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Author for correspondence: Padma Shri Professor P. Pushpangadan
Amity Institute for Herbal and Biotech Products Development,
3- Ravi Nagar, Peroorkada P.O, Thiruvananthapuram -695 005,
Kerala, India
E-mail: palpupraku lam@yahoo.co.in
Tel.: +91-9895066816
Plant based anti-inflammatory secondary metabolites
P. Pushpangadan, T.P. Ijinu and V. George
Amity Institute for Herbal and Biotech Products Development, 3 Ravi Nagar, Peroorkada Post Office,
Thiruvananthapuram 695 005, Kerala, India
Received March 20, 2015: Revised April 15, 2015: Accepted April 20, 2015: Published online June 30, 2015
Copyright @ 2015 Ukaaz Public ations. All rights reserved.
Email: ukaaz@yahoo.com; Webs ite: www.ukaazpublications. com
Abstract
Inflammation is the body’s natural response to harmful stimuli arising in tissue in response to
tra umatic, infectious, post-ischemic, toxic or autoimmune injury. The resolution inflammation
requires the termination of pro-inflammatory signaling pathways and clearance of inflammatory
cells allowing the restoration of normal tissue functions. Non-steroidal anti-inflammatory drugs
(NSAIDs) are the most well recognized drugs worldwide for the treatment of inflammation and
associated diseases. However, prolonged u se of NSAID s causes adverse gastroin testinal
complications, immunodeficiency and humoral disturbances, leading to chronic problems. In this
context, the identification of new chemical entities with high efficacy and safety has a paramount
importance. Natural products are considered to be a promising avenue for the discovery of new
drug molecules. The discovery of aspirin was a basis for the treatment of inflammatory diseases.
This review summarizes the molecular mechanisms through which several phytochemicals may
inhibit inflammation.
Key words: Inflammation, plant bioactives, NSAIDs, cyclooxygenase, NF-B, cytokines
1. Introduction
Inflammation is a complex set of interactions among soluble factors
(cytokines) and cells that can arise in any tissue in response to
traumatic, infectious, post-ischaemic, toxic or autoimmune injury.
The process normally leads to recovery from infection and to
healing, however, if targeted destruction and assisted repair are not
properly phased, inflammation can lead to persistent tissue damage
by leukocytes, lymphocytes or collagen (Nathan, 2002). Chronic
inflammation can contribute to diseases such as arthritis, heart
attacks, Alzheimer’s disease and also makes individuals susceptible
to many forms of cancer. The culprits that drive this process are
inflammatory cells and signaling molecules of the innate immune
system, which recognizes potential threats without previous
exposure to them (Balkwill and Coussens, 2004; Mantovani, 2005).
Natural products, including those derived from plants have over
the years contributed to the development of modern therapeutic
drugs. Recently, much interest has been generated for a wide range
of phytoconstituents with reports demonstrating their role in the
modulation of inflammatory responses. Several natural product
drugs of plant origin are in clinical use and some are undergoing
Phase II and III clinical trials. The understanding of the cellular and
molecular mechanisms involved in the inflammatory process has
increased considerably in recent decades and this has permitted the
discovery of many promising targets for the development of new
drugs to treat inflammatory diseases.
ANNALS OF
PHYTOMEDICINE
An Intern ational Journal
Annals of Phytomedicine 4(1): 17-36, 2015
Journal homepage: www.ukaazpublications.com
ISSN : 2393-9885
1.1 Inflammatory cascade
Inflammation is the result of concerted participation of a large
number of vasoactive, chemotactic and proliferative factors at
different stages and there are many targets for anti-inflammatory
action. A major component of the inflammatiom process is the
arachidonic acid (AA) pathway because arachidonic acid is
immediately derived from the traumatized cellular membranes by
the action of enzyme phospholipase A2 (PLA2). This membrane
based arachidonic acid catalysed by cyclooxygenases (two isoforms,
namely; COX-1 an d COX-2), results in the formation of
prostaglandin G2 (PGG2) and in a subsequent peroxidase reaction
PGG2 undergoes a two-electron reduction to PGH2. PGH2 may
then be acted upon by various enzymes to yield prostaglandins
(PGD2 PGE2 PGF2), prostacyclin (PGI2) and thromboxane
(THA2). Prostaglandins play a key role in the generation of the
inflammatory response. They promote inflammation that is
necessary for healing, but also results in pain, and fever, support
the blood clotting function of platelets and protect the lining of the
stomach from the damaging effects of acid. Among the
prostaglandins, PGE2 has received the most attention because of
its contribution to nociception and inflammation. PGE2 stereo-
specifically exerts potent (i.e., within the nanomolar to micromolar
range) tissue and cell type selective actions. PGE2 is not only
thought to play a key role in nociception (e.g., intradermal PGE2 is
largely responsible for hyperalgesia in the peripheral nervous
system) but also appears to be involved in a wide variety of other
functions, including vasodilation, altered microvascular permeability,
and febrile responses (Pountos et al., 2011; Ricciotti and Gerald,
2010).
PGI2 is a potent vasodilator and inhibitor of platelet adhesion to
the endothelium. It inhibits platelet aggregation through stimulation
of adenylate cyclase leading to an increase in cyclic AMP in the
platelets. THA2 is a potent vasoconstrictor and its production is
Review
18
enhanced during inflammation and tissue injury, and following
platelet activation. It is important in producing arterial
vasoconstriction when a vessel is cut and bleeding (haemostatic
function) (Ricciotti and Gerald, 2010).
Along with the cyclooxygenase pathway, the lipoxygenase (LOX)
pathway is also a strong mediator of inflammation. Lipoxygenase
(LOX) catalyzes the insertion of one molecular oxygen into the
5-, 12- or 15- carbon position of arachidonic acid and are termed
5-LOX, 12-LOX and 15-LOX accordingly (Funk, 2001). The
primary products are 5S-, 12S-, or 15S-hydroperoxyeicosa-
tetraenoic acid (5-, 12-, or 15- HPETE), which can be further reduced
by glutathione peroxidase to the hydroxy forms, 5-, 8-, 12-, 15-
HETE, respectively. Further, 5-LOX has a unique activity of
catalyzing 5-HPETE to either 5-HETE or the unstable epoxide
leukotriene A4 (LTA4) (Peters-Golden, 1998; Funk, 2001). This is
later catalyzed to either LTB4 (a potent neutrophil chemoattractant
and stimulator of leukocyte adhesion to endothelial cells) or LTC4.
LTC4 might be converted to LTD4, which can be further converted
to LTE4. The LTC4, LTD4, and LTE4 are called peptidoleukotrienes
or cysteinyl leukotrienes (Chen, 2011; Pountos et al., 2011). The
arachidonic acid depended pathway of inflammation is shown in
Figure 1.
Stimulus MEMBRANE PHOSPHOLIPIDS
Tissue specific isomerases / synthases
COX reaction 5 LOX 12 / 15 LOX
ARACHIDONIC ACID
PGD2 PGE2 PGI2 PGF2
TxA2 12 /15 HETE Lipoxins
5HPETE
5 HETE LTA4
LTB4 LTC4 LTD4 LTE4
PGH2
12 HPETE / 15 HPETE
PLA2
Stimulus MEMBRANE PHOSPHOLIPIDS
Tissue specific isomerases / synthases
COX reaction 5 LOX 12 / 15 LOX
ARACHIDONIC ACID
PGD2 PGE2 PGI2 PGF2
TxA2 12 /15 HETE Lipoxins
5HPETE
5 HETE LTA4
LTB4 LTC4 LTD4 LTE4
PGH2
12 HPETE / 15 HPETE
PLA2
Figure 1: Cyclooxygenase and lipoxygenase pathways of inflammatory cascade
19
1.2 NF-B in inflammation
The nuclear factor B (NF-B) is an inducible transcription factor
comprised of homo- and hetero-dimers of the NF-B and Rel
protein family (Hoffmann et al., 2006). It has been reported that
NF-B plays major roles in leukemia, inflammatory bowel disease,
arthritis, sepsis, asthma, multiple sclerosis, colitis, diabetic
neuropathy and AIDS (Cameron and Cotter, 2008). The NF-B
proteins are localized in the cytoplasm of the cell and are associated
with a family of inhibitory proteins known as IB (Gupta et al.,
2001; Wang et al., 2004a). The IB proteins are normally bound to
NF-B and block their nuclear localization signal. A variety of
provoking stimuli can degrade the IB and result in the nuclear
translocation of NF-B to be free to activate the gene expression of
inflammatory cytokines (Maroon et al., 2010). They include pro-
inflammatory cytoines (e.g., IL-1, IL-2, IL-6, TNF- etc.),
chemokines (e.g., IL-8, MIP-1, MCP1, RANTES, eotaxin, etc.),
adhesion molecules (e.g., ICAM, VCAM, E-selectin), inducible
enzymes (COX-2 and iNOS), growth factors, some of the acute
phase protein and immune receptors. All these inflammatory
cytokines play a critical role in controlling most of the inflammatory
processes (Barnes and arin, 1997; Ghosh and arin, 2002).
Therefore, NF-B is the master switch for inflammation.
Gene expression of inflammatory cytokine leads to another stage
of the inflammatory cascade. In conjunction with chemokines and
various co-stimulatory molecules, proinflammatory molecules
facilitate the recruitment of effector cells, such as monocytes and
neutrophils, to the site of disturbance. Neutrophils create a cytotoxic
environment by releasing noxious chemicals from cytoplasmic
granules (a process called degranulation). Rapid release of these
chemicals requires consumption of both glucose and oxygen, known
as the respiratory burst. Toxic chemicals released include reactive
oxygen species (ROS) and reactive nitrogen species (RNS),
respectively an d various proteinases. These substances are
destructive to both pathogens and hosts and essentially induce
liquefaction of surrounding tissue to stave off microbial metastasis
(Nathan 2002; Ashley et al., 2012). These effector mechanisms are
thus major contributors to host collateral damage. The net effect of
these interactions culminates in the stereotypical cardinal signs of
local inflammation: heat, swelling, redness, pain, and loss of function
(Ashley et al., 2012).
1.3 NSAIDS and their mechanism of action
Salicylic acid and salicylates, obtained from natural sources, have
long been used as medicaments. Salicylic acid was chemically
synthesized in 1860 and was used as antiseptic, antipyretic and
antirheumatic. Almost 40 years later, aspirin was developed as a
more palatable form of salicylate. Soon after, other drugs having
similar actions to aspirin were discovered, and the group was termed
the ‘aspirin-like drugs’ (also now termed the nonsteroidal anti-
inflammatory drugs (NSAIDs) (Vane and Botting, 1998). In 1971,
Vane discovered the mechanism by which aspirin exerts its anti-
inflammatory, analgesic and antipyretic actions. He proved that
aspirin and other NSAIDs inhibit the activity of the enzyme cyclo-
oxygenase which leads to the formation of prostaglandins (PGs)
that cause inflammation, swelling, pain and fever. In 1982, he was
awarded the Nobel Prize in Physiology or Medicine (Vane and
Botting, 1996; Vane and Botting, 2003; Botting, 2010). This
discovery by John Vane, was followed twenty years later by the
discovery of COX-2 and the rapid development of selective
inhibitors of this enzyme (Botting, 2010).
Mostly NSAIDs inhibit the activity of both COX-1 and COX-2,
and thereby the synthesis of prostaglandins, prostacycline and
thromboxane. The constitutive COX-1 is responsible for
physiological functions and inducible COX-2 involved in
inflammation. Inhibition of COX explains both the therapeutic
effects (inhibition of COX-2) and side effects (inhibition of COX-1)
of NSAIDs. NSAIDs which selectively inhibit COX-2 are likely to
retain maximal anti-inflammatory efficacy combined with less
toxicity (Vane and Botting, 1996). According to the results of various
studies on the ranking scheme in terms of COX-2 selectivity, one
can consider rofecoxib, celecoxib, and meloxicam as posing the higher
COX-2 selectivity, followed by ibuprofen, diclofenac and piroxicam.
Aspirin, indomethacin and ketorolac have the lowest COX-2
selectivity (Brooks et al., 1999; Warner et al., 1999). Aspirin,
sodium salicylate, rofecoxib and ibuprofen also inhibit of NF-B,
and in addition to this aspirin and sodium salicylate have shown to
inhibit activator protein-1 (AP-1) (Budsberg, 2010).
Several NSAIDs affect the production or actions of cytokines and
this property has been considered to be a component of their actions,
positive or negative. Indomethacin and some other NSAIDs may
increase production of IL-1 or TNF- and these effects have been
considered important in the development of gastrointestinal ulcers
and asthma attributed to these drugs. However, some other NSAIDS
such as nimesulide inhibit IL-6 and TNF- (Rainsford, 2005) while
ibuprofen inhibits TNF- (Jiang et al., 1998). TNF- induction of
the NF-B/IB signalling pathway is inhibited by salicylate at the
level of the activity of IB kinase and cAMP-response element
binding protein (CREB) (Rainsford, 2004).
The inhibitory effects on signalling pathways, especially those
involving NF-B/IB and MAP kinases, may have particular
significance in subsequent inhibition of the expression of mRNAs
and the proteins of COX-2, iNOS and PLA2 (Rainsford, 2004;
Rainsford, 2007). With nimesulide there is also an interesting
additional property that this drug activates glucocorticoid receptors
leading to dow n-regu lation of a number of cytokines,
metalloproteinase enzymes, COX-2, iNOS and PLA2 (Rainsford,
2005). Some NSAIDs also affect the response of T-cells to IL-2
(Hall and Wolf, 1997) and this together with reduction in the effects
of PGE2, due to blockade of the production of this prostanoid by
NSAIDs, may form a component of their immuno-regulatory effects
(Smith et al., 1971; Goodwin et al., 1977, 1978; Rainsford, 2007).
Recent findings have exposed the fatal side effects associated with
NSAIDs, and considering these harmful outcomes, a range of novel
therapeutically relevant biological targets, which particularly include
NF-B and Jak/STAT signaling pathways, have received growing
attention.
1.4 Plant derived bioactives
Many plant-derived compounds have been used as drugs, either in
their original or semi-synthetic form. Plant secondary metabolites
can also serve as drug precursors, dru g prototypes and
pharmacological probes (Salim et al., 2008). Despite the recent
interest in drug discovery by molecular modeling, combinatorial
chemistry, and other synthetic chemistry methods, natural product
derived compounds are still proving to be an invaluable source of
medicines for human well being. At present, numerous studies
20
have established that the plant bioactives contribute protective
effects against acute and chronic in flammatory diseases.
Traditionally several plants are used against inflammatory diseases
and many of the natural compounds isolated from these plants
show potent anti-inflammatory action in in vitro and in vivo animal
models. They work by inhibiting the inflammatory pathways in a
similar manner as NSAIDs.
Several mechanisms of action have been proposed to explain the
anti-inflammatory actions of phytochemicals, such as (i) Antioxidative
and radical scavenging activities; (ii) Modulation of cellular activities
of inflammation-related cells (mast cells, macrophages, lymphocytes,
and neutrophils); (iii) Modulation of proinflammatory enzyme
activities such as PLA2, COX and LOX and the NO producing
enzyme, NOS; (iv) Modulation of the production of other
proinflammatory molecules and (v) Modulation of proinflammatory
gene expression (Bellik et al., 2013). Some of the potent anti-
inflammatory bioactives isolated from plants in recent years and
their anti-inflmmatory mechanisms are described below:
Acetylsalicylic acid or aspirin
It is one of the most widely used drugs worldwide and is a starting
point for the treatment of inflammation and associated diseases. It
was derived from salicylic acid found in the bark of the Spiraea
ulmaria, which has traditionally been used to treat fever and
inflammation (Recio et al., 2012). In antithrombotic and anti-
inflammatory actions, it acetylates COX-1 and COX-2, thereby,
irreversibly blocking the conversion of arachidonic acid to
prostanoids for the production of prostaglandins, thromboxanes
and prostacyclins, the essential fatty acid signalling molecules
(Amann and Peskar, 2002; Vane and Botting, 2003; Bala et al.,
2008). Recently Alfonso et al. (2014) raised the intriguing
possibility that aspirin may interact and acetylate cellular molecules
such as RNA, and metabolites such as CoA, leading to a change in
their function. Research in this area will provide a greater
understanding of the mechanisms of action of this drug.
O O
OO
CH3
H
Acetylsalicylic acid
Epigallocatechin-3-gallate
The compound (-)-epigallocatechin-3-gallate (EGCG) is the major
catechin found in Camellia sinensis. It has shown remarkable anti-
inflammatory and cancer chemopreventive effects in many animal
tumor bioassays, cell culture systems and epidemiological studies
(Ahmad et al., 2000; Le Marchand, 2002). Hwang et al. (2007) have
reported that the anti-inflammatory action is through the activation
of AMPK. Activation of AMPK has been shown to inhibit the
production of several proinflammatory mediators including TNF-
, IL-1, IL-6, MCP-1, iNOS and COX-2 with LPS stimulation
(Jeong et al., 2009). Another study indicates that EGCG inhibits
the IL-1-induced production of NO in human chondrocytes by
interfering with the activation of NF-B through a novel mechanism
(Singh et al., 2002; Ahmed et al., 2002). EGCG has also been shown
to inhibit metalloproteinases (Rasheed et al., 2009), COX-2, PGE2,
MAPKs and AP-1 (Singh et al., 2003) in IL-1 stimulated human
osteoarthritic chondrocytes.
O
OO
O
O
O
O
O
O
O
O
H
H
H
H
H
H
H
H
Epigallocatechin-3-gallate
Triptolide
It is a diterpenoid triepoxide purified from a Chinese herb,
Tripterygium wilfordii. Triptolide inhibits both Ca2+-dependent and
Ca2+-independent pathways and affects T-cell activation through
inhibition of IL-2 transcription at a site different from the target of
cyclosporin A. It also shows inhibitory effects on a variety of
proinflammatory cytokines and mediators and on the expression
of adhesion molecules by endothelial cells (Chen, 2001). It inhibits
the transcriptional activation of the IL-2 gene by inhibiting activation
of the purine-box regulator of NFAT target DNA sequence in the
IL-2 enhancer and by inhibiting NF-B activation (Qiu et al., 1999).
Wen et al. (2013) reported triptolide treatment significantly
attenuates cardiac inflammation and fibrosis through suppressing
the activity and the expression of NF-B, resulting in improved
left ventricular function in experimental diabetic cardiomyopathy.
OH
O
O
OO
O
O
H
CH3
CH3
CH3
Triptolide
Boswellic acid
In Ayurveda, the plant Boswellia serrata has long been used for the
treatment of inflammatory diseases. Boswellic acids were isolated
from the gum resin of this plant and is inhibited the leukotriene
synthesis via 5-LOX (Ammon et al., 1993). Clinical studies also
suggest its efficacy in some autoimmune diseases including
rheumatoid arthritis, Crohn’s disease, ulcerative colitis and bronchial
asthma (Ammon, 2006).
H
HO
O
O
H
H
H
Boswellic acid
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Andrographolide
It is a diterpene lactone found in the plant Andrographis paniculata,
which is widely used in traditional Indian and Chinese medicines. It
shows a reduction of the production of proinflammatory mediators,
such as COX-2, iNOS and cytokines, such as IL-1, IL-6 and IL-
10 (Asahara et al., 1997; Shouda et al., 2001). The molecular
mechanism of andrographolide implies the reduction of the activation
of transcription factors as NF-B, AP-1, STAT3 (Hidalgo et al.,
2005) and NFAT (Carretta et al., 2009) and the inhibition of
intracellular signaling pathways. In clinical trials, it showed
effectiveness for symptom relief and reduced serological parameters
in patients with rheumatoid arthritis (Hidalgo et al., 2013).
H
H
HO
O
H
O
O
O
Me
Me
H2C
Andrographolide
Curcumin
Curcuma longa has a long history of use in Ayurvedic medicine as
a treatment for inflammatory conditions. The anti-inflammatory
effect of curcumin, a highly pleiotropic molecule, isolated from
this plant is most likely mediated through its ability to inhibit
COX-2, LOX and iNOS. Improper upregulation of COX-2 and/or
iNOS has been associated with the pathophysiology of certain
types of human cancer as well as inflammatory disorders (Abe et
al., 1999; Jobin et al., 1999; Surh et al., 2001; Menon and Sudheer,
2007; Goel et al., 2008).
Curcumin also downregulates various pro-inflammatory cytokine
expressions such as TNF-, interleukins (IL-1, IL-2, IL-6, IL-8, IL-
12) and chemokines, most likely through inactivation of NF-B
(Strimpakos and Sharma, 2008; Zhou et al., 2011). In animal model,
curcumin inhibited arachidonic acid metabolism and inflammation in
mouse skin epidermis via downregulation of the COX and LOX
pathways (Huang et al., 1991; Jurenka, 2009). The primary obstacle
to utilizing curcumin therapeutically has been its limited systemic
bioavailability (Anand et al., 2007; Jurenka, 2009; Prasad et al., 2014).
Curcumin
Ellagic acid
It is a phenolic acid naturally occurring in many food plants like
strawberries, raspberries, blackberries and walnuts and also in some
medicinal plants. Favarin et al. (2013) reported, ellagic acid as a
potential therapeutic agent for acute lung injury-associated
inflammation by reducing COX-2-induced exacerbation. It also
inhibits a number of cell-signaling pathways that are important to
tumor growth, including inflammatory signaling such as TNF-
induced COX-2 protein expression and NOS inhibition (Adams et
al., 2006; Chiang et al., 2003). Adams et al. (2006) found that
Punica granatum fruit juice containing ellagic acid significantly
suppressed TNF- induced COX-2 protein expression in human
colon cancer cells. Ellagitannins and punicalagin from P. granatum
have also been reported to inhibit cancer cell proliferation and
apoptosis through the modulation of NF-B signaling pathway
and suppression of NF-B regulated gene expression.
Ellagic acid
Honokiol
It is a major component isolated from the bark, root and stem of
various Magnolia species (Wang et al., 2004b). Traditionally these
plants are used against a variety of inflammatory and neuronal
diseases (Liou et al., 2003; Ou et al., 2007). Kim and Cho (2008)
reported, the anti-inflammatory effect is due to an inhibitory effect
on the PI3K/Akt pathway. Several research groups (Maulik and
Das, 2002; Bharti and Aggarwal, 2002; Bochkov and Leitinger,
2003) have reported that honokiol strongly inhibited NF-B
translocation.
Honokiol
Genistein and Daidzein
The main bioactive isoflavones are genistein and daidzein, which
are abundant in soybean and soy products. Epidemiologic studies
in humans indicate that increased soy consumption could be
cardioprotective. Hamalainen et al. (2007) study shows that
genistein inhibited activation of STAT-1 and NF-B. Genistein
also inhibited the production of NO and PGE2 by inhibiting iNOS
and COX-2 expression. The increased release and expression of
inflammatory cytokines, including IL-1, TNF-, by LPS, were
also markedly reduced by genistein (Jeong et al., 2014). Mohammad-
Shahi et al. (2011) study shows that genistein and daidzein reduced
the TNF-, IL-6, adiponectin and leptin serum concentrations and
significantly improved rheumatoid arthritis symptoms.
Further more, pre-treatment of the mice with daidzein markedly
attenuated TNF- induced lung inflammation and inhibited CxCl2
expression in lung tissues and in MLE-12 cells in vitro (Li et al.,
2014). Choi et al. (2012) study shows daidzein also significantly
inhibited the production of NO and IL-6, as well as their mRNA
expression in LPS-treated RAW264.7 cells.
H
H
O
OO
O
Genistein Daidzein
22
Myrtucommulone
It is a nonprenylated acylphloroglucinol contained in the leaves of
Myrtus communis, a Mediterranean shrub used as a culinary spice
and as a folk medicine. Myrtucommulone has been reported to
suppress the biosynthesis of eicosanoids by inhibition of 5-LOX
and COX-1 in vitro and to inhibit the release of elastase and the
formation of ROS in activated polymorphonu-clear leukocytes
(Rossi et al., 2009).
According to Koeberle et al. (2009), myrtucommulone is the first
natural product to inhibit mPGES-1 that efficiently suppresses
PGE2 formation without significant inhibition of the COX enzymes.
Rossi et al. (2009) demonstrated that myrtucommulone attenuates
the production of TNF- and IL-1 in pleural exudates and lungs of
carrageenan-treated mice.
Myrtucommulone
Arzanol
The acylphloroglucinol arzanol has recently been suggested as an
active ingredient responsible for the anti-inflammatory effects of
the plant Helichrysum italicum, grows in the Mediterranean area.
Arzanol is a potent inhibitor of 5-LOX and mPGES-1 in both cell-
free and cell-based assays (Bauer et al., 2010; 2011). It also inhibits
the activation of inflammatory transcription factor NF-B, HIV
replication in T cells, releases of IL-1, IL-6, IL-8, and TNF-
(Appendino et al., 2007; Kothavade et al., 2013).
Arzanol
Thymoquinone
It is one of the most active ingredients of Nigella sativa seeds
(Ragheb et al., 2009; Woo et al., 2012). Chehl et al. (2009) reported
that anti-inflammatory activity of thymoquinone in PDA cells, is
by the inhibition of NF-B. The study results of Taka et al. (2014)
suggest that thymoquinone could have a neuroprotection potential
and may provide a means for the treatment of neurodegenerative
diseases such as Alzheimer and Parkinson’s diseases. Thymoquinone
also attenuates allergic airway inflammation by inhibiting Th2
cytokines and eosinophil infiltration into the airways (El Gazzar et
al., 2006).
Thymoquinone
Shikonin
It is an analog of naphthoquinone pigments isolated from the root of
Lithospermum erythrorhyzon. Results suggest that shikonin exerts
anti-inflammatory properties in LPS-mediated ALI, possibly through
inhibition of the NF-B signaling pathway (Liang et al., 2013). It can
be also mediated by suppression of TNF- promoter activity
(Staniforth et al., 2004) or by regulation of TNF- pre-mRNA splicing
(Chiu and Yang, 2007). Shikonin treatment substantially affected
transgenic and/or endogenous expression of TNF-, GM-CSF and
other cytokine genes in mouse skin tissues in vivo (Su et al., 2008)
and in DCs or monocytes ex-vivo (Chiu et al., 2010). Several other
studies demonstrated that shikonin has a significant antitumor
potential, inducing cell death and inhibiting the cell growth by
sequential activation of caspases in various types of cancer cell lines
(Wu et al., 2004; Hsu et al., 2004; Min et al., 2008; Mao et al., 2008;
Thangapazham et al., 2008; Chen et al., 2012).
Shikonin
Emodin-8-O--D-glucoside
It is extracted from the traditional Chinese medicinal herb Polygonum
cuspidatum and is widely used to treat acute hepatitis. Wang et al.
(2007) reported that emodin-8-O--D-glucoside is able to provide
neuroprotection against cerebral ischemia-reperfused injury and
glutamate induced neuronal damage. Emodin-6-O--D-glucoside,
isolated from Reynoutria japonica, has shown to exert potent anti-
inflammatory and barrier protective effects in HUVE cells and also
in animal model (Lee et al., 2014).
Emodin-8-O--D-glucoside
Resveratrol
It is a naturally occurring stilbene, considered to have a number of
beneficial effects, including anticancer, antiaethrogenic, antioxidative,
anti-in flammatory, antimicrobial and estrogen ic activity
(Piotrowska et al., 2012). It is found in many plants including
grapes, peanuts, berries and medicinal plants, such as Polygonum
cuspidatum (Baur and Sinclair, 2006).
The anti-inflammatory mechanisms of action, mostly in inhibition
of COX activity, inhibition of some activated immune cells, and
proinflammatory mediators, and inhibition of transcriptional factor
like NF-B and activator protein (Das and Das, 2007). In addition
to COX inhibition resveratrol also suppress the activity of NF-B
and IB kinase (Kundu et al., 2006), reduced the production of
PGE2 and the formation of ROS in LPS activated microglial cells
(Candelario-Jalil et al., 2007; Kim et al., 2007).
23
O
O
O
H
H
H
Resveratrol
Piceatannol
It is a phenolic stilbenoid and a metabolite of resveratrol. Piceatannol
was first isolated from the seeds of Euphoribia lagascae (Ferrigni
et al., 1984; Wieder et al., 2001). Piceatannol commonly exhibits
anti-inflammatory, antiplatelet and antiproliferative activity (Ko et
al., 2013). When examined for the mechanism, Ashikawa et al.
(2002) found that piceatannol inhibited TNF-induced IB
phosphorylation, p65 phosphorylation, p65 nuclear translocation,
and IB kinase activation. Although piceatannol has been shown
to induce apoptosis in cancer cells and also inhibits Syk kinase,
which plays a crucial role in the coordination of immune recognition
receptors and orchestrates multiple downstream signaling pathways
in various hematopoietic cells (Piotrowska et al., 2012).
Piceatannol
Apocynin
The apocynin was first described by Schmiedeberg in 1883 and
was isolated from the roots of Apocynum cannabinum, and its
extract used as remedy for dropsy and heart troubles. In 1971,
apocynin was identified during activity-guided isolation of
immunomodulatory constituents from the root of Picrorhiza
kurroa, a native plant grown in the mountains of India, Nepal,
Tibet and Pakistan. Apocynin has been used as an efficient inhibitor
of the complex NADPH-oxidase in many experimental models
involving phagocytic and nonphagocytic cells (Lafeber et al., 1999;
Zhang et al., 2005). NADPH-oxidase mediated superoxide plays
an important role in the pathogenesis of brain injury and that
inhibition of NADPH-oxidase by apocynin can attenuate brain
injury following experimental ischemic stroke (Tang et al., 2007).
Moreover, another study showed that apocynin prevented COX-2
expression in stimulated human monocyte (Barbieri et al., 2004)
and the prevention of the activation of NF-B (Barnes and Karin,
1997; Hougee et al., 2006). Recently, Ghosh et al. (2012) reported
that diapocynin exhibits profound neuroprotective effects in a animal
model of Parkinson’s disease by attenuating oxidative damage and
neuroinflammatory responses.
Apocynin
Celastrol
It is a triterpene molecule, a major active ingredient of Chinese
herb, Tripterygium wilfordii, has exhibited a broad spectrum of
pharmacological activities, including anti-inflammation, anticancer
and immunosuppression (Yang et al., 2014). It attenuates excessive
production of NO and proinflammatory cytokines such as TNF-
and IL-1 in LPS-stimulated BV-2 cells. Thus, it may be an
effective therapeutic candidate for use in the treatment of
neurodegenerative human brain disorders (Jung et al., 2007).
Celastrol also decreased the induced expression of class II MHC
molecules by microglia (Allison et al., 2001). Yang et al. (2014)
demonstrated that celastrol significantly reduced nociceptive pain
through CB2 signaling.
CH3
CH3
CH3
CH3
H3C
H3C
H
H
O
O
O
H
O
Celastrol
Wilforlide A
Tripterygium wilfordii has a long history of use in China for more
than 2,000 years. Traditionally, it has been used as an anticancer
drug, male contraceptive, a drug used to suppress the immune system
and as an anti-inflammatory agent. The anti-inflammatory and
immunosuppressive effect of wilforlide A, a triterpene isolated from
this plant was studied and compared to that of triptolide (Xue et al.,
2010). They used several models of inflammation and the results
indicate that wilforlide A has obvious anti-inflammatory properties.
Wilforlide A serves as a quality control standard of Tripterygium
Glycosides, is effective in the treatment of patients with a variety of
inflammatory and autoimmune diseases and is listed in Drug Standard
of Ministry of Public Health, China (Xue et al., 2010).
Wilforlide A
Asiaticoside
It is isolated from Centella asiatica, which has been used for a long
time as a memory enhancer drug in India. It is a triterpenoid molecule
found to exhibit antioxidant and anti-inflammatory activities in
several experimental animal models. These effects could be
associated with the inhibition of proinflammatory mediators,
including TNF- and IL-6 levels, COX-2 expression and PGE2
production, as well as MPO activity, which might be mediated by
24
the upregulation of HO-1 (Wan et al., 2013). The neuroprotective
effect against transient cerebral ischemia and reperfusion in mice
might be associated with the anti-inflammation via inhibiting over
activation of p38 MAPK pathway (Chen et al., 2014).
H
H
H
H
H
H
H
H
H
H
H
H
O
OO
HO
O
OO
O
O
O
OO
O
O
OO
O
O
O
H
H
O
Asiaticoside
Madecassoside
It is also a triterpenoid product isolated from Centella asiatica.
Results suggest that madecassoside can effectively alleviate
inflammatory response on collagen induced arthritis. The inhibition
of proinflammatory mediators, including COX-2 expression, PGE2
production, TNF- and IL-6 levels and the up-regulation anti-
inflammatory molecule IL-10 also attributed the anti-inflammatory
effect of madecassoside (Li et al., 2009). In another study, Won et
al. (2010) reported that the anti-inflammatory effects of madecassic
acid are caused by iNOS, COX-2, TNF-, IL-1, and IL-6 inhibition
via the downregulation of NF-B activation in RAW 264.7
macrophage cells.
H
H
H
H
H
H
O
O
H
O
O
OO
O
O
O
OO
O
O
OO
O
O
O
H
O
H
OH
HHH
H
H
H
Madecassoside
Parthenolide
It is a sesquiterpene lactone isolated from the medicinal herb,
Tanacetum parthenium. It appears to inhibit the pro-inflammatory
enzymes 5-LOX, phosphodiesterase-3 and phosphodiesterase-4
(Kwok et al., 2001). It also inhibited the release of pro-inflammatory
mediators NO, PGE2 and TNF- from macrophages and TNF-,
IL-2, IFN- and IL-4 from human peripheral blood mononuclear
cells (Wong et al., 2008). Study on molecular mechanisms supporting
the potential use of parthenolide in periodontitis treatment (Zhang
et al., 2014). These therapeutic effects have been attributed mostly
to inhibition of NF-B. However, in addition to its anti-NF-B
activity, Juliana et al. (2010) reported that parthenolide is a potent
inhibitor of NLRP3 inflammasome.
O
O
O
CH3
CH2
H3C
Parthenolide
Helenalin
The sesquiterpene lactone helenalin, which can be isolated from several
plant species of the Asteraceae family such as Arnica montana and A.
chamissonis ssp. foliosa, are used traditionally as anti-inflammatory
remedy. Lyss et al. (1997) and Lim et al. (2012) reported inhibition
activity of transcription factor NF-B. In human granulocytes, helenalin
inhibited both the 5-LOX and LTC-4 synthase in a concentration and
time-dependent fashion (Tornhamre et al., 2001).
OO
O
H
H
O
Helenalin
Cucurbitacin E
It is a triterpenoid compound isolated from Cucurbitaceae plants,
possesses a wide range of biological activities including anti-
inflammatory properties. The anti-inflammatory effect is through
the suppression of NF-B nuclear translocation leading to a
decreased expression of TNF- and IL-1 in LPS-stimulated RAW
264.7 cells (Qiao et al., 2013) and inhibition of COX-2 (Abdelwahab
et al., 2011; Jang et al., 2008). Dong et al. (2010) reported
Cucurbitacin E is an effective drug candidate against tumor
angiogenesis by inhibiting VEGFR2 mediated Jak-STAT3 and
mitogen activated protein kinases signaling pathways.
HH
H
O
O
O
O
O
H
O
O
HH
O
Cucurbitacin E
Dihydrocucurbitacin B
It is a triterpene isolated from roots of Cayaponia tayuya.
Dihydrocucurbitacin B modified the evolution of the clinical symptoms,
reducing the swelling of bone and tissue damage along with the
development of the disease, modifying the cell infiltration and the
expression of both NOS and COX-2. In addition, it decreased the TNF-
and IL-1 production in lymphocytes (Escandell et al., 2006).
Moreover, the analysis of inflamed tissu es showed that
dihydrocucurbitacin B reduced the presence of the most relevant
cytokines implicated in these processes, including IL-1, IL-4, and
TNF-. Dihydrocucurbitacin B was also found to inhibit the
proliferation of phytohemagglutinin-stimulated human T
lymphocytes, halting the cell cycle in the G0 phase. Finally,
dihydrocucurbitacin B was found to exert a selective inhibition on
NFAT cells in human lymphocytes. Thus, it curbs DTH reactions
by inhibiting NFAT, which in turn suppresses the proliferation of
the most relevant cells involved in DTH reactions, namely the T
cells (Escandell et al., 2007).
25
Dihydrocucurbitacin B
Embelin
It is identified primarily from the Embelia ribes. Embelin possesses
anti-inflammatory and anticarcinogenic properties in vivo, and these
features have been related to interference with multiple targets
including XIAP (Wehrkamp et al., 2014), NF-B (Ahn et al., 2007),
STAT-3 (Dai et al., 2014), Akt and mTOR (Kim et al., 2013; Huang
et al., 2014). Schaiblea et al. (2013) revealed human 5-LOX and
microsomal mPGES-1 as direct molecular targets of embelin and
suppressed the biosynthesis of eicosanoids. Kumar et al. (2011)
reported anti-inflammatory activity of embelin both in acute and
chronic irritant contact dermatitis in vivo.
Embelin
Pinitol
It is a component of Abies pindrow, reported to suppress NF-B
activation both induced by inflammatory stimuli and carcinogens
and constitutive NF-B activation noted in most tumor cells. The
suppression of NF-B activation by pinitol occurred through
inhibition of the activation of IB kinase, leading to sequential
suppression of IB phosphorylation and degradation, p65
phosphorylation and nuclear translocation, and NF-B-dependent
reporter gene expression. The inhibition of NF-B activation
thereby led to down-regulation of gene products involved in
inflammation (COX-2), proliferation (cyclin D1 and c-Myc),
invasion (MMP-9), angiogenesis (VEGF), and cell survival (cIAP1,
cIAP2, XIAP, Bcl-2, and Bcl-xL). Suppression of these gene
products by pinitol enhanced the apoptosis induced by TNF and
chemotherapeutic agents and suppressed TNF-induced cellular
invasion (Sethi et al., 2008; Aggarwal et al., 2011).
Pinitol
Abruquinone
It is the isoflavanquinone isolated from the roots of Abrus
precatorius have strong anti-inflammatory and antiallergic effects.
Wang et al. (1995) suggests that the anti-inflammatory effect of
abruquinone is mediated partly by suppressing the release of
chemical mediators from mast cells and partly by preventing
vascular permeability changes caused by mediators.
Abruquinone
Flavocoxid
Altavilla et al. (2009) studied the anti-inflammatory activity of
flavocoxid, a mixed extract containing baicalin and catechin from
Acacia catechu that acts as a dual inhibitor of COX and 5-LOX
enzymes. It significantly inhibited COX-2, 5-LOX and inducible
iNOS expression in LPS-stimulated peritoneal rat macrophages.
Flavocoxid
Marmelin
It is an ethyl acetate fraction of Aegle marmelos extracts, suppressed,
TNF- mediated activation and translocation of NF-B, inhibited
AKT and ERK phosphorylation both in vitro and in tumor
xenografts (Subramaniam et al., 2008).
Marmelin
Emodin
It is an active component from Aloe vera, exerts anti-inflammatory
effects through the suppression activity of NF-B in human
umbelical vein endothelial cells in a dose- and time-dependent
manner. Emodin inhibited degradation of IB, an inhibitory subunit
of NF-B. Thus, emodin also downmodulated adhesion molecules
like ICAM-1, VCAM-1, and ELAM-1 contain NF-B binding
sites in their promoter region in endothelial cells (Kumar et al.,
1998).
Emodin
Azadirachtin
Azadirachta indica is known for its medicinal properties since
ancient time. A recent report indicated that azadirachtin obtained
from this plant possesses antitumor property and has the potential
to target NF-B (Thoh et al., 2010).
26
CH3
H3CO
H3C
CH3
H3C
H3C
OOH
H
O
O
O
O
O
O
O
O
OO
HO
H
H
H
O
Azadirachtin
Berberine
Berberine isolated from the plant Berberis aristata, was shown to
abolish NF-B activation induced by various inflammatory agents
and carcinogens. This alkaloid also suppressed constitutive NF-
B activation found in certain tumor cells. Suppression of NF-B
activation occurred through the inhibition of phosphorylation and
degradation of IB- by the inhibition of IB kinase activation,
leading to suppression of phosphorylation and nuclear translocation
of p65, and finally to inhibition of NF-B reporter activity.
Inhibition of IB kinase by berberine was direct and could be
reversed by reducing agents. Berberine also suppressed the
expression of NF-B-regulated gene products involved in
antiapoptosis, proliferation, inflammation an d invasion.
Suppression of antiapoptotic gene products correlated with
enhancement of apoptosis induced by TNF and chemotherapeutic
agents and with inhibition of TNF induced cellular invasion (Pandey
et al., 2008).
O
O
N
O
O
CH3CH3
Berberine
Betulinic acid
It is a triterpinoid compound isolated from Callicarpa macrophylla,
has been reported to be a selective inducer of apoptosis in tumor
cells. It has been reported to suppress the activation of NF-B
activation through suppression of IB kinase, thus abrogate the
phosphorylation and degradation of IB-. Treatment of cells with
betulinic acid also suppressed NF-B dependent reporter gene
expression and the production of NF-B regulated gene products
such as COX-2 and MMP-9 induced by inflammatory stimuli.
Furthermore, betulinic acid enhanced TNF-induced apoptosis
(Takada and Aggarwal, 2003). It also inhibits constitutive activation
of STAT3 and STAT3-regulated gene products such as Bcl-xL, Bcl-
2, cyclin D1 and survivin (Pandey et al., 2010).
O
HO
O
H
H
H
H
H
Betulinic acid
Guggulsterone
It is a plant sterol derived from the gum resin (guggulu) of the tree
Commiphora mukul. Guggulsterone mediates gene expression
through regulation of various transcription factors, including NF-
B (Shishodia and Aggarwal, 2004), STAT-3 (Ahn et al., 2008) and
various steroid receptors such as an drogen receptor an d
glucocorticoid receptors (Burris et al., 2005).
Guggulsterone
Citral
It is isolated from Cymbopogon citratus, showed reduction in the
release of pro-inflammatory mediators TNF- and NO, significantly
indicating an anti-inflammatory effect (Tiwari et al., 2010).
Citral
Rohitukine
It is a chromane alkaloid, a precursor of flavopiridol, a promising
anticancer compound. Rohitukine was first reported from Amoora
rohituka followed by that in Dysoxylum binectariferum
(Mohanakumara et al., 2010). Flavopiridol is known as potent
inhibitor of several CDKs and currently undergoes Phase III clinical
trial. Flavopilidol suppressed NF-B in a dose and time dependent
manner in several cell types. Flavopiridol also inhibited the
expression of the TNF induced NF-B-regulated gene products
cyclin D1, COX-2, and MMP-9 (Takada and Aggarwal, 2004;
Takada et al., 2008).
27
Rohitukine
Anethole
Dried fruits of Foeniculum vulgare possess a fragrant odour and a
pleasant aromatic taste. Anethole, a chief constituent of this plant,
has been shown to block both inflammation and carcinogenesis.
Pretreatment with anethole decreased LPS-induced histopathological
changes. The anti-inflammatory mechanism of anethole is by
suppression of NF-B by blocking IB- degradation (Kang et al.,
2013). Besides NF-B, anethole also suppressed TNF-induced
activation of the transcription factor AP-1, c-jun N-terminal kinase
and MAPK kinase (Chainy et al., 2000).
Anethole
Gambogic acid
It is an active component of Garcinia cambogia. Pandey et al.
(2007) reported that gambogic acid enhanced apoptosis induced by
TNF and chemotherapeutic agents, inhibited the expression of gene
products involved in antiapoptosis, proliferation, invasion and
angiogenesis, all of which are known to be regulated by NF-B.
Gambogic acid suppressed NF-B activation induced by various
inflammatory agents and carcinogens and this, accompanied by the
inhibition of TAK1/ TAB1 mediated IB kinase activation, inhibited
IB- phosphorylation and degradation, suppressed p65
phosphorylation and nuclear translocation, and finally abrogated
NF-B dependent reporter gene expression.
H
H
O O
O
O
H
H
O
O
O
O
Gambogic acid
Indirubin
It is an active principle from Indigofera tinctoria, has been
demonstrated that it had anti-inflammatory and anticancer activities
through suppression of NF-B. Sethi et al. (2006) reported that
indirubin suppressed NF-B activation induced by various
inflammatory agents and carcinogens. NF-B reporter activity
induced by TNFR1, TNF receptor-associated death domain,
TRAF2, TAK1, NF-B-inducing kinase, and IB kinase- was
inhibited by indirubin.
N
O
N
O
HH
Indirubin
Armepavine
It is an active compound from Nelumbo nucifera, has been shown
to exert immunosuppressive effects both in vitro and in vivo through
inhibition of NF-B activation pathways (Weng et al., 2009). In
vitro, armepavine suppressed NF-B activation and MAPK
phosphorylations and in vivo it attenuated the mRNA expression
levels of col12, TGF-1, TIMP-1, ICAM-1, iNOS, and IL-6
genes. Armepavine also shown the downregulation of iNOS and
TNF- expression via NF-B modulation another active compound
(Weng et al., 2009).
O
MeO NMe
MeO
H
Armepavine
Ursolic acid
It is a pentacyclic triterpene acid from Ocimum sanctum, has been
reported to suppress NF-B activation induced by various
carcinogens including TNF, phorbol ester, okadaic acid, H2O2, and
cigarette smoke. Ursolic acid inhibited degradation and
phosphorylation of IkB-, IB kinase activation, p65 phosphory-
lation, p65 nuclear translocation, and NF-B-dependent reporter
gene expression. The inhibition of NF-B activation correlated with
suppression of NF-B-dependent cyclin D1, COX-2, and MMP-9
expression (Shishodia et al., 2003). It also inhibited both constitutive
and IL-6-inducible STAT3 activation in a dose and time dependent
manner in multiple myeloma cells (Pathak et al., 2007).
O
HO
O
H
H
H
Ursolic acid
Picroliv
It is an iridoid glycoside derived from Picrorhiza kurroa, interfered
the activation of NF-B signal cascade. Picroliv abrogated TNF-
induced activation of NF-B through inhibition of IB kinase,
leading to inhibition of phosphorylation and degradation of IB-.
28
It also inhibited phosphorylation and nuclear translocation of p65.
NF-B inhibition by picroliv leads to suppression of NF-B-
regulated proteins, including those linked with cell survival (inhibitor
of AP-1, Bcl-2, Bcl-xL, survivin, and TNF receptor-associated factor 2),
proliferation (cyclin D1 and COX-2), angiogenesis (VEGF), and
invasion (intercellular adhesion molecule-1 and matrix
metalloproteinase-9). Suppression of these proteins enhanced
apoptosis induced by TNF (Gaddipati et al., 1999; Anand et al.,
2008; Aggarwal et al., 2011).
Piperine
The fruits of Piper longum and P. nigrum contain the alkaloid
piperine, possess inhibitory activities on prostaglandin and
leukotrienes COX-l inhibitory effect, as well as on NF-B activation
(Stohr et al., 2001; Singh et al., 2008).
O
O
O
N
Piperine
Plumbagin
The root of Plumbago zeylanica is a major source of plumbagin, has
been used in the Indian medicine since the period of Charaka, from
750 B.C. (Tilak et al., 2004). Plumbagin has been shown to exert
anticancer and antiproliferative activities in animal models as well as
in cells in culture. Sandur et al. (2006) suggest that plumbagin may be
effective against cancer not only by suppressing invasion but also by
inhibiting angiogenesis and inflammation through inhibition of the
NF-B signaling pathway. Plumbagin inhibited both constitutive
and interleukin 6-inducible STAT3 phosphorylation in human
multiple myeloma cells and this correlated with the inhibition of c-
Src, JAK-1, and JAK-2 activation (Sandur et al., 2010).
O
O
O
CH3
H
Plumbagin
Mollugin
The roots of the plant Rubia cordifolia is used traditionally as anti-
inflammatory, haemostatic, antidysentric, antipyretic, analgesic and
anthelmentic agent. Mollugin, one of the active compounds obtained
from the plant was shown to inhibit TNF- induced expression of
inflammatory molecules by inhibiting NF-B activation in colon
cancer cells (Kim et al., 2009).
Mollugin
Sesamin
Harikumar et al. (2010) found that sesamin, a lignan from Sesamum
indicum, inhibited the proliferation of a wide variety of tumor cells
including leukemia, multiple myeloma, and cancers of the colon,
prostate, breast, pancreas, and lung. Sesamin also potentiated TNF-
induced apoptosis and this correlated with the suppression of gene
products linked to cell survival (Bcl-2 and survivin), proliferation
(cyclin D1), inflammation (COX-2), invasion (MMP-9, ICAM-
1), and angiogenesis (VEGF). Sesamin downregulated constitutive
and inducible NF-B activation induced by various inflammatory
stimuli and carcinogens, and inhibited the degradation of IB,
through the suppression of phosphorylation of IB- and inhibition
of activation of IB kinase, thus resulting in the suppression of
p65 phosphorylation and nuclear translocation (Aggarwal et al.,
2011).
Sesamin
Brucine and brucine N-oxide
Brucine and brucine N-oxide isolated from the dried seeds of
Strychnos nux-vomica are reported to exert anti-inflammatory
effects through reduction of PGE2 release (Yin et al., 2007).
H3C
CH3
N
O
N
O
O
OH
H
H
Brucine
Amarogentin
The secoiridoid glycoside, amarogentin, isolated from the plant Swertia
chirata is reported to suppress COX-2 (Saha et al., 2006) and also
possesses various biological activities such as chemopreventive,
antibacterial, anticholinergic and antihepatitis activity.
HOH2C
O
H
O
H
O
O
O
O
O
OO
OO
H
H
HHH
Amarogentin
29
Eugenol
Syzygium aromaticum is traditionally used to treat respiratory and
digestive ailments. Eugenol, the principle component of this plant
has been shown to have ROS scavenging activity and antitumor
potentials targeting COX-2, cMyc, H-Ras (Banerjee et al., 2006).
Eugenol
Octacosanol
It is a straight chain aliphatic 28-carbon primary fatty alcohol.
Octacosanol isolated from Tinospora cordifolia downregulates
VEGF gene expression by inhibiting nuclear translocation of NF-
kappaB and its DNA binding activity (Thippeswamy et al., 2008).
Octacosanol
Diosgenin
It is a steroidal saponin present in Trigonella foenum-graecum and
some other plants, has been shown to suppress inflammation, inhibit
proliferation, and induce apoptosis in a variety of tumor cells. It
down-regulates TNF- induced expression of NF-B-regulated gene
products involved in cell proliferation, antiapoptosis and invasion
(Shishodia et al., 2006). It also inhibits STAT3 signaling pathway
leading to suppression of proliferation and chemosensitization of
human hepatocellular carcinoma cells (Li et al., 2010).
CH3
CH3
H3C
CH3
O
O
O
H
H
HH
H
H
Diosgenin
Withanolides
The plant Withania somnifera also known as Indian ginseng, is
widely used in the Ayurvedic system of medicine. Withanolides
isolated from this plant suppressed NF-B activation induced by
a variety of inflammatory and carcinogenic agents, including TNF-
, IL-1, doxorubicin, and cigarette smoke condensate. It also
suppressed both inducible and constitutive NF-B activation. The
suppression occurred through the inhibition of inhibitory subunit
of IB- kinase activation, IB- phosphorylation, IB-
degradation, p65 phosphorylation, and subsequent p65 nuclear
translocation (Ichikawa et al., 2006). Withanolide sulfoxide, another
active compound of this plant inhibits COX-2 expression
(Mulabagal et al., 2009).
O
H
O
OO
O
O
O
OH
H
H
Withanolide
2. Conclusion
Inflammation has been associated with many diseases like cancer,
diabetes, neurological disorders, etc. There has been some concern
over the use of synthetic COX-2 inhibitors such as rofecoxib and
valdecoxib for therapeutic interventions because of fatal side effects,
some of these therapeutic products are either withdrawn or made
to carry a warning by the Food and Drug Authority (FDA) (Naesdal
and Brown, 2006). Due to risk of cardiovascular and skin related
toxicities, rofecoxib and valdecoxib were withdrawn from the market
in September 2004 and March 2005, respectively (Greenberg et al.,
2009).
Since ancient times traditional herbal medicines are used for the
treatment of inflammatory and related disorders. Inhibition of the
synthesis or action of COX, LOX, PLA2, pro-inflammatory
cytokines and NO are important targets for the treatment of
inflammatory diseases. Various medicinal plants which are used in
Ayurveda for the treatment of inflammation and associated diseases
have been found to contain chemical constituents that inhibit
inflammatory mediators like TNF-, IL-1, NF-B, COX, LOX,
etc. in various in vitro and in vivo studies.
Guggulsterone isolated from Commiphora mukul, curcumin form
Curcuma longa, boswellin / boswellic acid from Boswellia serrata,
salicin from Populus tremula, etc. are clinically tested and shown
effective against inflammatory diseases by reducing post surgical
edema, tenderness, pain; improved disease conditions of osteo
arthritis and rheumatoid arthritis, etc. Some of the traditional
formulations marketed in India, for inflammatory diseases or as
immunomodulatory agents are Shallaki (Boswellia serrata), Hadjod
(Cissus quadrangularis), Curril capsules (Ocimum sanctum),
Ashwagandharista (Withania sominifera), Himalaya Guduchi
(Tinospora cordifolia), Himcolin (Vitex negundo), etc. Development
of standardized, safe and effective herbal formulations with proven
scientific evidence can provide an alternative in treatment for
inflammatory diseases. Thus, plants have the potential to serve as
a source of new chemical entities for the development of future
drugs in the treatment of various inflammatory diseases.
Acknowledgements
The authors express their sincere thanks to Dr. Ashok K. Chauhan,
Founder President, Ritnand Balved Education Foundation (RBEF)
and Amity Group of Institutions for con stant support and
encouragement and to Dr. Atul Chauhan, President, RBEF and
Chancellor, AUUP, Noida for facilitating this work.
30
Conflict of interest
We declare that we have no conflict of interest.
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