthiazol-2-yl)-
2,5-diphenyltetrazolium bromide (MTT) assay. The eﬀects
of E. oﬃcinalis extracts on induction of OC apoptosis
were studied using the terminal dUTP nick-end labeling
(TUNEL) assay and immunocytochemical analysis of Fas
receptor expression. Extracts of E. oﬃcinalis were able to
induce programmed cell death of mature OCs, without
altering the process of osteoclastogenesis. Emblica oﬃcinalis
increased the expression levels of Fas, a critical member
of the apoptotic pathway. Interestingly, the extracts of E.
oﬃcinalis inhibited in both the cellular systems described
by Nicolis et al. [11] and by Penolazzi et al. [13] the
expression of the pro-inflammatory IL-6 gene when analyzed
by reverse transcriptase-polymerase chain reaction (RT–
PCR) and immunocytochemistry.
Eﬀects of plant extracts on cytokines have been recently
published in eCAM by Zhao et al. [14], Saad et al. [15] and
Park et al. [16]. The use of botanicals in osteoarthritis and
rheumatoid arthritis has also been proposed by Ahmed et al.
[17].
2. Looking for Lead Compounds within
Plant Extracts
After the formal demonstration of a relevant biological
activity, including possible eﬀects on specific molecular
targets, two complementary approaches can be followed for
identification of putative lead compounds. The first (action
IV of Figure 1) is a direct chemical analysis of plant extracts,
based on several methods such as gas chromatography/mass
spectrometry (GC-MS) and high-performance liquid chro-
matography/MS (HPLC-MS). The second (action III of
Figure 1) is an activity of data mining focusing on what is
available in the literature concerning bioactive plant extracts.
Both these approaches can generate sets of molecules that
are possibly responsible for biological activity found in
analyzed extracts (actions V-a and V-b of Figure 1). This is an
important process that will ultimately help in identifying lead
compounds to be employed in preclinical studies. Examples
of this process are those reported by Nicolis et al. [11] who
identified pyrogallol as the bioactivemolecule within extracts
of E. oﬃcinalis that inhibit IL-8 gene expression.
More recently, Guerrini et al. [18] have found that
citropten and bergapten, detected in epicarps of Citrus
bergamia fruits, are powerful inducers of diﬀerentiation and
γ-globin gene expression in human erythroid cells. These
data could have practical relevance, since pharmacologically
mediated regulation of human γ-globin gene expression,
with the consequent induction of fetal hemoglobin, is con-
sidered as a potential therapeutic approach in hematological
disorders, including β-thalassemia and sickle cell anemia [9].
3. Identification of Molecular Targets and
Studies of Structurally Related Compounds
Collaboration between chemists, molecular and cellular
biologists is of great added value. The identification of
putative molecular targets is important for at least two
I
II
III
IV
V-a
VI
V-c
VIII VII
V-b
Plant extracts
Screening for
molecular targets
Bioactivo
plant extracts
Screening
for identification
of relevant biological
activity
Bioactive
compounds
Analysis of chemical
composition of
bioactive plant extracts
Biological
validation
Virtual screening by
docking to target
molecules relevant
to human pathologies
Chemical
library
Data mining
Figure 1: The interplay between several actions contributing to
the characterization of biological activity of natural products from
plant extracts. Numbering (I–VIII) facilitates the presentation
of the diﬀerent activities leading to the final identification of
bioactive compounds starting from plant extracts, through inter-
mediate products (databases from bioactive plant extracts, chemical
libraries).
reasons: (i) development of advanced biological assays and
(ii) screening of sets of structurally related compounds.
Several research groups have hypothesized specific cellular
targets for lead compounds identified in medicinal plant
extracts. For instance, Dat et al. [19] identified the phenolic
constituents of Amorpha fruticosa that inhibit NF-κB activa-
tion and related gene expression. When the identification of
a molecular target is available, then novel approaches might
be undertaken to characterize both mechanisms of action,
binding modes and novel bioactive molecules (actions VI–
VIII of Figure 1). Piccagli et al. [20] recently reported a
docking study to NF-κB-p50 on a data set of 27 molecules
from extracts of two diﬀerent medicinal plants. The purpose
of the study was to develop a docking protocol fit for the
target under study [20]. They enhanced the simple docking
procedure bymeans of a sort of combined target- and ligand-
based drug design approach. The results sustain the concept
that docking performance is predictive of a biochemical
activity. Through molecular docking simulations, this article
represents an example of successful indentification, starting
from a set of molecules found in plant extracts, of a lead
compound promising for inhibition of NF-κB-p50 biological
activity and modulation of expression of NF-κB-regulated
genes (in this case the IL-8 gene) [20]. Similar computer-
based strategies have been recently applied to other natural
products, looking for eﬀects on diﬀerent biological functions
by Rollinger et al. [21] on Ruta graveolens extracts, by Chen
et al. [22] on suanzaroen decotion and by Paoletta et al.
[23] using a data set from 240 herbs used in traditional
Chinese medicine. These recent studies support the concept
that computer-assisted approaches, such as pharmacophore
modeling, virtual screening, docking and neural networking
will help in identifying bioactive metabolites in extracts
Evidence-Based Complementary and Alternative Medicine 3
from medicinal plants [24]. Integrated computer-assisted
strategies may help to process the huge amount of available
structural and biological information in a reasonably short
time for a straightforward search of bioactive natural prod-
ucts (action V-c of the flow chart shown in Figure 1) [24, 25].
4. Final Comments
Analyzing biological activity of plant extracts is rapidly
moving from simple observations to integrated research
approaches involving analytical chemistry, chemical syn-
thesis, molecular and cellular biology, proteomics, tran-
scriptomics and bioinformatics. The comparative analysis
of complementary studies will bring novel information
on bioactive compounds from natural products, including
molecular targets and putative mechanisms of action. In
particular, in silico tools, combined with classical research
methods, are expected to be more frequently applied by
natural product scientists in an eﬀort to maximize eﬃcacy in
drug discovery. These multidisciplinary studies are expected
to bring novel molecules of great biomedical relevance. The
journal eCAM is deeply involved in bringing to the scientific
community high-level relevant communications.
References
[1] R. Cooper, D. J. Morre´, and D. M. Morre´, “Medicinal benefits
of green tea: part II. Review of anticancer properties,” Journal
of Alternative and Complementary Medicine, vol. 11, no. 4, pp.
639–652, 2005.
[2] J. R. C. Vieira, I. A. de Souza, S. C. do Nascimento,
and S. P. Leite, “Indigofera suﬀruticosa: an alternative anti-
cancer therapy,” Evidence-Based Complementary and Alterna-
tive Medicine, vol. 4, no. 3, pp. 355–359, 2007.
[3] E. Lambertini, R. Piva, M. T. Khan et al., “Eﬀects of extracts
from Bangladeshi medicinal plants on in vitro proliferation
of human breast cancer cell lines and expression of estrogen
receptor alpha gene,” International Journal of oncology, vol. 24,
no. 2, pp. 419–423, 2004.
[4] M. T. H. Khan, A. Ather, K. D. Thompson, and R. Gambari,
“Extracts and molecules from medicinal plants against herpes
simplex viruses,” Antiviral Research, vol. 67, no. 2, pp. 107–
119, 2005.
[5] C. Tohda, N. Nakayama, F. Hatanaka, and K. Komatsu,
“Comparison of anti-inflammatory activities of six Cur-
cuma rhizomes: a possible curcuminoid-independent pathway
mediated by Curcuma phaeocaulis extract,” Evidence-Based
Complementary and Alternative Medicine, vol. 3, pp. 255–260,
2006.
[6] S.-C. Chun, S. Y. Jee, S. G. Lee, S. J. Park, J. R. Lee, and S.
C. Kim, “Anti-inflammatory activity of the methanol extract
of Moutan Cortex in LPS-activated Raw264.7 cells,” Evidence-
Based Complementary and Alternative Medicine, vol. 4, no. 3,
pp. 327–333, 2007.
[7] K.-H. Lee, A.-J. Kim, and E.-M. Choi, “Antioxidant and
antiinflammatory activity of pine pollen extract in Vitro,”
Phytotherapy Research, vol. 23, no. 1, pp. 41–48, 2009.
[8] M. Wu and Z. Gu, “Screening of bioactive compounds from
moutan cortex and their anti-inflammatory activities in rat
synoviocytes,” Evidence-Based Complementary and Alternative
Medicine, vol. 6, pp. 57–63, 2009.
[9] N. Bianchi, C. Zuccato, I. Lampronti, M. Borgatti, and
R. Gambari, “Fetal hemoglobin inducers from the natural
world: a novel approach for identification of drugs for the
treatment of -thalassemia and sickle-cell anemia,” Evidence-
Based Complementary and Alternative Medicine, vol. 6, pp.
141–151, 2009.
[10] I. Lampronti, M. T. H. Khan, M. Borgatti, N. Bianchi, and R.
Gambari, “Inhibitory eﬀects of Bangladeshi medicinal plant
extracts on interactions between transcription factors and
target DNA sequences,” Evidence-Based Complementary and
Alternative Medicine, vol. 5, no. 3, pp. 303–312, 2008.
[11] E. Nicolis, I. Lampronti, M. C. Dechecchi et al., “Pyrogallol, an
active compound from themedicinal plant Emblica oﬃcinalis,
regulates expression of pro-inflammatory genes in bronchial
epithelial cells,” International Immunopharmacology, vol. 8,
no. 12, pp. 1672–1680, 2008.
[12] M. Borgatti, V. Bezzerri, I. Mancini et al., “Silencing of genes
coding for transcription factors: Biological eﬀects of decoy
oligonucleotides on cystic fibrosis bronchial epithelial cells,”
Minerva Biotecnologica, vol. 20, no. 2, pp. 79–83, 2008.
[13] L. Penolazzi, I. Lampronti, M. Borgatti et al., “Induction
of apoptosis of human primary osteoclasts treated with
extracts from the medicinal plant Emblica oﬃcinalis,” BMC
Complementary and Alternative Medicine, vol. 8, article 59,
2008.
[14] L. Zhao, J. Tao, S. Zhang, F. Jin, R. Pang, and J. Dong, “N-
butanol extract from Melilotus suaveolens Ledeb aﬀects pro-
and anti-Inflammatory cytokines and mediators,” Evidence-
Based Complementary and Alternative Medicine, vol. 7, no. 1,
pp. 97–106, 2007.
[15] B. Saad, B. S. Abouatta, W. Basha et al., “Hypericum triquet-
rifolium—derived factors downregulate the production levels
of LPS-induced nitric oxide and tumor necrosis factor-α in
THP-1 cells,” Evidence-Based Complementary and Alternative
Medicine. In press.
[16] K. Park, B. Kim, and I. Chang, “Inhibitory potencies of sev-
eral iridoids on cyclooxygenase-1, cyclooxygnase-2 enzymes
activities, tumor necrosis factor- and nitric oxide production
In Vitro,” Evidence-Based Complementary and Alternative
Medicine, vol. 7, no. 1, pp. 41–45, 2007.
[17] S. Ahmed, J. Anuntiyo, C. J. Malemud, and T. M. Haqqi,
“Biological basis for the use of botanicals in osteoarthritis and
rheumatoid arthritis: a review,” Evidence-Based Complemen-
tary and Alternative Medicine, vol. 2, no. 3, pp. 301–308, 2005.
[18] A. Guerrini, I. Lampronti, N. Bianchi et al., “Bergamot (Citrus
bergamia Risso) fruit extracts as γ-globin gene expression
inducers: phyto-chemical and functional perspectives,” Jour-
nal of Agricultural and Food Chemistry, vol. 57, no. 10, pp.
4103–4111, 2009.
[19] T. D. Nguyen, J.-H. Lee, K. Lee, Y.-S. Hong, H. K. Young, and
J. L. Jung, “Phenolic constituents of Amorpha fruticosa that
inhibit NF-κB activation and related gene expression,” Journal
of Natural Products, vol. 71, no. 10, pp. 1696–1700, 2008.
[20] L. Piccagli, E. Fabbri, M. Borgatti et al., “Docking of molecules
identified in bioactive medicinal plants extracts into the p50
NF-κB transcription factor: correlation with inhibition of
NF-κB/DNA interactions and inhibitory eﬀects on IL-8 gene
expression,” BMC Structural Biology, vol. 8, pp. 38–48, 2008.
[21] J. M. Rollinger, D. Schuster, B. Danzl et al., “In silico
targer fishing for rationalized ligand discovery exemplified on
constituents of Ruta graveolens,” Planta Medica, vol. 75, pp.
195–204, 2009.
[22] C. Y. Chen, Y. F. Chen, and H. Y. Tsai, “What is the eﬀective
component in suanzaoren decotion for curing insomnia?
4 Evidence-Based Complementary and Alternative Medicine
Discovery by virtual screening and molecular dynamic simu-
lation,” Journal of Biomolecular Structure & Dynamics, vol. 26,
pp. 57–64, 2008.
[23] S. Paoletta, G. B. Steventon, D. Wildeboer, T. M. Ehrman, P. J.
Hylands, and D. J. Barlow, “Screening of herbal constituents
for aromatase inhibitory activity,” Bioorganic and Medicinal
Chemistry, vol. 16, no. 18, pp. 8466–8470, 2008.
[24] J. M. Rollinger, T. Langer, and H. Stuppner, “Integrated in
silico tools for exploiting the natural product’s bioactivity,”
Planta Medica, vol. 72, no. 8, pp. 671–678, 2006.
[25] J. M. Rollinger, T. Langer, and H. Stuppner, “Strategies for
eﬃcient lead structure discovery from natural products,”
Current Medicinal Chemistry, vol. 13, no. 13, pp. 1491–1507,
2006.
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Predictive Analyses of Biological Effects of Natural Products: From Plant Extracts to Biomolecular Laboratory and Computer Modeling

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