ARTICLE IN PRESS

Antiinflammatory Potential of
Medicinal Plants: A Source for
Therapeutic Secondary
Metabolites
Nirit Bernstein*,1, Muhammad Akram†, Muhammad Daniyal‡,§,
Hinanit Koltai¶, Marcelo Fridlender¶, Jonathan Gorelickk
*Institute of Soil Water and Environmental Sciences, Volcani Center, Rishon LeZion, Israel
†
Department of Eastern Medicine, Directorate of Medical Sciences, Government College University,
Faisalabad, Pakistan
‡
TCM and Ethnomedicine Innovation & Development Laboratory, School of Pharmacy, Hunan University of
Chinese Medicine, Changsha, China
§
College of Biology, Hunan Province Key Laboratory of Plant Functional Genomics and Developmental
Regulation, Hunan University, Changsha, China
¶
Institute of Plant Sciences, Volcani Center, Rishon LeZion, Israel
k
Judea Regional Research and Development Center, Kiryat Arba, Israel
1
Corresponding author: e-mail address: nirit@agri.gov.il

Contents
1. Introduction 3
2. Recent Approaches for the Analysis of the Antiinflammatory Potential of Plants
and Plant-Derived Compounds 4
3. Classification of Antiinflammatory Substances 12
3.1 Synthetic Antiinflammatory Substances 12
3.2 Plant-Derived Antiinflammatory Compounds 12
4. Medicinal Plants With Confirmed Antiinflammatory Activity 21
4.1 Abrus precatorius (Fabaceae) 21
4.2 Agave americana (Asparagaceae) 21
4.3 Ageratum conyzoides L. (Asteraceae) 22
4.4 Ajuga bracteosa Benth. (Lamiaceae) 22
4.5 Allium sativum (Liliaceae) 22
4.6 Aloe vera (Xanthorrhoeaceae) 22
4.7 Alstonia boonei (Apocynaceae) 23
4.8 Ammi majus Linn. (Umbelliferae) 23
4.9 Arctium lappa L. (Asteraceae) 23
4.10 Azadirachta indica (Meliaceae) 23
4.11 Bauhinia racemosa (Fabaceae) 24
4.12 Bauhinia variegata (Fabaceae) 24
4.13 Bauhinia variegata (Fabaceae) 24
4.14 Boswellia carteri (Burseraceae) 24
4.15 Boswellia serrata (Burseraceae) 24

Advances in Agronomy # 2018 Elsevier Inc. 1

ISSN 0065-2113 All rights reserved.
https://doi.org/10.1016/bs.agron.2018.02.003
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2 Nirit Bernstein et al.

4.16 Calotropis procera (Asclepidaceae) 25

4.17 Camellia japonica (Theaceae) 25
4.18 Cannabis sativa (Cannabinaceae) 25
4.19 Cinnamomum osmophloeum (Lauraceae) 25
4.20 Clerodendrum petasites (Lamiaceae) 26
4.21 Eupatorium perfoliatum (Asteraceae) 26
4.22 Eupatorium purpureum (Asteraceae) 26
4.23 Ficus carica (Moraceae) 26
4.24 Foeniculum vulgare (Apiaceae) 27
4.25 Geranium nepalense (Geraniaceae) 27
4.26 Glechoma hederacea (Lamiaceae) 27
4.27 Kalopanax pictus (Araliaceae) 28
4.28 Leonotis leonurus (Lamiaceae) 28
4.29 Nigella sativa (Ranunculaceae) 28
4.30 Parinari polyandra (Rosaceae) 28
4.31 Pfaffia glomerata (Amaranthaceae) 28
4.32 Phrygilanthus acutifolius (Loranthaceae) 29
4.33 Polygonum bistorta (Polygonaceae) 29
4.34 Pongamia pinnata L. (Fabaceae) 29
4.35 Rosa damascena (Rosaceae) 29
4.36 Rosmarinus officinalis L. (Lamiaceae) 30
4.37 Schima wallichii (Theaceae) 30
4.38 Sideritis javalambrensis (Lamiaceae) 30
4.39 Sphenocentrum jollyanum (Menispermaceae) 30
4.40 Stachys inflata (Lamiaceae) 31
4.41 Taraxacum officinale (Asteraceae) 31
4.42 Taxus wallichiana (Taxaceae) 31
4.43 Thespesia populnea (Malvaceae) 31
4.44 Trichodesma indicum (Boraginaceae) 31
4.45 Verbena officinalis (Verbenaceae) 32
4.46 Vernonia cinerea (Asteraceae) 32
4.47 Vitex negundo (Lamiaceae) 32
4.48 Zingiber officinale (Zingiberaceae) 32
5. Future Perspectives and Conclusions 33
References 33
Further Reading 51

Abstract
Plants containing natural products have been used worldwide in traditional medicine
since antiquity and are a source of potential and powerful drugs. The potential of higher
plants as a source for new drugs is still largely unexplored, and among the estimated
250,000–500,000 plant species, only a small fraction has been submitted to biological
or pharmacological screening. Medicinal plants and their isolated compounds are utilized
worldwide in traditional medicine for the treatment of various inflammatory conditions,
and the therapeutic potential of traditionally used plants and their constituents is currently
a target of research in the pursuit of novel antiinflammatory drugs. Inflammation is the
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Antiinflammatory Potential of Medicinal Plants 3

normal reaction of animal living tissue to all forms of injury. It is a dynamic and complex
tissue reaction provoked by cellular injury, which involves a cascade of biochemical
events. Although inflammation is a protective measure taken by the organism to elimi-
nate the injurious stimuli, uncontrolled inflammation can lead to damage. For this reason,
inflammation is closely regulated by the body or with the aid of administrated
antiinflammatory compounds. The search for alternative substances capable of interfering
with the inflammatory process has become a significant issue in scientific research, espe-
cially with reference to the search for natural substances and the reduction of negative
side effects of conventional medications. Although dozens of plant species were reported
in ethnomedicine for the treatment of inflammation, only a fraction of these were con-
firmed in antiinflammatory studies. This review evaluates the current state of knowledge
concerning promising antiinflammatory activity of herbal plants and plant substances that
have been tested in inflammatory models using modern scientific systems.

1. INTRODUCTION
Throughout human history, plants have been the primary source for
therapeutic substances. Traditional use of plants as medicine was widespread
in every region and culture, and plants are routinely examined to-date for
their medicinal potential (Stankovi
c et al., 2016). Plants have been used
to treat practically all types of illness ranging from infectious agents such
as bacteria or fungi, to metabolic and neurological disorders and everything
in between. In fact, many of the initial drugs developed in modern western
medicine were inspired by natural plant products.
Inflammation, part of the body’s innate immune response to injury and a
central component in a number of inflammatory-related diseases, is no
exception. Many plants have been traditionally used for the treatment of
inflammation (Taylor et al., 2001). In fact, one of the first examples of a
plant-inspired pharmaceutical, aspirin, the semisynthetic acetylsalicylate, is
based on the natural occurring salicylic acid found in willow bark and used
traditionally for treating fever and pain (Taylor et al., 2001).
Inflammation, the response by the body to tissue damage caused by any
number of factors including physical, chemical, or pathogenic sources, can
be divided into two groups: acute and chronic. Acute inflammation is a vital
short-term physiological process involving the infiltration of leukocytes to an
inflamed region, which attempt to quickly neutralize the source of the inflam-
mation and subsequently repair the damaged tissue (Medzhitov, 2008).
In contrast, chronic inflammation is a prolonged and usually dysregulated
response usually involving the accumulation of proinflammatory cytokines
and their downstream signals and is associated with a number of serious
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4 Nirit Bernstein et al.

disorders including arthritis, asthma, colitis, dermatitis, and even neurodegen-

erative diseases including Alzheimer’s and Parkinson’s disease (Medzhitov,
2008). It is therefore no surprise that many plants have been used traditionally
for the treatment of inflammation and inflammation-related diseases. While
the number of plants used traditionally for treating inflammation is quite large,
the antiinflammatory activity of a number of these plants has been supported
by in vitro and in vivo studies (see Section 5).
While plants seem to be a natural treasure chest of medicinal com-
pounds, only a fraction of the known medicinal plants have been harnessed
clinically. This is at least partially due to the intrinsic complexities associated
with plant-based medicines, seriously hampering their introduction into
conventional western medicine. In many instances, plants played multiple
roles simultaneously serving as a food, a flavor and aroma enhancer (spice), a
preservative, and a medicine (Gupta et al., 2013a,b; Lee et al., 2016). The
complexity of plant-based medicine both with regards to the multiple roles
any given plant filled as well as the large number of diverse bioactive com-
pounds plants contain makes the scientific evaluation of plant-based treat-
ments anything but straightforward. A plant-based remedy containing
multiple therapeutic ingredients may often treat a number of conditions
via a range of mechanisms. This complexity is only compounded by the
chemical variability generated by differences in genetic and environmental
conditions (Gorelick and Bernstein, 2014, 2017).
However, there are still many more plants, which have not yet been
sufficiently evaluated for antiinflammatory activity. In addition, the com-
pounds responsible for the antiinflammatory activity as well as their mode
of action have yet to be elucidated. Many of the assays previously utilized
were very crude and simplistic in vitro models having only little relevance
to any potential clinical efficacy. Hopefully, the more recent development of
more relevant and specific approaches will lead to the future development
of plant-based therapies which can more successfully be developed into
effective treatments.

2. RECENT APPROACHES FOR THE ANALYSIS OF THE

ANTIINFLAMMATORY POTENTIAL OF PLANTS AND
PLANT-DERIVED COMPOUNDS
For the determination of antiinflammatory activity, sensitive and reli-
able bioassays are needed. They should be sensitive to low concentrations
of active compounds, in small sample sizes, be suitable to a variety of
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Antiinflammatory Potential of Medicinal Plants 5

antiinflammatory molecules and a range of activities associated with different

modes of action and an array of inflammatory-associated diseases. On the
other hand, these bioassays should be inexpensive, and relatively easy and
quick to perform (Brito, 1996; Brito and Nunes, 1997).
For the determination of antiinflammatory activity in vitro, the level of
several inflammation-associated components should be compared in treated
and control cells. Cell culture-based models are tested for their response to
plant extracts, purified compounds, or synthetic drugs. Commercially avail-
able cell lines are commonly used (for more details in relation to available cell
lines, please see ATCC website http://www.atcc.org/Products/Cells_and_
Microorganisms/Cell_Lines.aspx). For more specific in vitro tests, for exam-
ple, for examination of cellular response of certain cells isolated from human
patients, isolated cells should go through transformation to obtain a relatively
stable cell line (e.g., Dittfeld et al., 2010).
Inflammation in cells usually involves activation of leukocytes, endothelial
cells, and macrophages that produce proinflammatory cytokines. Inflamma-
tion is regulated by several key regulators, with the transcription factor,
nuclear factor-kappa B (NF-κB), being a major one. It plays an important role
in the inflammatory response by regulating the expression of genes that
encode proinflammatory cytokines, growth factors, adhesion molecules,
chemokines, and enzymes (Hanada and Yoshimura, 2002). During inflamma-
tion, cells express high levels of tumor necrosis factor-alpha (TNF-α), a major
mediator of inflammation in many diseases, and a strong activator of NF-κB.
The expression of TNF-α is also regulated by NF-κB (Aggarwal, 2003).
In addition to TNF, expression of NF-κB is activated by many different
agents, including inflammatory cytokines, microorganisms (bacteria and
viruses), different chemicals, and stress conditions (Aggarwal, 2004; Ahn
and Aggarwal, 2005; Karin and Greten, 2005; Kumar et al., 2004; Sethi
et al., 2008; Tergaonkar, 2006). NF-κB regulates many inflammation-
associated components, such as inflammatory cytokines, chemokines, adhe-
sion molecules, enzymes, and kinases (Hoesel and Schmid, 2013). Of the
proinflammatory cytokines, interleukins (ILs) further promote the inflam-
matory response and transduce inflammation between cells (Strober and
Fuss, 2011). Thus, NF-κB, TNF-α, and their regulated genes are a desired
target for control and relief of inflammatory conditions.
In addition to the proinflammatory cytokines, inflammation is associated
with the induction of antiinflammatory cytokines, such as IL-10 (Li et al.,
2005). Among the proinflammatory enzymes produced by inflamed cells
are nitric oxide synthase (iNOS) and cyclooxygenase (COX). These are
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6 Nirit Bernstein et al.

responsible for increasing the levels of nitric oxide (NO) and prostaglan-
dins (PEG2). Both NO and PEG2 are known to be involved in different
chronic diseases, including multiple sclerosis and colon cancer (e.g.,
Yan, 2007).
Detection of the different inflammation-associated components may
allow determination of the level of inflammation in the cell. More specifically,
in the last three decades the involvement and role of cytokines have been
studied both in vitro and in vivo for many different diseases and conditions
including cancer (Lippitz, 2013), endothelial dysfunction and atherosclerosis
(Kleemann et al., 2008; Raines and Ferri, 2005), Alzheimer’s diseases (Mrak
et al., 1995; Rubio-Perez and Morillas-Ruiz, 2012), inflammatory bowel
diseases (IBD) (Baumgart and Sandborn, 2012; Ordás et al., 2012; Sartor,
2006), infections (Hackett et al., 2001; Van Deuren et al., 1992), central
nervous system (CNS) injuries and diseases (Lucas et al., 2006), fibromyalgia
€
syndrome (Uçeyler et al., 2011), rheumatoid arthritis (Arend and Dayer,
1990; Feldmann et al., 1996), bipolar disorder (Munkholm et al., 2013),
pregnancy and parturition (Keelan et al., 2003), and alcoholism (Achur
et al., 2010). The key role of cytokines and their regulators in mediating
inflammation together with the development of cytokine and anticytokine
therapies (Vilček and Feldmann, 2004) has led to the improvement and inven-
tion of new cytokine assays (Whiteside, 2002).
Measurement of cytokine activity in vivo would be the preferred
method to understand the association and contribution of these molecules
to the inflammation process. Performing such assays in humans requires
the injection of the tested cytokines and therefore can be carried out only
in clinical setting involving cytokine therapies. Thus, in most cases, cyto-
kines are detected and measured by in vitro bioassays that utilize body fluids
of cytokine-treated animals or humans. The most common assays available
for evaluation of cytokines are ex vivo assays performed using either body
fluids or cell-cultured supernatants. Two types of such assays exist: (1) immu-
noassays that evaluate cytokine’s levels but not their activity, (2) bioassays
that measure both levels and activity (reviewed in Whiteside, 2002).
Expression levels of proinflammatory cytokines and their key regulators
have been tested in both human and animals in order to understand how
these important molecules affect inflammation processes. Among the most
used ex vivo tests are those performed for detection of the level of the dif-
ferent ILs. In studies where potential drugs or plant extracts have been tested,
expression levels of the target molecule(s) were compared in cell cultures
either treated or untreated with the tested agent. Ex vivo bioassays aimed
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Antiinflammatory Potential of Medicinal Plants 7

at the detection of changes in ILs expression levels are done either at the
messenger RNA (mRNA) level or the protein level.
Four kinds of bioassays are currently used with each measuring a differ-
ent effect produced by cytokine incubation: (a) growth proliferation inhi-
bition assays; (b) cytotoxicity assays; (c) assays dependent on the induction
of a specific cell function, for example, chemotaxis; and (d) induction assays
assessing the amount of protein produced in the target cells. Bioassays to
detect soluble cytokines, cytokine–receptor complexes, or cytokine–serum
protein aggregates have been developed (reviewed in Whiteside, 2002). In
most cases, studies on proinflammatory cytokines have used more than one
technique in order to better understand the mechanisms involved.
In the 1980s and 1990s, Northern Blot analysis was the most common
method to detect specific mRNA molecules implying the expression of
their specific genes. After isolation of RNA molecules from tissues or cells,
RNA was denatured and size separated by gel electrophoresis. Then, mol-
ecules were transferred to a membrane (nylon or nitrocellulose) by blotting
it with the gel. Finally, the membrane was hybridized with a DNA or RNA
radioactive of fluorescent probe that due to its specific sequence allows
detection of the RNA of interest. mRNA from cytokines such as IL-6,
IL-1α, IL-1β, IL-3, IL-4, IL-5, IL-12, IL-17, and IL-8 was detected using
Northern Blot analysis (Frei et al., 1989; Ito et al., 2000; Kotake et al., 1999;
Kubin et al., 1994; Lieb et al., 1996; Massengale et al., 1999; Noma
et al., 1989). However, the main pitfalls using Northern Blot analysis
are: (1) time-consuming method, (2) requires large amounts of RNA,
(3) inaccurate for low-abundant RNAs, (4) no multiplexing (testing more
than one gene at a time) possibilities.
A second method used to evaluate gene expression is reverse transcriptase
polymerase chain reaction (RT-PCR). The core of this technique is the
enzyme reverse transcriptase that converts mRNA into its complement
DNA (cDNA) which is then amplified by additional PCR cycles. The
amplified DNA is then blotted as in Northern Blots and allows a qualitative
gene expression study. Several chemokines and cytokines such as IL-16,
IL-1β, TNF-α, MIP-1α and MIP-1β, IL-6, IL-8, IL-13Rα1,
IL-13Rα2, IL-4Rα, IL-22 were studied using this method (Atanackovic
et al., 2012; Baqui et al., 1998; Bernard et al., 2001; Brand et al., 2006;
Jee et al., 2004; Krzysiek et al., 1999; Massengale et al., 1999).
Real-time PCR is a major advancement in quantifying mRNA and thus
gene expression. Upon creating a cDNA from mRNA molecules by reverse
transcriptase, specific primers are used in order to detect it throughout the
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8 Nirit Bernstein et al.

course of amplification, i.e., “real-time” and allowing quantitative gene

expression analysis. Detection can be obtained using either (a) nonspecific
fluorescent dyes, such as SYBR Green, that intercalate to any double
DNA molecule or (b) sequence-specific fluorescent probes (TaqMan, Molec-
ular Beacons, and Scorpion Probes) that are detected only after hybridization
to their complement DNA sequence occurs. This method is also called qRT-
PCR or qPCR due to its quantitative feature. In addition to this advantage,
other benefits are its sensitivity (detects low-abundant RNA molecules) and
the fact that no post-PCR steps are required. Due to the mentioned features,
qPCR became a standard method used for analyses of both relative and abso-
lute gene expression as well as a technique to validate microarray results. Gene
expression for the following chemokines, cytokines, and inflammation medi-
ators has been evaluated using qPCR: IL-16, INF-γ, Perforin, IL-1α, IL-1β
and IL-1RΑ, SOCS3, CXCL1, CXCL2, CXCL5, CXCL6, IL-8, CCL20,
IL-22, IL-17A, IL-17F, IL-22, IL-1b, IL-6, and TNF-α (Atanackovic et al.,
2012; Brand et al., 2006; Elkabets et al., 2009; Keita et al., 2010; Schoenher
et al., 2010; Sun et al., 2013; Wang et al., 2014a,b).
Western Blot analysis (also called immunoblot analysis) and enzyme-
linked immunosorbent assay (ELISA) have been used extensively to test
for detection of cytokines at the protein level (Whiteside, 2002; Yang and
Ma, 2009). As done for RNA used in Northern Blots, proteins for Western
Blots are also denatured and separated by size. This is achieved by electro-
phoresis on a SDS-polyacrylamide gel. The second step involves transferring
the proteins to a nitrocellulose or PVDF (polyvinylidene difluoride) mem-
brane that is then stained with specific antibodies that are linked to a reporter
enzyme (usually horseradish peroxidase) which drive a colorimetric or pho-
tometric reaction (Yang and Ma, 2009). In a few of the studies mentioned
earlier, Western Blot was used to detect the cytokine at the protein level
in addition to its mRNA expression (Atanackovic et al., 2012; Jee et al.,
2004; Schoenher et al., 2010; Wang et al., 2014a,b).
In contrast to Western Blot in which proteins are denatured in order to
be detected, ELISA exploits several antibodies that detect the native protein,
allowing the use of bodily fluids or cell culture supernatant as samples. These
are relatively fast and easy tests and can be performed in 96-well plates so mul-
tiple samples can be analyzed simultaneously. Furthermore, ELISA is a sensi-
tive and specific test if the right antibodies are used. ELISA can be used for
both qualitative and quantitative results. ELISA relies on an enzymatic reac-
tion that converts a colorless substrate into a colored product and thus reveals
the presence of the antigen (Ag) or antibody (Ab) of interest in the sample.
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Antiinflammatory Potential of Medicinal Plants 9

The enzyme driving the reaction is attached to one of the antibodies used in
the test. Initially antigens or antibodies in the sample are allowed to stick to a
polyvinyl plate in a step called coating. This step is followed by blocking step
that “blocks” all unbound sites on the plate. Finally antibodies are added and
detection takes place.
In cases where the antibody-labeled enzyme binds the Ag or Ab of
interest, the test is called a direct ELISA. However, when the antibody-
labeled enzyme specifically binds another enzyme, the test is an indirect
ELISA. Competitive ELISA and “Sandwich ELISA” are modified indirect
ELISA tests. ELISPOT (enzyme-linked immunospot) is a modified cyto-
kine “Sandwich ELISA” developed for detection of cytokine production
by cells in response to stimulation (Czerkinsky et al., 1988; DeForge and
Remick, 1991; Whiteside, 2002; Yang and Ma, 2009). “Sandwich ELISA”
targets a cytokine sandwiched between capture and detection antibodies
is the most abundant cytokine assay and has been used for detection of
IL-16, TNF, IL-1, IL-6, interferon-γ (IFN-γ), IL-10, basic fibroblast
growth factor 2 (bFGF), vascular endothelial growth factor (VEGF),
IL-1α, IL-1β and IL-1RΑ, IL-8, TNF-α, IL-13Rα2, IL-17, IL-11,
IL-33, and IFN-α (Atanackovic et al., 2012; Baqui et al., 1998; Bernard
et al., 2001; DeForge and Remick, 1991; Faulkner et al., 2014; Hebisch
et al., 2004; Heinisch et al., 2005; Ito et al., 2000; Jee et al., 2004; Keita
et al., 2010; Kotake et al., 1999; Koumantaki et al., 2001; Lieb et al.,
1996; Massengale et al., 1999; Mueller et al., 2006; Zhang et al., 2012).
Cytokine-producing cells can be detected either in single cells or tis-
sues. Improvements in flow cytometry have enabled cytokine detection
in single cells. Such assays measure cytokine production, usually, in periph-
eral blood mononuclear cells (PBMCs). Increased membrane permeability
allows antibodies used in flow cytometry to penetrate the cells and thus
detect intracytoplasmic cytokines and not only the cell surface-associated
ones. Furthermore, multiple cytokines can be detected in the same cell
(Whiteside, 2002). These methods can detect cytokines such as IL-2,
IL-4, IFN-γ, TNF-α, IL-4Rα, IL-13Rα, IL-6 (Bernard et al., 2001;
Bradshaw et al., 2008; Picker et al., 1995; Waldrop et al., 1997).
A second widespread method for detection of produced cytokines in sin-
gle cells is ELISPOT (enzyme-linked immunospot assay). In practice
ELISPOT is a sensitive modified ELISA assay that detects cytokine-secreting
cells. For this purpose, cells are incubated in PVDF microplate wells pre-
coated with a specific capture antibody of interest in the presence or absence
of stimuli. The secreted cytokines are captured by the specific antibodies on
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10 Nirit Bernstein et al.

the surface. Cells are then washed and a specific biotinylated detection anti-
body is added. Finally, detection is done by adding an alkaline phosphatase
enzyme conjugated to streptavidin. Using a nonsoluble chromogenic sub-
strate (BCIP/NBT—5-bromo-4-chloro-30 -indolyphosphate/nitro-blue tet-
razolium) cytokines are detected as dark spots corresponding to the secreting
cells (Czerkinsky et al., 1991). ELISPOT has been widely used for detection
of several cytokines including INF-γ (Asai et al., 2000; Czerkinsky et al.,
1988; Smith et al., 2001), IL-1β, IL-2, IL-4, IL-6, IL-13 (Bailey et al.,
2002), IL-7 and IL-15 (Jennes et al., 2002), and IL-5 (Bennouna et al., 2002).
Immunohistochemistry is another important ex vivo technique that
allows localization of cytokines within tissues. After tissue harvesting, a fix-
ation step is require to avoid loss of cytokine during the following washing
steps. Finally, the antibody is applied and observations under light or fluo-
rescent microscope are used for cytokine detection. A large variety of com-
mercial polyclonal and monoclonal antibodies are available for different
techniques such as Western Blot and immunohistochemistry. Antibodies
that detect cytokines using Western Blot will not necessarily work in immu-
nohistochemistry and vice versa. Therefore, like other antibody-based assay,
successful immunohistochemistry assays depend on the selected antibodies
used. Examples for cytokines detected by immunohistochemistry assays
include IL-1α, IL-1β, IL-2, IL-4, IL-6, TNF-α, TNF-β, INF-γ, IL-3,
IL-5, IL-16 (Ackerman et al., 1994; Atanackovic et al., 2012; Chupp
et al., 1998; Elkabets et al., 2009; Garcı́a-Tuñón et al., 2003; Sander
et al., 1991). In relation to immunohistochemistry, cocultures, i.e., cell
cultures containing at least two different types of cells, can give an insight
to interactions between different types of cells organized in tissues, detected
in the cytokines level (Balkwill and Mantovani, 2012; Javaherian et al., 2013;
Miki et al., 2012). Among the cytokines studied using cocultures are IL-6
(Balkwill and Mantovani, 2012), VEGF (Kirkpatrick et al., 2011), INF-γ,
IL-4 (Linde et al., 2012), epidermal grow factor, IL-1α, and TGF-β1
(Wang et al., 2012).
However, the main drawback of most of the methods described earlier is
their capability to detect only a single (or in some cases only a few) cytokine
in a given assay. However, cytokines are pleiotropic molecules that interact
with different types of cells and a large variety of molecules. Thus, tech-
niques that allow for the multiplex detection of cytokines are in need.
Recent advancement in the human sequencing project supported devel-
opment of multiplexing techniques. One of these multiplexing techniques is
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Antiinflammatory Potential of Medicinal Plants 11

microarrays, which allow the simultaneous analysis of thousands of genes

(Pollack et al., 1999). A microarray is a collection of specific nucleic acid
sequences, i.e., probes, placed on a defined location on a solid phase such
as glass slides or nylon membranes. Nucleic acid samples are then hybridized
with the arrays. Analysis of hybridization between the probes and nucleic
acids in the sample provides data on the genes composing the sample.
DNA microarrays were the first to be developed. Today a variety of
DNA, RNA, and microRNA microarrays are available in the market and
used for different application and studies such as gene expression, screening
of single nucleotide polymorphisms, infectious diseases, genetics and cancer
diagnostics, pharmacogenomics, and forensics (Heller, 2002; Schulze and
Downward, 2001). The most well-known arrays are manufactured by
Affymetrix, Agilent Technologies, and Roche NimbleGen. Cytokine
expression studies using nucleic acids microarrays have been carried out
for different inflammation conditions (Gogos et al., 2000; Heller et al.,
1997; Li et al., 2007; Sana et al., 2005; Vukmanovic-Stejic et al., 2000).
Other methods for the simultaneous study of hundreds of proteins have
also been developed (Anderson et al., 2000). Protein microarrays can be
employed to evaluate the protein levels of different cytokines under different
inflammatory conditions. In these arrays, specific antibodies are spotted on
the solid phase and interact with cytokine-containing samples such as lysates,
plasma, serum, or cell culture supernatants. The Human Cytokine Array
Panel A (R&D Systems, Inc.) is an example of such an array. Other protein
arrays have been used in different multiple cytokine expression studies
(Bradshaw et al., 2008; Kingsmore and Patel, 2003; Schweitze et al., 2002).
RNA sequencing (Seq) is another multiplexing method developed as a
consequence of the human sequencing project. This high-throughput novel
sequencing technology enables mapping and quantifying of transcriptomes,
the set of all mRNA molecules transcribed in one cell or a population of cells
and therefore is superior to microarrays. Further analysis of RNA-Seq
experiments is usually verified by qPCR (reviewed in Wang et al., 2009).
Multiple studies used this method for analysis of inflammation. Examples
include profiling of gene expression for type 1 diabetes in the human pan-
creatic islet transcriptome that suggested that cytokines modify alternative
splicing in human islet cells (Eizirik et al., 2012), and transcriptional profiles
of IBD in different models, emphasizing the need for careful selection and
interpretation of qualified animal models in preclinical research (Holgersen
et al., 2015).
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12 Nirit Bernstein et al.

3. CLASSIFICATION OF ANTIINFLAMMATORY
SUBSTANCES
3.1 Synthetic Antiinflammatory Substances
Synthetic antiinflammatory compounds can be classified into three main
groups. The first major group of antiinflammatories is steroids, which target
the glucocorticoid receptor such as cortisol and prednisone (Rhen and
Cidlowski, 2005). However, various cardiovascular, endocrine, and even
neuropsychiatric side effects associated with corticosteroids stimulated the
development of the second group of synthetic antiinflammatories, the non-
steroidal antiinflammatory drugs (NSAIDs) which primarily target eicosanoid
biosynthesis (Ricciotti and Fitzgerald, 2011). Examples include the previously
mentioned aspirin, as well as ibuprofen, naproxen, and COX-2-selective
inhibitors such as celecoxib and rofecoxib (Vioxx). Unfortunately, side effects
including gastrointestinal and cardiovascular complications were eventu-
ally reported with NSAIDs as well (Ng and Chan, 2010). More recently,
biological treatments primarily utilizing monoclonal antibodies which
target cytokine signaling are being developed without the side effects of
NSAIDs (Rider et al., 2016). However, while some success has been dem-
onstrated in the treatment of a number of diseases including RA, more
research is needed to confirm the efficacy and safety of these novel
treatments.

3.2 Plant-Derived Antiinflammatory Compounds

Following extraction from the plant and fractionation, active compounds
from extracts may be purified and structures determined using different
spectroscopic methods such as mass spectrum (MS), MS-MS, MALDI-
TOF, or NMR (Kim et al., 2010). A number of different compounds that
have antiinflammatory activities were identified from different plant spe-
cies, including herbs, spices, and medicinal plants. Antiinflammatory com-
pounds found in plants can be divided into a number of major chemical
classes.

3.2.1 Phenylpropanoids
The phenylpropanoid biosynthetic pathway produces a number of chemical
classes with antiinflammatory activity. These include flavonoids, hydrox-
ycinnamic acids and their derivatives, and stilbenoids.
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Antiinflammatory Potential of Medicinal Plants 13

3.2.1.1 Polyphenols
Polyphenols are secondary metabolites produced by many plant species.
More than 5000 polyphenols have been identified in plants. Many of them
are associated with a wide spectrum of health effects (Cheynier et al., 2015),
including antiinflammatory, antimicrobial, anticarcinogenic, anti-HIV, car-
dioprotective, and neuroprotective activity.
Among the most active polyphenols are flavonoids (Ullah and Khan,
2008). Different classes of flavonoids are present in plants, in relatively small
amounts, ranging from 0.2–0.4 g/kg in Lamiaceae herbs to 7 g/kg in bay
leaf (Shan et al., 2005). Flavonoids are often hydroxylated at different posi-
tions and are usually present as conjugated compounds in plants.
Flavonols are a well-studied subclass of flavonoids, which include quer-
cetin and rutin. Quercetin and rutin are found in onions, apples, broc-
coli, tea, berries, and Gingko. Other subclass of flavonoids are flavanones
(hesperidin, naringenin), flavones (apigenin, luteolin), flavanols (catechins,
epicatechins, EGCG), isoflavones (genistein, biochanin A), and anthocyanidins
(delphinidin, malvidin) (Nijveldt et al., 2001).
Flavonoids are known to have strong antiinflammatory activity.
A number of in vitro studies have shown that quercetin is capable of
inhibiting lipopolysaccharides (LPSs)-induced TNF-α production in mac-
rophages and LPS-induced IL-8 production in lung cells (A549), as well
as reduce mRNA levels of TNF-α and IL-1 (reviewed by Nathiya
et al., 2014).
The ability of polyphenols in general and flavonoids in particular to have
antiinflammatory effect probably relies on their ability to act as antioxidants.
Reactive oxygen species (ROS) are a major contributor to many diseases,
including those associated with inflammation (Blaser et al., 2016). ROS
were shown to damage many biomolecules, including lipids, proteins,
DNA, and small molecules. Natural antioxidant molecules found in food
can either counter ROS directly or enhance the body antioxidant capacity
(Shahidi and Ambigaipalan, 2015).
In the case of polyphenols, their antioxidant activity is mainly due to
their redox properties and their ability to block the production of ROS. This
ability is based probably on their free radical scavenging activity, transition
metal-chelating activity, and/or singlet oxygen quenching capacity (Shahidi
and Ambigaipalan, 2015). They also stimulate synthesis of endogenous
antioxidant molecules in cells via activating the Nrf-2/HO-1 pathway
(Shi et al., 2013). Quercetin is a very potent scavenger of ROS, including
O2  and NO (Gibellini et al., 2010). This activity is based on its molecular
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14 Nirit Bernstein et al.

structure: the catechol group in the B ring and the OH group at position 3
on the AC ring (Formica and Regelson, 1995; Heijnen et al., 2001a,b).
Moreover, ROS also promote inflammatory processes by activation of
transcription factors, such as NF-κB and activator protein (AP-1), which
induces the production of cytokines like TNF-α (e.g., Redhu et al.,
2011). In accordance, evidence suggests that natural antioxidants affect the
complex network of transcription factors, enzyme, and cytokines production
associated with the functional signaling of inflammation. Quercetin can
modulate the level of NF-κB and thereby inhibit the expression of TNF-
α in human PBMCs (Nair et al., 2006). Also, by blockade of NF-κB activa-
tion, quercetin modulates the levels of iNOS, COX-2, and C-reactive
protein (Garcı́a-Mediavilla et al., 2007).
One of the most potent polyphenols is curcumin (diferuloylmethane),
derived from the spice turmeric (also an ingredient of curry powder)
(Sathiyabama et al., 2016). It is well known in folklore to be an effective
agent against various inflammatory diseases. Indeed, Singh and Aggarwal
(1995) demonstrated that curcumin is a potent inhibitor of NF-κB activation
induced by different inflammatory stimuli (Singh and Aggarwal, 1995). This
inhibitory activity of curcumin is at least partially due to inhibition of IκB-α
kinase (inducer of NF-κB) and AKT, resulting in the suppression of NF-κB-
dependent gene products (reviewed by Kunnumakkara et al., 2017).
Curcumin also downregulates inflammatory-associated enzymes, such as
COX-2 and LOX-5, and proinflammatory cytokines (such as TNF-α, IL-1,
and IL-6) and mediates the suppression of numerous cell signaling pathways
including STAT3, Nrf-2, and ROS (reviewed by Kunnumakkara et al.,
2017). Curcumin’s bis-α,β-unsaturated β-diketone, two methoxy groups,
two phenolic hydroxy groups, and two double-conjugated bonds were
suggested to be essential for the antiinflammatory activities of curcumin
(Sandur et al., 2007). To summarize, curcumin affects the inflammatory pro-
cess at several different cellular levels.
Due to the important role of inflammation in most chronic diseases, cur-
cumin was found to be potent in relieving neoplastic, neurological, cardio-
vascular, pulmonary, and metabolic diseases (reviewed by Kunnumakkara
et al., 2017). Indeed, studies in animal models and human clinical trials dem-
onstrated the therapeutic potential of curcumin (reviewed by Kunnumakkara
et al., 2017). It was concluded that curcumin, by acting on several different
inflammation-related processes, may offer effective prophylaxis or treatment
of complex multifactorial inflammatory diseases, such as IBD, a major risk
factor for colon cancer.
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Antiinflammatory Potential of Medicinal Plants 15

3.2.1.2 Hydroxycinnamic Acids and Derivatives

Hydroxycinnamic acid compounds are an important source of antioxidants
due to their characteristic activities and their wide occurrence in plants and
in almost all food groups, including cereals, legumes, oilseeds, fruits, vege-
tables, beverages, herbs, and spices (Robbins, 2003).
Hydroxycinnamates and derivatives were shown to exert a myriad of
health benefits including antidiabetic, antioxidant, and antimelanogenic
activities (Kim et al., 2012a,b,c; references within), based mainly on their
antioxidant properties. This activity was suggested to be a result of their
chain-breaking antioxidants acting through radical scavenging activity, that
is, related to their hydrogen or electron donating capacity and to their ability
to delocalize/stabilize the resulting phenoxyl radical within their structure
(Teixeira et al., 2013).
Moreover, careful examination of structure–function relations suggested
that the presence of an orthodihydroxy phenyl group (catechol moiety) on
hydroxycinnamic acid is of significant importance to the antioxidant activ-
ity, while the presence of three hydroxy groups does not necessarily improve
the activity (Razzaghi-Asl et al., 2013).
The main antioxidant derivatives of hydroxycinnamic acid are caffeic
acid, chlorogenic acid, sinapic acid, ferulic acid, gallic, p-hydroxy cinnamic
acids, and p-coumaric acid, although with differing therapeutic activity. For
example, caffeic acid at 5 μM and sinapic acid at 10 μM protected copper-
induced low-density lipoprotein (LDL) against oxidation, inhibiting both
hydrogen peroxide formation and the increase of apoprotein negative
charge. However, ferulic, gallic, and p-hydroxy cinnamic acids were inef-
fective (Chalas et al., 2001).
Caffeic acid, one of the most effective antioxidants, is found in great
amounts in a number of Mediterranean culinary herbs, including sage, pars-
ley, thyme, and oregano (Wojdyło et al., 2007). Interestingly, coffee beans
contain a common polyphenol, chlorogenic acid, an ester of caffeic acid,
and quinic acid. Caffeic acid had stronger antioxidant activity than chlo-
rogenic acid and higher bioavailability. That combined with the fact that
chlorogenic acid is hydrolyzed into caffeic acid in the intestine, suggesting
that caffeic acid plays a major role in the protective effect of chlorogenic
acid against intestinal ischemia–reperfusion injury (Sato et al., 2011).
Caffeic acid showed a high antioxidant activity, inhibiting in macrophages
the production of NO, a free radicle, and signaling molecule in several
pathological processes. Furthermore, caffeic acid suppressed LPS-induced
signaling pathways, namely, p38 MAPK, JNK1/2, and NF-κB and
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16 Nirit Bernstein et al.

did not induce hepatotoxicity at antiinflammatory active concentrations

(Búfalo et al., 2013).
In acute and chronic skin inflammation, topical treatment with caffeic
acid inhibited 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced skin
edema in a dose-dependent manner, leading to substantial reductions in skin
thickness and various histopathological indicators. Also, this treatment sig-
nificantly reduced the level of TNF-α, IL-6, and IL-1β at the application
site, and TNF-α-induced NF-κB activation in human keratinocytes
in vitro (Zhang et al., 2014).
p-Coumaric acid is an important ingredient in oregano (Shan et al.,
2005). p-Coumaric acid from fruits of Cornus officinalis was shown to inhibit
the expression of iNOS and COX-2 in vitro, in PC12 cells. Blockade of
nuclear translocation of the p65 subunit of NF-κB and phosphorylation
of IκB-α was also observed after p-Coumaric acid treatment as well as com-
prehensively inhibition of NF-κB activity (Yoon et al., 2014).
Effect of p-Coumaric acid was demonstrated in vivo to have immuno-
modulatory and antiinflammatory properties, leading to reduced cell-
mediated immune responses and macrophage phagocytic index. It also led
to a decrease in the expression of the inflammatory mediator TNF-α and
circulating immune complexes in an in vivo model of the rheumatoid arthri-
tis (Pragasam et al., 2013).
Also, oral administration of p-Coumaric acid significantly inhibited LDL
oxidation and reduced LDL levels in vivo (Zang et al., 2000).
Eugenol (4-allyl-2 methoxyphenol), the major component of cloves
(Syzygium aromaticum) (Shan et al., 2005), was shown in vitro to inhibit
the production of IL-6 and IL-10, and to prevent the IL effects of LPS, pos-
sibly via the suppression of the NF-κB pathway (Bachiega et al., 2012).
Protection against free radical-mediated lipid peroxidation by eugenol
was demonstrated using both in vitro and in vivo models. Eugenol signifi-
cantly inhibited the rise in serum glutamic oxalacetic transaminase activity
and cell necrosis without protecting the endoplasmic reticulum damage
(Nagababu et al., 2010). Also, eugenol was demonstrated to effectively alle-
viate an in vitro model of acute lung injury, a clinical syndrome that results
from complex responses of the lung to a multitude of direct and indirect
insults. The suggested mechanism of eugenol activity was the decreased pro-
duction of proinflammatory cytokines through regulating the inflammation
and redox status (Huang et al., 2015).
Rosmarinic acid is typically found in Lamiaceae plants, such as basil
(Ocimum spp.), rosemary (Rosmarinus spp.), thyme (Thymus spp.), mint
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Antiinflammatory Potential of Medicinal Plants 17

(Mentha spp.), and oregano (Origanum spp.) (reviewed by Petersen and

Simmonds, 2003).
Rosmarinic acid has two orthodihydroxy groups (catechol structures), an
important structural feature for strong antioxidant activity in phenolic com-
pounds. It significantly inhibited both intracellular superoxide and peroxide
formation in differentiated HL-60 cells, suggesting rosmarinic acid to be an
effective antioxidant in biological systems through the scavenging of super-
oxides (Nakamura et al., 1998).
Rosmarinic acid has been shown to reduce IL production following
T cell stimulation and selectively induce T cell apoptosis in aberrant
lymphocytes, but not normal/quiescent T cells. Furthermore, this mole-
cule was shown to affect specific tyrosine kinase enzymes inside T cells
(Stansbury, 2014).
Indeed, in an in vivo model it was shown that rosmarinic acid can aid in the
treatment of acute liver toxicity following CCl4 intoxication. CCl4 intoxi-
cation causes hepatic necrosis and triggers an inflammatory response in mice
liver by activating NF-κB, coinciding with the induction of TNF-α and
COX-2. Rosmarinic acid was shown to inhibit the CCl4-induced apoptosis,
which was evident from decreased cleavage of caspase-3, and improved his-
tological and serum markers of liver damage. It also significantly ameliorated
oxidative/nitrosative stress and the inflammatory response in liver tissue.
Additionally, rosmarinic acid prevented transforming growth factor-beta1
(TGF-β1) and alpha-smooth muscle actin (α-SMA) expression, suggesting
suppression of a profibrotic response. It was concluded that rosmarinic acid
possesses antioxidant, antiinflammatory, antiapoptotic, and antifibrotic activ-
ity against acute liver toxicity (Domitrovi
c et al., 2013).
Moreover, in rat models of systemic and local inflammation, rosmarinic
acid produced a dose–response effect, suggesting that rosmarinic acid was
the main contributor to the antiinflammatory effect. In the thermal injury
model, rosmarinic acid significantly reduced multiorgan dysfunction markers
(liver, kidney, lung) by modulating NF-κB and metalloproteinase-9 (Rocha
et al., 2015).

3.2.1.3 Stilbenoids
Another group of important secondary metabolites in the phenylproponoid
pathway are the stilbenoids. While a number of bioactive stilbenoids have
been discovered in plants, the most well known and studied by far is resver-
atrol, found in a number of plants including wine and peanuts. A number
of therapeutic claims have been attributed to resveratrol, including
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18 Nirit Bernstein et al.

antiinflammatory activity. Resveratrol has been shown to inhibit COX-1

and PGES-1 activity (Candelario-Jalil et al., 2007) and reduce COX-2 gene
expression (Annabi et al., 2012).
In animal models, resveratrol was shown decrease the levels of
proinflammatory cytokines including TNF-α, IL-1, and IL-6 (Jeon et al.,
2012; Wang et al., 2013). Resveratrol reduced inflammation in a rodent
model of arthritis (Bereswill et al., 2010; Elmali et al., 2007; Larrosa et al.,
2009). With the extensive in vitro and in vivo evidence for resveratrol’s
antiinflammatory activity, it is somewhat surprising that the clinical data are
somewhat conflicting. Only a small number of studies observed a decrease
in inflammatory markers (Bo et al., 2013; Tome-Carneiro et al., 2012).
On the other hand, more than half of the human trials with resveratrol did
not reveal any therapeutic effect (Tom
e-Carneiro et al., 2013). This discrep-
ancy may be at least partially due to the poor bioavailability of resveratrol.
In addition to resveratrol, a number of other stilbenoids have been shown
to possess antiinflammatory activity. Pinosylvin, found in Pinus and Alnus,
reduced NO and IL-6 production, reducing carrageenan-induced paw
inflammation in mice (Laavola et al., 2015) and inhibited neutrophil activity
in an animal model of arthritis (Jančinová et al., 2012). Piceatannol decreased
the expression of TNF-α and IL-8 in stimulated mast cells (Ko et al., 2013)
and inhibited LPS-induced production of PGE2 and NO in macrophages
(Djoko et al., 2007).

3.2.2 Terpenes
Terpenes are composed of combinations of several 5-carbon-base (C5) units,
dimethylallyl diphosphate (DMAPP), and isopentenyl diphosphate (IPP),
typically by condensation of DMAPP with one or more IPP molecules
(Oldfield and Fu-Yang, 2012). Subsequent secondary enzymatic modifica-
tions (redox reaction) ascribe different functional properties to various mod-
ified terpenes (Rubió et al., 2013).
Monoterpenes and diterpenes are found in herbs and medicinal plants, and
constitute 90% of the essential oils. Two important terpenes are thymol and
carvacrol (Rubió et al., 2013). Essential oils from oregano and thyme con-
taining thymol and carvacrol were shown to have antiinflammatory activity,
inhibiting inflammatory edema and leukocyte migration (Fachini-Queiroz
et al., 2012). The antiinflammatory activity of thymol and carvacrol was
shown in a cellular model of atherosclerosis to be associated with a decrease
in proinflammatory TNF-α, IL-1b, and IL-6 cytokines synthesis, and an
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Antiinflammatory Potential of Medicinal Plants 19

increase in the production of the antiinflammatory cytokine IL-10 (Ocana-

Fuentes et al., 2010).
Thymol and carvacrol are also recognized as antioxidants (Aeschbach
et al., 1994), and as radical scavengers (Kruk et al., 2000). Also, thymol
and carvacrol act in preventing the autoxidation of lipids (Yanishlieva and
Marinova, 2006) and more specifically the copper-induced oxidation of
LDLs (Kulisi
c et al., 2007). These compounds also have wide antimicrobial
activity (e.g., Guarda et al., 2011; P
erez-Alfonso et al., 2012).
Lai et al. (2009) demonstrated that rosmanol, a natural diterpene from
rosemary, downregulates the gene expression of the inflammatory iNOS
and COX-2 through interfering with phosphatidylinositol 3-kinases
(PI3K/Akt) activation and MAPK signaling, thereby inhibiting NF-κB
and STAT3. Other diterpenes found in rosemary are carnosic acid and
carnosol, along with rosmarinic acid, a hydroxycinnamic acid ester. Car-
nosic acid and carnosol have strong antioxidant activity (Frankel et al.,
1996). Accordingly, rosemary extract is one of the most widely used and
commercialized plant extracts used as an antioxidant in raw and processed
foods and cosmetics (e.g., Birti
c et al., 2015; Jordán et al., 2014; Zhang
et al., 2010).
Regarding the antiinflammatory activity of carnosol and carnosic acid, it
was shown that extracts containing these compounds activate the peroxi-
some proliferator-activated receptor gamma, implying antiinflammatory
activity. Also, in human polymorphonuclear leukocytes, they inhibit the
formation of proinflammatory leukotrienes and potently antagonize intra-
cellular Ca2+ mobilization induced by chemotactic stimulus. They also
attenuated the formation of ROS and the secretion of human leukocyte
elastase (Poeckel et al., 2008; Rau et al., 2006).
Carnosic acid had relatively high bioavailability in rats, being absorbed
into the blood stream following oral administration and reached 40% after
360 min following administration (Doolaege et al., 2011).

3.2.3 Alkaloids
One of the largest classes of bioactive secondary metabolites are the
nitrogen-containing alkaloids. While the first and possibly most famous alka-
loid identified was morphine isolated from poppie, alkaloids can be found in
many plants especially in the nightshade family (Solanaceae). Based on their
chemical structural, alkaloids can be divided into a number of groups with
the most studied being the isoquinoline, indole, diterpene, and amide
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20 Nirit Bernstein et al.

alkaloids, although there are many more groups. Alkaloids have been uti-
lized therapeutically for a number of conditions including inflammation.
While the most famous isoquinoline alkaloid, morphine, is a well-
known analgesic, a number of isoquinoline alkaloids have been identified
with antiinflammatory activity. Berberine, found in Barberry (Berberis)
and additional species, has been used traditionally for treating gastrointes-
tinal and more recently for metabolic disorders. A number of preclinical
studies suggest that berberine and related compounds possess significant
antiinflammatory activity in models of colitis (Yesilada and Kupeli, 2002;
Zhou and Mineshita, 2000), rheumatoid arthritis (Wang et al., 2014a,b),
and metabolic syndrome (Li et al., 2015).
Another important isoquinoline alkaloid with antiinflammatory activity
is colchicine. Found in crocus (Colchicum), colchicine was traditionally
used for treating gout (Wallace and Roberts, 1953). This traditional use
was supported by preclinical studies showing colchicine inhibits histamine
release in mast cells (Gillespie et al., 1968) and expression of LPS-induced
TNF-α (Li et al., 1996). In fact, colchicine was even found effective at
reducing inflammation in a clinical trial of osteoarthritis (Das et al., 2002)
and is currently approved by the FDA for treating gout.
Of the indole alkaloids, the most well known, strychnine, is from the
strychnine tree (Strychnos). Although used traditionally in Ayurveda medi-
cine, the toxicity of strychnine makes future development difficult. How-
ever, the related compound, brucine, possesses much lower toxicity and
shows promising therapeutic activity in animal models (Chen et al., 2012;
Yin et al., 2003).
Regarding diterpene alkaloids, Aconitum species were found to contain
a number of antiinflammatory alkaloids including aconitine and related
compounds (Nesterova et al., 2014; Wangchuk et al., 2015). While these
compounds possess acute toxicity, the therapeutic index based on mouse
models of histidine and carrageenan-induced inflammation was determined
to be sufficient to merit further development.
Another group of alkaloids with significant antiinflammatory activity is
capsaicin and the related capsaicinoids. Responsible for the spiciness in chili
peppers (Capsicum) in which it is naturally found, capsaicin also possesses
antiinflammatory activity. Capsaicin inhibited LPS-induced PGE2 produc-
tion as well as IKB degradation, effectively inactivating NF-κB in mouse
macrophages (Kim et al., 2003). Capsaicin pretreatment alleviated inflam-
mation in a rat model of pulmonary arterial hypertension via MAPK inhi-
bition (Xu et al., 2017). In adipose tissue of obese mice, capsaicin suppressed
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Antiinflammatory Potential of Medicinal Plants 21

IL-6 and MCP-1 expression (Kang et al., 2007) and the level of inflamma-
tory cytokines (Kang et al., 2010).
While successful clinical studies led to capsaicin’s approved use in the
United States for treating localized pain (Casanueva et al., 2013), trials
demonstrating efficacy against inflammation are less convincing. Capsaicin
alleviated some of the symptoms in IBS patients (Bortolotti and Porta,
2011). However, it was not effective in treating inflammatory osteoarthri-
tis (Altman and Barthel, 2011), although a meta-analysis claimed to find
sufficient evidence, suggesting capsaicin is effective for treating osteoar-
thritis (de Silva et al., 2011). Further clinical studies are needed to more
accurately evaluate the efficacy of capsaicin at alleviating inflammation.

4. MEDICINAL PLANTS WITH CONFIRMED

ANTIINFLAMMATORY ACTIVITY
Of the hundreds of plants used traditionally to treat inflammation and
inflammation-related disorders, a large number have been tested scientifi-
cally to confirm their antiinflammatory activity. In this review, we focused
on plants with significant evidence based on in vitro and in vivo models of
inflammation. We present here a partial list of some of the most promising
plants, describing their distribution, plant parts used, known chemical con-
stituents, and pharmacological activity.

4.1 Abrus precatorius (Fabaceae)

Parts used: Roots, seeds, and leaves. Geographic distribution: It is found
Taiwan, China, Asia, and Africa (Hata et al., 2014). Chemical Constituents:
Orientin, abrectorin, luteolin, anthocyanins, triterpenoids, precol, precasine,
abrasine, polygalacturonic acids, campesterol, abraline, abrusin-20 -O-apioside
(Narendra and Atul, 2014). Pharmacological activity: Antiinflammatory, antimi-
crobial, antioxidant, and immunomodulant (Tilwari et al., 2011). Study:
Significant antiinflammatory activity of the acetate extract of Abrus precatorius
in the croton oil ear model of inflammation (Anam, 2001).

4.2 Agave americana (Asparagaceae)

Parts used: Pulp of plant, leaves. Geographic distribution: It is found in South
America and the United States (Pinkie et al., 2011). Chemical constituents:
It contains saponin, agavegenin, and homoisoflavonoid (Tinto et al.,
2005). Medicinal uses: It is used in constipation, acidity, boils, pimples, and
cancer (Anajwala et al., 2010). Pharmacological activity: It is antiinflammatory
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22 Nirit Bernstein et al.

and cytotoxic (Anajwala et al., 2010). Study: Agave americana L. reduced

carrageenan-induced rat paw edema at dose of 200 and 300 mg/kg (Peana
et al., 1997).

4.3 Ageratum conyzoides L. (Asteraceae)

Parts used: Whole plant, leaves, and root. Geographic distribution: It is found in
West Indies, South America, and Nigeria (Moody et al., 2006). Pharmacolog-
ical activity: Antiinflammatory, anticancer, and gastroprotective (Adebayo
et al., 2010). Study: Hydroalcoholic extract of Ageratum conyzoides reduced
the cotton pellet granuloma by 38.7% in a subacute model of inflammation
and in carrageenan-induced edema in rats (Moura et al., 2005).

4.4 Ajuga bracteosa Benth. (Lamiaceae)

Parts used: Leaves. Geographic distribution: It is found in Pakistan, India, Kashmir,
and Nepal (Shivanee et al., 2013). Chemical constituents: It contains bractic acid,
sphingolipids, bractin, and limonene (Abhishek and Harpreet, 2011). Medicinal
uses: It is used in malarial fever (Chandel and Bagai, 2010). Pharmacological activ-
ity: It is astringent, antiinflammatory, antiplasmodial, tonic, and antiarthritic
(Gaurav et al., 2012). Study: Ethanolic extract of Ajuga bracteosa exhibited
significant antiinflammatory activity at a dose of 0.5 and 1 mg/ear in TPA-
induced mouse ear edema (Gautam et al., 2010).

4.5 Allium sativum (Liliaceae)

Parts used: Bulb. Geographic distribution: It is native to the Middle East and
Central Asia (Ashraf et al., 2013). Chemical constituents: It contains diallyl disul-
fide, diallyl trisulfide, phytocidin, acrolein, alliin, allicin, scordicin, and ajoene
(Ledezma and Apitz, 2006). Medicinal uses: It is used in flu, cough, chest
infections, diarrhea, dysentery, urinary tract infections, and cardiovascular
disorders (Ginter and Simko, 2010). Pharmacological activity: It is antiseptic,
antimicrobial, hypotensive, circulatory stimulant, digestive, diaphoretic,
cholagogue, and antioxidant (Meriga et al., 2012). Study: Allium sativum
(garlic) modulated cytokine production and leukocyte cell proliferation
and inhibited production of IL-12, tumor necrosis factor, and cytokines
(Hodge et al., 2002).

4.6 Aloe vera (Xanthorrhoeaceae)

Parts used: Leaves. Geographic distribution: It is found in Indian Ocean Islands,
Arabian Peninsula, and Mexico (Vazquez et al., 1996). Chemical constituents:
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Antiinflammatory Potential of Medicinal Plants 23

It contains anthraquinones including aloin and emodin; salicylic acid, sapo-

nins, beta-carotene, vitamin B12, folic acid, choline (Atherton, 1998). Phar-
macological activity: Antiinflammatory, antibacterial, anticeptic, and wound
healing (Atherton, 1998; Dat et al., 2012). Study: Aqueous extract of Aloe
vera exhibited significant antiinflammatory effect in carrageenan-induced
edema in rats (Vazquez et al., 1996).

4.7 Alstonia boonei (Apocynaceae)

Parts used: Bark. Geographic distribution: It is found in Northern Angola,
Southern DR, Congo, and Nigeria (Olanlokun et al., 2012). Pharmaco-
logical activity: Antiinflammatory, analgesic, and antipyretic (Olajide
et al., 2000). Study: A methanol extract of Alstonia boonei exhibited signif-
icant antiinflammatory activity in carrageenan-induced paw edema in rats
(Olumayokun et al., 2000).

4.8 Ammi majus Linn. (Umbelliferae)

Parts used: Aerial parts. Geographic distribution: It is found in India, Western
Asia, Mediterranean region, Europe, and Egypt (Yasser and Nabil, 2012).
Chemical constituents: It contains bergapten and furanocoumarin (Ekiert and
Gomółka, 2000). Medicinal uses: It is used in AIDS, cancer, and vitiligo
(Venkateswaran, 1955). Pharmacological activity: It is antiinflammatory
(Selim and Ouf, 2012). Study: Ammi majus contains coumarin that has
antiinflammatory activity (Yasser and Nabil, 2012).

4.9 Arctium lappa L. (Asteraceae)

Parts used: Root and seeds. Geographic distribution: It is found in Asian,
North America, and Europe (Chan et al., 2011). Pharmacological activity:
Antiinflammatory, antioxidant, gastroprotective, and hepatoprotective
(Lin et al., 2000). Study: Arctigenin isolated from this plant inhibits
IL-6, tumor necrosis factor, and NO production (Zhao et al., 2009).

4.10 Azadirachta indica (Meliaceae)

Parts used: Leaves and bark. Geographic distribution: It is found in Sri Lanka,
Bangladesh, Pakistan, Nepal, and India (Mercy et al., 2010). Pharmacological
activity: Antiinflammatory and hypoglycemic (Khosla et al., 2000). Study:
Significant antiinflammatory activity was exhibited by Azadirachta indica
in rat paw edema (Okpanyi and Ezeukwu, 1981).
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24 Nirit Bernstein et al.

4.11 Bauhinia racemosa (Fabaceae)

Parts used: Leaves. Geographic distribution: It is found in Sri Lanka and India
(Parveen et al., 2012). Pharmacological activity: Antiinflammatory, ant-
ihyperlipidemic, and antioxidant (Rashed and Butnariu, 2014). Study:
Significant antiinflammatory activity was exhibited by a methanol extract
of Bauhinia racemosa at a dose of 200 mg/kg body weight in carrageenan-
induced paw edema (Gupta et al., 2005).

4.12 Bauhinia variegata (Fabaceae)

Parts used: Leaves. Geographic distribution: It is found in Sri Lanka and Pakistan
(Hussain et al., 2004). Pharmacological activity: Antihyperlipidemic, antioxi-
dant, antiinflammatory, antidiabetic, and hepatoprotective (Bodakhe and
Ram, 2007). Study: Rao et al. reported that Bauhinia variegata inhibited func-
tion of inflammation-related macrophages, reducing the levels of IL-6,
tumor necrosis factor, NO, and interferon (Rao et al., 2008).

4.13 Bauhinia variegata (Fabaceae)

Parts used: Leaves. Geographic distribution: It is found in China, Burma,
Nepal, Central India (Yadava and Reddy, 2003). Pharmacological activity:
Antiinflammatory, hypolipidemic, and antioxidant (Rajani and Ashok,
2009). Study: Bauhinia variegata Linn. has compounds (including 5,7,30 ,40 -
tetrahydroxy-3-methoxy-7-O-alpha-L-rhamnopyranosyl(1 !3)-O-beta-
galactopyranoside) that exhibit antiinflammatory activity (Yadava and
Reddy, 2003).

4.14 Boswellia carteri (Burseraceae)

Parts used: Gum resin. Geographic distribution: It is found in Japan (Banno
et al., 2006). Pharmacological activity: Antiinflammatory, chemopreventive,
immunomodulant, antioxidant, and cardioprotective (Zaki et al., 2014).
Study: Boswellia carteri inhibited 12-O-tetradecanoylphorbol-13-acetate
(TPA)-induced inflammation at a dose of 1 μg/ear in mice (Banno
et al., 2006).

4.15 Boswellia serrata (Burseraceae)

Parts used: Gum resin. Geographic distribution: It is found in the Middle East,
Northern Africa, and India (Kimmatkar et al., 2003). Pharmacological activity:
Antiarthritic and antiinflammatory (Abdel et al., 2011). Study: Boswellia
serrata inhibited tumor necrosis factor, IL-1, and NO (Gayathri et al., 2007).
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Antiinflammatory Potential of Medicinal Plants 25

4.16 Calotropis procera (Asclepidaceae)

Parts used: Leaves and flowers. Geographic distribution: It is found in South, Cen-
tral, and North America, Pacific Islands, and Australia (Leal et al., 2013).
Chemical constituents: It contains proceoside, calotropin, calotoxin, beta
amyrin, syriogenin, saponins, and flavonoids (Moustafa et al., 2010). Medicinal
uses: It is used in cold, cough, asthma, indigestion, and inflammation (Alencar
et al., 2004). Pharmacological activity: It is an expectorant, nerve tonic, anthel-
mintic, and anticonvulsant (Lima et al., 2012). Study: Calotropis procera
inhibited cyclooxygenase and NO synthase involved in the inflammation
process (Freitas et al., 2012).

4.17 Camellia japonica (Theaceae)

Parts used: Seeds. Geographic distribution: It is found in Indonesia, Japan,
Southern, and Eastern Asia (Ueno et al., 2000). Chemical constituents: It con-
tains kaempferol, quercetin, and triterpenoids (Thao et al., 2010). Medicinal
uses: It used in inflammation, degenerative disorders, and bacterial infections
(Kim et al., 2001). Pharmacological activity: It is antibacterial, antioxidant, and
antiinflammatory (Kim et al., 2012a,b,c). Study: Camellia japonica inhibited
NO synthase and induction of cyclooxygenase (Kim et al., 2012a,b,c).

4.18 Cannabis sativa (Cannabinaceae)

Parts used (medicinal): Nonfertilized female flowers and seeds. Geographic
distribution: It is indigenous to central Asia and the Indian subcontinent
(ElSohly, 2007). Chemical constituents: It contains cannabinoids, terpenes, terpe-
noids, and flavonoids (Gorelick and Bernstein, 2017). Medicinal uses: It is used
for a wide range of indications including degenerative disorders, neurological
problems, nausea, and vomiting during chemotherapy, improve appetite
in people with HIV/AIDS, reduce chronic pain and muscle spasms, post-
traumatic stress disorder, IBD, cancer, and more (Borgelt et al., 2013).
Pharmacological activity: It is antibacterial, antioxidant and antiinflammatory,
anxiolytic, sedative, analgesic, and more. Study: Summarized in Borgelt
et al. (2013).

4.19 Cinnamomum osmophloeum (Lauraceae)

Parts used: Leaves. Geographic distribution: It is found in Southern Asia, India, and
China (Pasupuleti and Siew, 2014). Chemical constituents: It contains benzalde-
hyde, pinene, camphene, cinnamaldehyde, phenyl propionaldehyde, eugenol,
isobornylacetate, and cinnamylacetate (Tung et al., 2010). Medicinal uses:
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26 Nirit Bernstein et al.

It is used in inflammation, cardiovascular disorders, and hyperlipidemia

(Lin et al., 2011). Pharmacological activity: It is antibacterial, antihyper-
uricemic, insecticidal, antifungal, antidyslipidemic, and antiinflammatory
(Tung et al., 2008). Study: An extract inhibited pro-IL-1beta protein
involved in the inflammatory process (Chao et al., 2008).

4.20 Clerodendrum petasites (Lamiaceae)

Parts used: Roots, stem, and leaves. Geographic distribution: It is found in
Thailand (Panthong et al., 2004). Pharmacological activity: Antiinflammatory,
antipyretic, and bronchodilator (Hazekamp et al., 2001). Study: Methanolic
extracts of wood of Clerodendrum petasites exhibited strong antiinflammatory
activity in ethyl phenylpropionate-induced inflammation (Panthong
et al., 2004).

4.21 Eupatorium perfoliatum (Asteraceae)

Parts used: Aerial parts. Geographic distribution: It is found in Canada and the
United States (Laura and Ray, 2009). Chemical constituents: It contains lac-
tones, flavonoids, and caffeic acid (Maas et al., 2008). Medicinal uses: It is used
in fever and flu (Hensel et al., 2011). Pharmacological activity: It is antipyretic
and antimalarial (Lira et al., 2006). Study: Eupatorium perfoliatum L. exhibits
antiinflammatory effect against LPS-stimulated macrophages by inhibiting
the release of NO (Maas et al., 2011).

4.22 Eupatorium purpureum (Asteraceae)

Parts used: Roots. Geographic distribution: It is found in North America
(Habtemariam, 2001). Chemical constituents: It contains benzofurans, euparin,
cistifolin, and euparone (Wu et al., 2012). Medicinal uses: It is used in kidney
stones, gout, chronic uterine disease, and inflammation (Habtemariam,
2001). Pharmacological activity: It is antiinflammatory and antirheumatic
(Habtemariam, 2001). Study: Eupatorium purpureum reduced carrageenan-
induced rat edema at dose of 10 and 50 mg/kg in a dose-dependent manner
(Habtemariam, 1998).

4.23 Ficus carica (Moraceae)

Parts used: Root and fruits. Geographic distribution: It is found in the Middle
East and Western Asia. Chemical constituents: It contains beta sitosterol, ficin,
nicotinic acid, glycosides, and furanocoumarins (Jain et al., 2013). Medicinal
uses: It is used to treat intestinal worms, diabetes mellitus, anemia, small pox,
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Antiinflammatory Potential of Medicinal Plants 27

tachycardia, scrofula, boils, carbuncles, constipation, paralysis, inflamma-

tion, fever, ringworm, leucoderma, leprosy, and herpes infection (Lazreg
et al., 2011). Pharmacological activity: It is a deobstruent, diaphoretic, anti-
diabetic, antidysenteric, antigonorrheal, aphrodisiac, styptic, astringent, lax-
ative, demulcent, emollient, hepatoprotective, diuretic, expectorant, nerve
stimulant, antiinflammatory, lithotriptic, alexiteric, purgative, antipyretic,
tonic, anthelmintic, and antimicrobial (Aref et al., 2010). Study: Ficus carica
exhibited significant antiinflammatory activity, possibly due to the presence
of steroids (Ali et al., 2011).

4.24 Foeniculum vulgare (Apiaceae)

Parts used: Seeds. Geographic distribution: It is found in the Mediterranean
(Kwon et al., 2002). Pharmacological activity: Analgesic, antiinflammatory,
and antioxidant (Ruberto et al., 2000). Study: Foeniculum vulgare extract
increased catalase and plasma superoxide dismutase activity and high-density
lipoprotein levels at a dose of 200 mg/kg (Choi and Hwang, 2004).

4.25 Geranium nepalense (Geraniaceae)

Parts used: Aerial parts. Geographic distribution: It is found in China (Lu et al.,
2012). Chemical constituents: It contains gallic acid, kaempferol, lignin, quer-
cetin, and pyrogallol (Lu et al., 2012). Medicinal uses: It is used in kidney
problems and hyperlipidemia (Changhyun and Uhee, 2012). Pharmacological
activity: It is astringent and antiinflammatory (Chopra et al., 1986). Study:
Geranium nepalense exhibits antiinflammatory effect on tetradecanoyl
phorbol acetate (TPA)-induced mouse ear edema at dose of 2.5 g/kg
(Lu et al., 2012).

4.26 Glechoma hederacea (Lamiaceae)

Parts used: Aerial parts. Geographic distribution: It is found in Japan, Northern
Asia and Europe, Colorado, Tennessee, Georgia, New Zealand, and North
and South island (Michael and Elizabeth, 2003). Chemical constituents: It
contains rosmarinic acid, glucopyranoside, and sesquiterpene lactones
(Kim et al., 2011). Medicinal uses: It is used in flu, sinusitis, chest infections,
ear problems, and gouty arthritis (Masuda et al., 2013). Pharmacological activ-
ity: It is expectorant, astringent, diuretic, and antioxidant (Milovanovic
et al., 2010). Study: Glechoma hederacea inhibits nitric oxide synthase, cyclo-
oxygenase, and tumor necrosis factor (Kim et al., 2012a,b,c).
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28 Nirit Bernstein et al.

4.27 Kalopanax pictus (Araliaceae)

Parts used: Stem bark, Geographic distribution: It is found in temperate Asia and
Korea (Kim et al., 2004). Pharmacological activity: Antiinflammatory, antioxi-
dant, antinociceptive, and antirheumatic (Choi et al., 2002). Study: Kalopanax
pictus reduced production of NO, prostaglandin, and tumor necrosis factor
and exhibited significant antiinflammatory activity in carrageenan-induced
paw edema in a dose-dependent manner (Kim et al., 2004).

4.28 Leonotis leonurus (Lamiaceae)

Parts used: Aerial parts. Geographic distribution: It is found in South Africa
(Mnonopi et al., 2011). Medicinal uses: It is used in diabetes mellitus, inflam-
mation, hypertension, and epilepsy (Bienvenu et al., 2002). Pharmacological
activity: Antiinflammatory, antidiabetic, antinociceptive, and cardioprotective
(Mnonopi et al., 2011). Study: Aqueous extract of Leonotis leonurus exhibited
significant antiinflammatory activity at dose of 50 and 800 mg/kg i.p. in
albumin-induced paw edema in rats (Ojewole, 2005).

4.29 Nigella sativa (Ranunculaceae)

Parts used: Seeds. Geographic distribution: It is found in Mediterranean region,
Middle East, East Africa, North America, Southeast Asia, India, and Europe
(Ali and Bluden, 2003). Pharmacological activity: Antiinflammatory, antihyper-
tensive, antioxidant, and anticancer (Randhawa and Alghamdi, 2011). Study:
Aqueous extract of Nigella sativa exhibited significant antiinflammatory effect
on Carrageenan-induced paw edema (Al-Ghamdi, 2001).

4.30 Parinari polyandra (Rosaceae)

Parts used: Fruit. Geographic distribution: It is found in Nigeria (Vongtau et al.,
2004). Chemical constituents: Saponin glycosides, tannins, and flavonoids. Phar-
macological activity: Antiinflammatory, antinociceptive, immunostimulant, and
hypoglycemic (Ighodaro et al., 2012). Study: The methanolic extract of
Parinari polyandra exhibited significant antiinflammatory activity at 200 mg/kg
per oral in albumin-induced hind paw edema in rats (Vongtau et al., 2004).

4.31 Pfaffia glomerata (Amaranthaceae)

Parts used: Roots. Geographic distribution: It is found in Asia and Brazil (Marques
et al., 2004). Pharmacological activity: Antiinflammatory, antioxidant, and
antileishmanial (Neto et al., 2004). Study: Hydroalcoholic extract of Pfaffia
glomerata root exhibited antiinflammatory activity in carrageenan-induced
edema in rats at doses of 100, 200, and 300 mg/kg (Neto et al., 2005).
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Antiinflammatory Potential of Medicinal Plants 29

4.32 Phrygilanthus acutifolius (Loranthaceae)

Parts used: Flowers. Geographic distribution: It is found in South America (Daud
et al., 2006). Pharmacological activity: Antiinflammatory, antinociceptive, and
antimicrobial (Daud et al., 2006). Study: An aqueous extract of Phrygilanthus
acutifolius exhibited significant antiinflammatory activity in carrageenan-
induced edema (Daud et al., 2006).

4.33 Polygonum bistorta (Polygonaceae)

Parts used: Stem seeds and root. Geographic distribution: It is found in
Europe (Intisar et al., 2012). Chemical constituents: It contains vitamin E,
glycosides, flavonoids, caffeic acid, emodin, phlobaphenes, and gallic acid
(Intisar et al., 2012). Medicinal uses: It is used in wounds, bruises, strains,
sprains, diarrhea, dysentery, hemorrhage, and inflammation (Duwiejua
et al., 1999). Pharmacological activity: It is a demulcent, antihemorrhoidal, anti-
septic, expectorant, antigonorrheal, tonic, diuretic, antipyretic, antidysenteric,
antiemetic, antituberculosis, antidiarrheal, antibilious, and anticancer
(Manoharan et al., 2007). Study: Polygonum bistorta reduced carrageenan-
induced rat paw edema with the activity attributed to friedelanol and
5-glutinen-3-one (Duwiejua et al., 1999).

4.34 Pongamia pinnata L. (Fabaceae)

Parts used: Fruit, leaves. Geographic distribution: It is found in the Pacific
Islands, Australia, Japan, China, and India (Singh and Pandey, 1996). Chem-
ical constituents: It contains sterols, galactosides, hiraginic acid, beta-sitosteryl
acetate, monoenoic acid, oleic acid, dienoic acid, palmitic acid, trienoic
acid, octadecatrienoic acid, and stearic acid (Shameel et al., 1996).
Medicinal uses: It is used in stomach problems, inflammation, and pyrexia
(Singh and Pandey, 1996). Pharmacological activity: It is antiinflammatory,
antibacterial, antinociceptive, and antidiabetic (Sikarwar and Patil, 2010).
Study: Pongamia pinnata exhibited antiinflammatory effects in carrageenan-
induced rat paw edema, inhibiting prostaglandin- and bradykinin-induced
inflammation via modulation of eicosanoid-related processes (Singh and
Pandey, 1996).

4.35 Rosa damascena (Rosaceae)

Parts used: Flowers. Geographic distribution: It is found in Central Asia, East Asia,
and Iran (Hajhashemi et al., 2010). Pharmacological activity: Antiinflammatory, car-
minative, and antimicrobial (Shokouhinejad et al., 2010). Study: Rosa damascene
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30 Nirit Bernstein et al.

exhibited antiinflammatory activity in carrageenan-induced edema in rats

with a dose-dependent response at doses of 250, 500, and 1000 mg/kg
body weight (Hajhashemi et al., 2010).

4.36 Rosmarinus officinalis L. (Lamiaceae)

Parts used: Leaves. Geographic distribution: It is found in the Mediterranean
(Takaki et al., 2008). Pharmacological activity: Antiinflammatory, antioxidant,
antiproliferative, antinociceptive, and antimicrobial (Bernardes et al., 2010).
Study: Significant antiinflammatory activity was exhibited by Rosmarinus off-
icinalis at doses of 250, 500, and 750 mg/kg in carrageenan-induced paw
edema in rats (Takaki et al., 2008).

4.37 Schima wallichii (Theaceae)

Parts used: Bark. Geographic distribution: It is found in Indonesia, South
China, Burma, and North East India (Diantini et al., 2012). Chemical con-
stituents: The leaves contain saponins, tannins, and kaempferol (Diantini
et al., 2012). Medicinal uses: It is used in hysteria, uterine disorders, and inflam-
mation (Dewanjee et al., 2011). Pharmacological activity: It is antiinflammatory
and antiplasmodial (Barliana et al., 2014). Study: Schima wallichii reduced
carrageenan-induced rat paw edema as well as tumor necrosis factor and
IL-6 at doses of 150 and 300 mg/kg p.o. (Dewanjee et al., 2011).

4.38 Sideritis javalambrensis (Lamiaceae)

Parts used: Aerial parts. Geographic distribution: It is found in Spain (Alcaraz
and Jimenez, 1989). Pharmacological activity: Antiinflammatory and antioxi-
dant (Rios et al., 1992). Study: A hexane extract of Sideritis javalambrensis
exhibited significant antiinflammatory activity in carrageenan-induced
edema (Alcaraz and Jimenez, 1989).

4.39 Sphenocentrum jollyanum (Menispermaceae)

Parts used: Bark. Geographic distribution: It is found in South Africa
(Olorunnisola and Afolayan, 2013). Medicinal uses: It is used in sexual dis-
orders, hyperlipidemia, hyperglycemia, and intestinal worms (Gbolade and
Adeyemi, 2008). Pharmacological activity: Antiinflammatory, antioxidant
(Olorunnisola and Afolayan, 2013). Study: Isolated constituents and crude
extract of Sphenocentrum jollyanum exhibited significant antiinflammatory
activity in carrageenan-induced hind paw edema in albino rats (Moody
et al., 2006).
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Antiinflammatory Potential of Medicinal Plants 31

4.40 Stachys inflata (Lamiaceae)

Parts used: Aerial parts. Geographic distribution: It is found in Pakistan, China,
and Iran (Maleki et al., 2001). Pharmacological activity: Antiinflammatory,
immunostimulant, and antimicrobial (Saeedi et al., 2008). Study: Stachys
inflata exhibited antiinflammatory effect in carrageenan-induced edema in
rats at dose of 50 mg and 200 mg/kg (Maleki et al., 2001).

4.41 Taraxacum officinale (Asteraceae)

Parts used: Leaves, roots, flowers, and stem. Geographic distribution: It is found in
South and North America (Keane et al., 2005). Chemical constituents: It con-
tains coumarin, cinnamic acid, and flavonoids (Williams et al., 1996). Medic-
inal uses: It is used in eczema, dropsy, diabetes, anemia, hepatitis, and jaundice
(Hfaiedh et al., 2014). Pharmacological activity: It is an antioxidant,
antiinflammatory, and diuretic (Clare et al., 2009). Study: Chloroform frac-
tions inhibited production of prostaglandins, NO, and cytokines, and the
cyclooxygenase pathway was inhibited by ethyl acetate and chloroform frac-
tions in LPS-stimulated macrophages (Koh et al., 2010).

4.42 Taxus wallichiana (Taxaceae)

Parts used: Aerial parts. Geographic distribution: It is found in Taiwan, Hengduan
mountains, Yunnan Plateau, Eastern Himalayas, and India (Banerjee et al.,
1996). Pharmacological activity: Antiinflammatory, antibacterial, and antifungal
(Nisar et al., 2008). Study: Taxus wallichiana and one of its constituents,
tasumatrol, displayed significant antiinflammatory activity in carrageenan-
induced edema in rats (Qayum et al., 2012).

4.43 Thespesia populnea (Malvaceae)

Parts used: Leaves, seeds, and fruit. Geographic distribution: This is found in
India (Ilavarasan et al., 2003). Pharmacological activity: Antiinflammatory,
hepatoprotective, and antioxidant (Ilavarasan et al., 2003). Study: The
ethanol extract exhibited antiinflammatory potential in carrageenan-induced
rat paw edema at 200 and 400 mg/kg in a dose-dependent manner (Vasudevan
et al., 2007).

4.44 Trichodesma indicum (Boraginaceae)

Parts used: Roots. Geographic distribution: It is found in the Philippines,
Burma, and India (Perianayagam et al., 2006). Medicinal uses: It is used in
dysentery, diarrhea, fever, inflammation, bacterial infection, and cough
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32 Nirit Bernstein et al.

(Srikanth et al., 2002). Pharmacological activity: Antiinflammatory, antimicro-

bial, and antidiarrheal (Perianayagam et al., 2006). Study: The chloroform
extract of Trichodesma indicum exhibited significant antiinflammatory activity
at a dose of 50, 100, and 200 mg/kg in carrageenan-induced edema
(Perianayagam et al., 2006).

4.45 Verbena officinalis (Verbenaceae)

Parts used: Aerial parts. Geographic distribution: It is found in Australia, Asia,
Africa, Europe, and North America (Nesom, 2010). Chemical constituents: It
contains daucosterol and 3,4-dihydroverbenalin (Zhang et al., 2000). Medic-
inal uses: It is used in depression, anxiety, tension, gallbladder disease, migraine,
headache, fever, cystitis, and inflammation (Calvo, 2006). Pharmacological
activity: It is a nerve tonic, antidepressant, cholagogue, diuretic, antispasmodic,
and neuroprotective (Lai et al., 2006). Study: Verbena officinalis reduced
carrageenan-induced rat paw edema (Deepak and Handa, 2000).

4.46 Vernonia cinerea (Asteraceae)

Parts used: Aerial parts. Geographic distribution: It is found in South and Central
America, Australia, and India (Mazumder et al., 2003). Pharmacological activity:
Antiinflammatory, cytotoxic, and antioxidant (Arpona et al., 2013). Study:
Vernonia cinerea exhibited significant activity in serotonin, histamine, and
carrageen-induced edema at doses of 250 and 500 mg/kg (Mazumder
et al., 2003).

4.47 Vitex negundo (Lamiaceae)

Parts used: Leaves. Geographic distribution: It is found in Vietnam, Thailand,
Tanzania, Taiwan, Sri Lanka, Philippines, Nepal, Myanmar, Malaysia, Kenya,
Korea, Japan, Indonesia, India, China, Bhutan, Bangladesh, and Pakistan
(Pronobesh et al., 2012). Pharmacological activity: Antiinflammatory, antimicro-
bial, and antinociceptive (Gupta and Tandon, 2005). Study: An extract of
Vitex negundo L. inhibited prostaglandin synthesis and histamine release in
carrageenan-induced rat paw via inhibition of prostaglandin synthesis, antiox-
idant, and membrane stabilizing activities (Dharmasiri et al., 2003).

4.48 Zingiber officinale (Zingiberaceae)

Parts used: Rhizome. Geographic distribution: It is found in southern Asia and
India (Han et al., 2005). Chemical constituents: Zingiberene, citral, cineol,
myrcene, and curcumene. Pharmacological activity: Antiinflammatory,
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Antiinflammatory Potential of Medicinal Plants 33

carminative, hypoglycemic, and hypolipidemic (Al-Amin et al., 2006).

Study: Oral use of Zingiber officinale extract at doses of 200 and 500 mg/kg
reduced leucocyte adherence in a carrageenan-induced model of endothe-
lial interaction and chemotaxis (Nogueira de Melo and Grespan, 2011).

5. FUTURE PERSPECTIVES AND CONCLUSIONS

While there are significant cellular and animal studies supporting the
antiinflammatory activity of medicinal plants and their bioactive com-
pounds, there is surprisingly relatively little research performed in humans.
Only a handful of plant-derived compounds have been tested in clinical tri-
als. These include the previously mentioned resveratrol, curcumin, EGCG,
quercetin, colchicine, and capsaicin.
It is unfortunate considering the wealth of support for a number of plant-
derived compounds. This disparity may be at least partially due to the IP
issues involved with natural products. It is difficult to patent plants or their
bioactive compounds, deterring profit-seeking pharmaceutical companies.
Another significant hurdle is the previously mentioned poor bioavailability
common among many of the bioactive compounds. In any event, these and
other important issues including reliable and standardized production and
chemical characterization must be addressed before the wealth of potentially
therapeutic plant-based products can be more fully harnessed in the treat-
ment of inflammation.

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