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The aim of the study was to investigate the safety and anti-inflammatory effects of polysaccharide fraction (F1) of Curcuma longa (NR-INF-02) in classical rodent models of inflammation. F1 was evaluated for its acute oral toxicity and found to be safe upto 5000 mg/kg body weight in rats. The anti-inflammatory activity of F1 was evaluated in acute (carrageenan - induced paw edema; xylene - induced ear edema) and chronic (cotton pellet - induced granuloma) models of inflammation. The results of the study demonstrated that F1 significantly (p ≤ 0.05) inhibited carrageenan-induced paw edema at 1 h and 3 h at doses of 11.25, 22.5 and 45 mg/kg body weight in rats. Also, F1 at doses of 15.75, 31.5 and 63 mg/kg significantly inhibited the xylene induced ear edema in mice. In a chronic model, F1 at 11.25, 22.5 and 45 mg/kg doses produced significant reduction of wet and dry weights of cotton pellets in rats. Overall results indicated that F1 of NR-INF-02 significantly attenuated acute and chronic inflammation in rodent models. This study emphasizes on the importance of Curcuma longa polysaccharide's role in acute and chronic inflammation.
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Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2015, 14, 53-62 53
Anti-Inflammatory Activity of Polysaccharide Fraction of
Curcuma longa Extract (NR-INF-02)
Ramanaiah Illuri, Bharathi Bethapudi, Senthilkumar Anandakumar,
Sasikumar Murugan, Joshua A. Joseph, Deepak Mundkinajeddu, Amit Agarwal and
Chandrasekaran C.V.*
R&D Centre, Natural Remedies, Bangalore – 560 100, Karnataka, India
Abstract: The aim of the study was to investigate the safety and anti-inflammatory effects
of polysaccharide fraction (F1) of Curcuma longa extract (NR-INF-02) in classical rodent
models of inflammation. F1 was evaluated for its acute oral toxicity and found to be safe up-
to 5000 mg/kg body weight in rats. The anti-inflammatory activity of F1 was evaluated in
acute (carrageenan - induced paw edema; xylene - induced ear edema) and chronic (cotton
pellet - induced granuloma) models of inflammation. The results of the study demonstrated
that F1 significantly (p ≤ 0.05) inhibited carrageenan-induced paw edema at 1 h and 3 h at
doses of 11.25, 22.5 and 45 mg/kg body weight in rats. Also, F1 at doses of 15.75, 31.5 and 63 mg/kg signifi-
cantly inhibited the xylene induced ear edema in mice. In a chronic model, F1 at 11.25, 22.5 and 45 mg/kg do-
ses produced significant reduction of wet and dry weights of cotton pellets in rats. Overall results indicated that
F1 of NR-INF-02 significantly attenuated acute and chronic inflammation in rodent models. This study empha-
sizes on the importance of Curcuma longa polysaccharide’s role in acu te and chronic inflammation.
Keywords: Anti-inflammatory, Curcuma longa, NR-INF-02, Polysaccharide fraction.
Inflammation is generally life preserving which
arises in any tissue in response to trauma, infec-
tion, toxic stimuli and culminates in tissue repair,
recovery and healing. However, if the targeted re-
pair and destruction of harmful stimuli are not
phased properly, inflammation persists and leads
to diseases and disorders. Inflammation is reported
to play a major role in the pathogenesis of several
diseases like osteoarthritis, multiple sclerosis,
Crohn’s disease, and atherosclerosis and also dis-
eases of infectious origin viz., Helicobacter pylori
gastritis, filariasis, hepatitis C, tuberculosis etc.,
[1]. In view of role of inflammation in several dis-
eases and disorders, there is an inevitable need for
anti-inflammatory therapies.
*Address correspondence to this author at the Department of
Biology, Head of R&D Biology, Natural Remedies Pvt. Ltd.,
Bangalore, India; Tel: +91-80-40209717; Fax: +91-80-
40209817; E-mail:
A variety of anti-inflammatory agents are avail-
able, including the most widely used non-steroidal
and steroidal anti-inflammatory drugs. As these
drugs are associated with serious adverse effects,
research for the development of safe and effective
anti-inflammatory therapies is still ongoing [2].
Meanwhile, with the rising interests in herbal sub-
stances, extensive research to investigate the anti-
inflammatory properties of natural substances is
also growing at a faster pace [3].
One such herb that has a huge anti-inflammatory
potential is Curcuma longa. C. longa (turmeric)
belonging to the family Zingiberaceae is a peren-
nial herb, cultivated in Southeast Asia [4]. C.
longa consists of carbohydrates (69.4% of total
mass), curcuminoids (curcumin, demethoxycur-
cumin and bisdemethoxycurcumin), and essential
oil [5]. Curcuminoids especially curcumin is con-
sidered as a key active constituent of C. longa and
was extensively researched for its anti-inflammatory
activity. A great body of evidence in the available
literature indicates the anti-inflammatory activity
C.V. Chandrasekaran
1875-614X/15 $58.00+.00 © 2015 Bentham Science Publishers
54 Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2015, Vol. 14, No. 1 Illuri et al.
of curcuminoids via down-regulation of cyclooxy-
genase-2 (COX-2), lipoxygenase, inducible nitric
oxide synthase (iNOS), and by inhibition of tumor
necrosis factor-alpha (TNF-α), inflammatory cyto-
kines, monocyte chemoattractant protein (MCP)
etc. [6]. In addition, turmerones are also reported
for their anti-inflammatory effects in both acute
and chronic models of inflammation [7, 8]. How-
ever, only few reports on the pharmacological ac-
tivities such as anti-tumor, anti-diabetic, anti-
oxidant, anti-depressant and immune modulatory
of polar fractions that constitute majorly polysac-
charides of C. longa are available [9-12]. While,
curcuminoids and turmerones were explored and
established for their anti-inflammatory potentials,
the polar extracts or polysaccharides containing
extracts of C. longa were seldom reported for anti-
inflammatory activity. In view of the biological
activities of polysaccharides of C. longa, NR-INF-
02 a formulation that is a combination of turmeric
oil and aqueous extract of Curcuma longa stan-
dardized to contain polysaccharides (>10 % w/w)
was developed and investigated for its anti-
inflammatory activity.
In vitro studies on NR-INF-02 revealed anti-
inflammatory activity by inhibiting prostaglandins
and interleukins [13]. While, in vivo studies on
NR-INF-02 also reinstated the in vitro findings by
exhibiting anti-inflammatory activity in both acute
(Carrageenan and xylene) and chronic (cotton pel-
let granuloma) animal models of inflammation
[14]. In addition, the findings of randomized pla-
cebo controlled clinical study on NR-INF-02 are
also in conformity with the preclinical studies. The
clinical trial on NR-INF-02 in osteoarthritis sub-
jects revealed that this formulation is effective in the
management of painful knee osteoarthritis [15].
NR-INF-02 was fractionated into polysaccha-
ride rich fraction and polysaccharide free fraction
and both the fractions were tested for anti-
inflammatory activity in vitro and the polysaccha-
ride rich fraction was found to have remarkable
activity against inflammation [13]. Hence, this
fraction with the highest activity was considered as
active polysaccharide fraction (F1).
To further elucidate whether the active polysac-
charide fraction of NR-INF-02 contributes for the
anti-inflammatory activity in vivo, the present
study was undertaken. The current study evaluated
anti-inflammatory activities of active polysaccha-
ride fraction of NR-INF-02 (F1) in acute and
chronic inflammatory models. In order to ascertain
the safety of F1, an acute oral toxicity study in
rats, was also conducted.
The studies on acute oral toxicity and the anti-
inflammatory efficacy studies were performed in
accordance with the guidelines of Committee for
the Purpose of Control and Supervision of Ex-
periments on Animals, Ministry of Environment
and Forests, Government of India. The studies
were approved by the Institutional Animal Ethics
Committee, R&D Centre, Natural Remedies, Ban-
galore, India.
2.1. Test Substance
The preparation of the test substance (F1) has
been described in our earlier report [13]. In brief,
NR-INF-02 was dissolved in water and added to 5
volumes of ethanol. The above contents were cen-
trifuged at 2000 rpm for 20 min. The precipitate
obtained after centrifugation was stirred with 5
volumes of ethanol at room temperature for 10
min and filtered. The retentate obtained after filtra-
tion was dried under vacuum at < 70°C to obtain
polysaccharide fraction (F1).
2.2. Acute Oral Toxicity Study
Female nulliparous and non-pregnant albino
Wistar rats (8 - 10 weeks old) were accommodated
in individual polypropylene cage with stainless steel
grill top and clean bedding. Animals were provided
free access to rodent feed pellets (M/s Amrut
Laboratory Animal Feeds, India) and UV purified
water ad libitum and were housed under standard
laboratory conditions of 12 h/12 h light/ dark cycle
at 25±2oC with 30-70 % relative humidity.
2.2.1. Experimental Procedure
The study was conducted as per the Organisa-
tion for Economic Cooperation and Development
(OECD) guideline for the testing of chemicals
(Test guideline No. 420), acute oral toxicity - fixed
dose procedure, adopted on 17 December 2001
[16]. F1 in demineralized water was orally admin-
istered in one animal at 5000 mg/kg dose level in
the sighting study and four animals at 5000 mg/kg
in the main study. The experimental animals were
Anti-Inflammatory Activity of Polysaccharide Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2015, Vol. 14, No. 1 55
fasted overnight before dosing. On the day of dos-
ing, all the animals were observed for mortality
and clinical signs for first 10 min, 30 min, 1 h, 2 h,
4 h and 6 h after dosing and, thereafter, twice daily
for mortality and once a day for clinical signs, for
14 days. The body weights of animals were re-
corded individually before dosing and at weekly
intervals thereafter. Changes in the skin, fur, eyes
and mucous membrane; respiratory, circulatory,
autonomic and central nervous systems, somato-
motor activity and behavior pattern, if any, were
recorded. Particular attention was directed to ob-
servations of tremors, convulsions, salivation, di-
arrhoea, lethargy, sleep and coma. And at termina-
tion of the study, rats were sacrificed for complete
gross pathology examination.
2.3. Anti-Inflammatory Activity
The anti-inflammatory studies were performed
on albino Wistar rats (150-180 g) of either sex or
male Swiss albino mice (20-30 g) bred at Central
Animal Facility, Research and Development Cen-
tre, Natural Remedies, Bangalore. Animals were
provided free access to rodent feed pellets (M/s
Amrut Laboratory Animal Feeds, India) and UV
purified water ad libitum and were housed under
standard laboratory conditions of 12 h/12 h light/
dark cycle at 25 ± 20C with 30-70 % relative hu-
2.3.1. Drugs and Chemicals
The following drugs and chemicals were pur-
chased and used: Diclofenac sodium (Ankur Drugs
and Pharma, India), dexamethasone (Cadila
Healthcare, India), xylene (Ranbaxy Fine Chemi-
cals, India) λ -carrageenan (Sigma Life Science,
Switzerland) and carboxymethyl cellulose (CMC)
sodium salt (HiMedia, India).
2.3.2. Carrageenan-Induced Paw Edema in Rats
Male and female Wistar rats were administered
with CMC (0.5 %; 10 ml/kg), diclofenac sodium
(10 mg/kg), F1 (11.25, 22.5 and 45 mg/kg), re-
spectively to individual groups of six rats each
orally. Diclofenac sodium was used as a positive
control. Acute paw edema was produced by inject-
ing 0.1 ml of λ - carrageenan [prepared as 1% so-
lution in normal saline solution (0.9% w/v NaCl)]
into the sub plantar region of the right hind paw of
rats [17] 60 min after administration of vehicle/
diclofenac/test substance. The paw volume was
measured by the volume displacement method us-
ing a plethysmometer (PanLab, Spain) just before
(0 h), and on hourly intervals (1, 2, 3 and 4 h) fol-
lowing injection of carrageenan. The increase in
the paw volume at hourly intervals was recorded.
Accordingly, the percent increase in paw volume
was calculated.
2.3.3 Xylene-induced Ear Edema in Mice
The xylene-induced ear edema test was per-
formed as described by Atta and Alkofahi [18].
Male Swiss albino mice were randomly allocated
to five groups of six animals each and were ad-
ministered orally with vehicle (0.5 % CMC; 10
ml/kg), diclofenac sodium (50 mg/kg), and various
doses of F1 (15.75, 31.5 and 63 mg/kg) respec-
tively 1 h prior to the xylene application. Xylene
(50 µl) was applied to the anterior and posterior
surfaces of the right ear, while left ear was consid-
ered as control. After 4 h of xylene application,
mice were sacrificed, both the ears were dissected
and ear discs of 6 mm diameter were punched out
and weighed. The average weight difference be-
tween the right and left ear was taken as the meas-
ure for inflammatory response. The percent inhibi-
tion of ear edema between the F1/ diclofenac
treated groups and vehicle treated group was com-
puted as follows:
Percent inhibition (%) = (Rc-Lc) - (Rt-Lt)/(Rc - Lc)*100
Where Rc and Lc represent mean weights of right
and left ear discs of vehicle treated group, while Rt
and Lt represent mean weights of right and left ear
discs of Diclofenac/ F1 treated groups respec-
2.3.4. Cotton Pellet-induced Granuloma in Rats
Cotton pellet-induced granuloma test was per-
formed as described by D’ Arcy et al. [19]. Rats of
either sex were randomly allocated to five groups
(n = 6) and were anesthetized. Granuloma forma-
tion was induced by subcutaneous implantation of
sterile cotton pellets weighing 10 mg each in the
axilla and groin regions of the anesthetized rats.
Post cotton pellet implantation, rats of five groups
were orally administered vehicle (0.5% CMC; 10
ml/kg) or dexamethasone (0.5 mg/kg) or F1
(11.25, 22.5 and 45 mg/kg) once daily for seven
56 Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2015, Vol. 14, No. 1 Illuri et al.
consecutive days respectively. On the eighth day,
rats were sacrificed and the cotton pellets covered
by the granulomatous tissue were meticulously
excised, weighed and dried in hot air oven at 60°C
for 24 h.
2.4. Statistical Analysis
All the values were expressed as mean ± SEM.
Data were analyzed using one way ANOVA fol-
lowed by post-hoc Dunnett’s test. If error variance
was found to be heterogenous, logarithmic trans-
formation of raw data was performed and analyzed
accordingly. Values of p ≤ 0.05 were considered
statistically significant.
3.1. Acute oral Toxicity
Animals treated at the dose level of 5000 mg/kg
body weight in sighting and main study survived
throughout the study period and did not show any
major adverse clinical signs. Occurrence of loose
stools for transient period was observed only on the
day of dosing in two animals (one animal of sighting
study and one animal of main study) (Table 1).
Body weight in treated animals after 7 and 14 days
of treatment was found to be normal (Table 2). On
necropsy, no major gross pathological changes
were observed in any of the treated rats. Based on
the findings of this study, F1 was found to be safe up
to 5000 mg/kg body weight after oral administration
as a single dose to female albino Wistar rats.
3.2. Carrageenan-induced Paw Edema in Rats
The percent increase in paw swelling/edema
caused by 1% carrageenan injection is presented in
(Fig. 1). The paw edema in rats of carrageenan
control group increased along with the time course
up to 3 h and peak edema was observed at 3 h. The
standard drug, diclofenac sodium (10 mg/kg)
showed significant (p ≤ 0.05) reduction in the paw
edema volume at 1 h, 2 h and 3 h as compared to
Table 1. Summary of clinical symptoms, mortality and gross pathology observed in rats receiving single dose of F1.
Study Animal number Dose (mg/kg) Symptoms Time
Gross pathology
(n=1) 1 5000 Loose stools
3 h, 4 h post treatment –
6 h 0/1 NAD
2 5000 None - 0/1 NAD
3 5000 Loose stools 5 h post treatment – 6 h 0/1 NAD
4 5000 None - 0/1 NAD
5 5000 None - 0/1 NAD
h: hour.
NAD: No abnormality detected.
n= number of animals.
Table 2. Effect of F1 on body weight of rats.
Body weight (g)
Study Animal number Dose (mg/kg)
Day 0 Day 7 Day 14
Sighting (n=1) 1 5000 156 215 237
2 5000 165 192 215
3 5000 160 183 201
4 5000 164 204 215
Main (n=4)
5 5000 176 200 224
n= number of animals.
Anti-Inflammatory Activity of Polysaccharide Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2015, Vol. 14, No. 1 57
the carrageenan control group. Similarly, F1 at all
the dose levels significantly (p ≤ 0.05) reduced the
paw edema volume at 1 h, 2 h and 3 h after car-
rageenan injection as compared with the car-
rageenan control group.
3.3. Xylene-induced Ear Edema in Mice
The average weights of ear edema and percent-
age inhibition of edema are presented in Fig. 2 and
Table 3 respectively. Xylene demonstrated evident
increase in the weight of the right ear when com-
pared to left ear of the vehicle control group.
However, standard drug diclofenac, F1 administra-
tion at all dose levels significantly (p ≤ 0.05) de-
creased edema induced by xylene.
3.4. Cotton Pellet-induced Granuloma in Rats
The mean wet and dry weights of cotton pellets
are summarized in Table 4. The vehicle control
group showed marked inflammatory response evi-
dent from the increase in the wet and dry weights
of the pellets. Dexamethasone and F1 at all the
Fig. (1). Anti-inflammatory effect of F1 on carrageenan-induced paw edema in rats.
Fig. (2). Anti-inflammatory effect of F1 on xylene-induced ear edema in mice.
58 Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2015, Vol. 14, No. 1 Illuri et al.
dose levels showed significant (p ≤ 0.05) reduction
in the wet weights and dry weights of the cotton
pellets, as compared to the vehicle control.
Table 3. Percentage anti-inflammatory activity of F1 on
xylene-induced ear edema in mice.
Treatment Percentage inhibition (%)
Vehicle Control (10 ml/kg) -
Diclofenac sodium (50 mg/kg) 79.54
F1 (15.75 mg/kg) 63.57
F1 (31.5 mg/kg) 70.39
F1 (63 mg/kg) 54.57
Table 4. Anti-inflammatory effect of F1 on cotton pellet-
induced granuloma in rats.
Treatment Weight of cotton
pellets (mg) (wet)
Weight of cotton
pellets (mg) (dry)
Vehicle Control
(10 ml/kg) 171.79±5.14 39.83±1.64
(0.5 mg/kg) 95.92±2.47* 20.79±0.53*
F1 (11.25 mg/kg) 144.50±2.44* 34.50±0.88*
F1 (22.5 mg/kg) 146.00±3.62* 33.29±0.62*
F1 (45 mg/kg) 151.29±2.52* 34.54±0.54*
Results are expressed as dry and wet weights of cotton pellets.
Values represent the mean ± SEM, n = 6.
*p < 0.05 vs. Vehicle control.
Inflammation is a typical host response to
harmful stimuli. Nevertheless, inflammation dys-
function contributes to a range of acute and
chronic inflammatory diseases which are a major
cause of morbidity and mortality in the world [1].
These insights into inflammation provide an un-
derstanding that effective and safe anti-
inflammatory agents are vital in the treatment of
inflammatory conditions. Although synthetic drugs
available in plethora, are associated with adverse /
toxic effects and as a consequence of this a clear
shift in the interest of researchers and the people
towards herbal or plant therapies for the manage-
ment of inflammatory disorders. The fact that
global market for use of herbal drugs in the treat-
ment of inflammatory diseases constitutes 83%
worldwide provides evidence of inclination for
plant-based anti-inflammatory agents [3]. Since
ancient times a number of medicinal plants are be-
ing used for the treatment of inflammatory disor-
ders. In the recent times, research has been cen-
tered on a wide range of phytoconstituents includ-
ing phenolics, alkaloids, and terpenoids demon-
strating their role in the modulation of inflamma-
tory responses. Besides these, there are numerous
phytoprinciples that are still unexplored for their
anti-inflammatory potentials. Hence, investigating
the potential activity of the new bioactives that
could be beneficial to mankind becomes an impor-
tant goal of research in biomedical sciences [20].
In view of the aforesaid, a preparation of Curcuma
longa with negligible amount of curcuminoids and
rich in polysaccharides, NR-INF-02 has been for-
mulated and was investigated for its activity
against inflammation.
This novel preparation NR-INF-02 was tested
in vitro and in vivo for its anti-inflammatory activ-
ity. NR-INF-02 demonstrated strong inhibition on
LPS stimulated PGE2 and IL-12 production by
macrophages and also showed mild inhibitory ef-
fects on NO and IL-6 production in vitro [13]. In
in vivo models of acute and chronic inflammation,
NR-INF-02 showed marked effects in suppressing
the inflammation [14]. Additionally, a separate in
vitro study on polysaccharide rich (F1) and poly-
saccharide free fractions (F2) of NR-INF-02 re-
vealed that fraction with polysaccharide is effec-
tive against inflammation and is considered as ac-
tive fraction of NR-INF-02 [13]. In order to further
elucidate anti-inflammatory activities of active
fraction of NR-INF-02 (F1), in vivo and to clearly
understand if polysaccharides contribute for anti-
inflammatory activity of NR-INF-02, the current
study was undertaken. In addition safety of the F1
was tested in acute oral toxicity study in rats.
The acute oral toxicity study conducted as per
the experimental protocol recommended by OECD
revealed that F1 did not cause mortality or major
pathological changes up to dose level of 5000
mg/kg. Although there were few instances of loose
stools immediately after exposure, these signs
were limited to only brief periods and all treated
rats survived till termination of the study with
normal body weight gain. Therefore, F1 can be
categorized as “unclassified” according to the
Globally Harmonized System.
Anti-Inflammatory Activity of Polysaccharide Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2015, Vol. 14, No. 1 59
Inflammation is complex and diverse ranging
from acute to chronic inflammatory process. Acute
inflammation is characterized by cardinal signs
such as redness, swelling, pain, and heat and any
disruption in the checkpoints will hamper natural
resolution of acute inflammation which progresses
to chronic inflammation characterized by exces-
sive leukocyte infiltration, tissue damage and loss
of function. Uncontrolled chronic inflammation is
associated with cardiovascular, gastrointestinal,
nervous system pathologies etc., [21]. Hence
therapeutic agent that shows activity against acute
and chronic inflammation would be ideal and
beneficial. In the present study we have investi-
gated the protective effect of F1 on acute (car-
rageenan-induced paw edema and xylene-induced
ear edema) and chronic (cotton pellet-induced
granuloma) inflammatory models.
In order to study the effect of F1 on acute in-
flammation, carrageenan-induced paw edema and
xylene-induced ear edema models were employed.
These are animal models widely used to test the
protective effects of synthetic/natural products
against acute inflammation [22, 23]. The paw
edema induced by carrageenan is characterized as
biphasic event with release of various inflamma-
tory mediators in two phases. The initial phase of
edema is induced by histamine, bradykinin and
serotonin on vascular permeability. Second phase
of accelerated edema begins at the end of first hour
and persists through third hour and is characterized
by release of prostaglandins, interleukin beta, Tu-
mor Necrosis Factor alpha etc [24, 25]. Recently,
it has been reported that overproduction of nitric
oxide (NO) in the initial phase and inflammatory
prostaglandin such as PGE2 also play a key patho-
physiological role in inducing paw edema by car-
rageenan [26]. In the present study, paw edema
was maximum at third hour and such peaking at
third hour is also noticed in several published stud-
ies [27]. Moreover F1 at all dose levels signifi-
cantly inhibited development of paw edema in the
initial and the second phase. Similar effect was
observed in NR-INF-02 [14]. The reduction in
paw edema can be correlated to the inhibitory ef-
fects of F1 on inflammatory mediators PGE2 and
IL-12 secretion as reported by Chandrasekaran et
al. [13] in vitro. IL-12 is said to have inhibitory
activity on NO [28]. Thus dual inhibition of PGE2
directly and NO production indirectly by inhibi-
tion of IL-12 possibly might have attenuated car-
rageenan -induced edema.
Xylene-induced ear edema model reflects the
edematization during the early stages of acute in-
flammation. Xylene in mice induces neurogenous
edema, which is partially associated with sub-
stance P, an undecapeptide of central and periph-
eral nervous system. In the periphery, release of
substance P from sensory neurons directly causes
vasodilatation and plasma extravasations and indi-
rectly causes release of inflammatory mediators
causing swelling of ear in mice [29]. Substance P
is also reported to upstream expression of cy-
clooxygenase-2 and prostaglandin E2 through
JAK-STAT pathways [30]. The significant inhibi-
tory effects of F1 at all dose levels on xylene-
induced edema in the present study are likely indi-
cation of their anti-inflammatory effects against
acute inflammation. Such similar effects were
shown by NR-INF-02 [14]. The suppression of
edema induced by xylene is plausible either by an-
tagonizing effects of substance P or inhibiting the
inflammatory mediators released by substance P.
Though there is no enough evidence of F1 antago-
nizing or inhibiting substance P, the in vitro stud-
ies demonstrated inhibitory effects on PGE2 [13],
an inflammatory mediator released indirectly by
substance P. Hence, F1 might have shown protec-
tion against edema induced by xylene by inhibiting
Chronic inflammation is a condition character-
ized by continued inflammatory response, tissue
destruction and is suggested to have a serious role
in several diseases including osteoarthritis, diabe-
tes, cardiovascular, autoimmune etc [1]. The cur-
rent study used cotton pellet granuloma model, a
widely employed model to evaluate effects of test
substance on transudative, exudative and prolifera-
tive components of chronic inflammation [31].
The implanted wet weights of cotton pellets corre-
lates with the transudative and exudative phases of
chronic inflammation and dry weights correlate
with the proliferative phase of chronic inflamma-
tion [19]. F1 notably decreased wet and dry cotton
pellet weights. The primary effects of F1 on chronic
inflammation may be associated with inhibitory
effects on proinflammatory cytokines (IL-12) as
observed in in vitro studies [13]. IL-12 is a het-
erodimeric cytokine that induces cytokines pro-
duction, primarily of interferon gamma which
60 Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2015, Vol. 14, No. 1 Illuri et al.
plays a key role in chronic inflammation [32, 33].
However, the direct effects on monocytes and
macrophages need to be elucidated.
It is important to note that a substantial body of
evidence indicates that plant polysaccharides have
significant effects on immune functions and in-
flammation. Plant polysaccharides, such as Radix
astragali, Lentinus edodes, Agaricus blazei Muri,
Ginkgo biloba, Viola odorata L., Malva pusilla
Smith, Caesalpinia ferrea, Pholiota nameko and
Azadirachta indica have been shown to possess
anti-inflammatory effects [34-37]. Furthermore,
the evidence from studies on the animals and hu-
mans suggests that the oral glucans, arabinogalac-
tans and other polysaccharides are well tolerated in
toxicity studies and have immunomodulatory and
anti-inflammatory activities [38]. Hence, it is ap-
parent that polysaccharides are bioavailable, safe
and have activity against inflammation. In the pre-
sent study, F1 (polysaccharide fraction of NR-
INF-02) was found to be safe and revealed potent
anti-inflammatory activity suggesting that plausi-
bly the arabinogalactans/ukonans are the phytoac-
tives responsible for the anti-inflammatory activity
of F1. The findings of the current in vivo study are
in conformity to in vitro study results in which the
polysaccharide rich fraction of NR-INF-02 (F1)
demonstrated anti-inflammatory activity. In con-
clusion, the present study revealed that the poly-
saccharides of Curcuma longa contributed to the
observed anti-inflammatory activity of NR-INF- 02”.
ANOVA = Analysis of variance
CMC = Carboxymethyl cellulose
COX-2 = Cyclooxygenase-2
F1 = Active polysaccharide fraction of
IL-12 = Interleukin-12
IL-6 = Interleukin-6
iNOS = Inducible nitric oxide synthase
JAK-STAT = Janus kinase and signal transducer
and activator of transcription
LPS = Lipopolysaccharides
MCP = Monocyte chemoattractant protein
NaCl = Sodium chloride
NO = Nitric oxide
NR-INF-02 = A polysaccharide rich extract pre-
pared from rhizome of Curcuma
PGE2 = Prostaglandin E2
Rpm = Revolutions per minute
SEM = Standard error of mean
TNF-α = Tumor necrosis factor-alpha
UV = Ultraviolet
The author(s) confirm that this article content
has no conflict of interest.
The authors are thankful to Indo-Spanish Joint
Programme, Department of Biotechnology (DBT)
of India, Centre for the development of Industrial
Technology (CDTI) of Spain for providing partial
financial assistance to this study.
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Received: December 17, 2014 Revised: April 02, 2015 Accepted: April 03, 2015
... Numerous forms of cancers have been shown to be inhibited by curcumin, which has been examined extensively in recent years [11]. Along with its capacity to control cancer cell proliferation [12], tumour development [13], apoptosis [14] as well as migration, invasion, angiogenesis, metastatic growth [15], bioenergetics [15], oxidative stress [16], inflammation, and immuneregulating activities [17][18][19], curcumin has been shown to have favourable impacts on health [20]. The main challenge with curcumin is Curcumin's bioavailability has been shown to be very low, with several investigations reporting amounts in blood and extraintestinal tissue that were undetectable. ...
... A polysaccharide fraction (F1) of a C. longa aqueous-based extract (NR-INF-02) was also investigated in classical rodent models of inflammation. F1 has been considered for its potential in acute (carrageenan-induced paw edema and xylene-induced ear edema) and chronic (cottonpellet-induced granuloma) models of inflammation [37]. Dimethyl sulfoxide (DMSO) extracts and curcumin was investigated on human intervertebral disc cells and it was suggested that the intra-distal injection of curcumin could be an alternative approach to treating inflammation [38]. ...
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The Curcuma genus has been extensively used for therapeutic purposes in traditional or folk medicine worldwide, including for its anti-inflammatory activity. Curcuma spp.’s active constituents, such as alkaloids, flavonoids, and terpenoids, can act on various targets in the signaling pathway, restrain pro-inflammatory enzymes, lower the production of inflammatory cytokines and chemokines, and reduce oxidative stress, which subsequently suppresses inflammatory processes. Preclinical and clinical studies have reported the predominant anti-inflammatory activity of several Curcuma species. This review provides an overview of the anti-inflammatory effects of different extracts, preparations, and bioactive components in this genus. This analysis may provide a scientific basis for developing new and alternative methods for the isolation of a single entity from this genus to attenuate inflammatory conditions. The Curcuma genus is waiting for researchers interested in developing safe and efficient anti-inflammatory agents for further investigation.
Turmeric is well-known for its analgesic, anti-inflammatory and anti-arthritic properties but 69.4% of the turmeric rhizome contains Turmerosaccharides whose clinical benefit is still unexplored. Turmacin®/NR-INF-02 is an aqueous extract of Turmeric containing Turmerosaccharides (>10%w/w) with negligible curcuminoids. Previous study with low dose Turmacin® confirmed its safety and efficacy in alleviating induced knee pain in healthy volunteers. Hence, this study aimed to assess the safety and explore the efficacy of moderately high dose Turmacin®. It was an open-label, single-arm interventional trial conducted from August 2018 - January 2019 in a tertiary care teaching hospital. Turmacin® was administered for seven days to 15 healthy volunteers as four capsules of 500 mg each in the morning with food. The stair mill at a speed of 60 steps per minute was used to induce knee pain and Visual Analogue Scale (VAS) was used to measure the pain intensity. Assessments were performed at baseline, Days 5 and 7. One participant reported dyspepsia of mild grade that resolved on its own. When compared to baseline, time to initial discomfort significantly increased on Day-5 (Mean Difference [MD] = 30s, p = 0.016) and Day-7 (MD = 32s, p = 0.007). Whereas the maximum VAS score decreased with time and on Day-7 and it was significantly low when compared with baseline (MD = -0.93, p = 0.008). In summary, Turmacin® supplements given at a dose of 2 g/day was safe and tolerable. Similar to the previous study with low dose Turmacin®, there was a significant increase in pain threshold and decrease in the maximum pain score post intervention.
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NR-INF-02 is a standardized extract containing turmerosaccharides from Curcuma longa that has anti-inflammatory, analgesic, and chondroprotective potential. In view of its potential uses, NR-INF-02 was evaluated for its safety in Wistar rats at an oral dose of 250, 500, and 1000 mg/kg in a 90-day repeated dose subchronic toxicity study. NR-INF-02 administered at 250, 500, and 1000 mg/kg for 90 days did not show any mortality or clinical signs of toxicity. Body weight gain, food consumption, ocular and neurological examination, and hematological, blood biochemical, hormone, and urine analysis revealed no evidence of toxicity of NR-INF-02 treatment in rats. Absolute and relative organ weights were comparable to control rats. The study did not reveal any major treatment related gross pathological and histopathological alterations in the tissues or organs examined. Thus, based on study observations, the no-observed adverse effect level (NOAEL) was found to be 1000 mg/kg body weight in albino Wistar rats.
Curcuma longa (C. longa) or turmeric is a plant with a long history of use in traditional medicine, especially for treating inflammatory conditions C. longa and its main constituent, curcumin (CUR), showed various pharmacological effects such as antioxidant and anti-microbial properties. The updated knowledge of anti-inflammatory, antioxidant, and immunomodulatory effects of C. longa and CUR is provided in this review article. Pharmacological effects of C. longa, and CUR, including anti-inflammatory, antioxidant, and immunomodulatory properties, were searched using various databases and appropriate keywords until September 2020. Various studies showed anti-inflammatory effects of C. longa and CUR, including decreased white blood cell, neutrophil, and eosinophil numbers, and its protective effects on serum levels of inflammatory mediators such as phospholipase A2 and total protein in different inflammatory disorders. The antioxidant effects of C. longa and CUR were also reported in several studies. The plant extracts and CUR decreased malondialdehyde and nitric oxide levels but increased thiol, superoxide dismutase, and catalase levels in oxidative stress conditions. Treatment with C. longa and CUR also improved immunoglobulin E (Ig)E, pro-inflammatory cytokine interleukin 4 (IL)-4, transforming growth factor-beta, IL-17, interferon-gamma levels, and type 1/type 2 helper cells (Th1)/(Th2) ratio in conditions with disturbance in the immune system. Therefore C. longa and CUR showed anti-inflammatory, antioxidant, and immunomodulatory effects, indicating a potential therapeutic effect of the plant and its constituent, CUR, for treating of inflammatory, oxidative, and immune dysregulation disorders.
Turmeric belongs to the family Zingiberaceae and is a yellow spice of high economic importance due to its medicinal value. Cultivated in tropical and sub-tropical regions around the world, it is used extensively as a colouring, flavouring and preserving agent. In recent years, several drugs derived from natural products have been developed and current drug research is actively investigating the possible therapeutic roles of many Ayurvedic medicines, most notable among those being examined is turmeric. The wide range of pharmacological activities attributed to turmeric come mainly from curcuminoids and two related compounds, demethoxycurcumin and bisdemethoxycurcumin. This comprehensive book brings together the research carried out on constituents obtained from turmeric and highlights their chemical and biological activities. Comprising 17 chapters, each written by experts in their respective field and curated by authorities, it will be invaluable to all those who are involved in the production, processing, marketing, and the use of turmeric. Appealing to researchers and professionals in natural products, nutraceuticals and food chemists, this book is exposing some of the myths and showing areas for possible future use.
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The herb dwarf lilyturf tube (Maidong, Ophiopogonis Radix) is widely used in Chinese Traditional Medicine to manage diabetes and its complications. However, the role of Maidong polysaccharide extract (MPE) in pancreatic β-cell function is unclear. Here, we investigated whether MPE protects β-cell function and studied the underlying mechanisms. We treated db/db and high-fat diet (HFD)-induced obese mice with 800 or 400 mg/kg MPE or water for 4 weeks, followed by an oral glucose tolerance test. Pancreas and blood were collected for molecular analyses, and clonal MIN6 β cells and primary islets from HFD-induced obese mice and normal chow diet (NCD)-fed mice were used in additional analyses. In vivo, MPE both increased insulin secretion and reduced blood glucose in the db/db mice, but increased only insulin secretion in the HFD-induced obese mice. MPE substantially increased the β-cell area in both models (3-fold and 2-fold, p < 0.01, for db/db and HFD mice, respectively). We observed reduced nuclear translocation of the p65 subunit of NFκB in islets of MPE-treated db/db mice, coinciding with enhanced glucose-stimulated insulin secretion (GSIS). In vitro, MPE potentiated GSIS and decreased interleukin 1β (IL-1β) secretion in MIN6 β cells. Incubation of MIN6 cells with tumor necrosis factor α (TNF-α), IFN-γ, and IL-1β amplified IL-1β secretion and inhibited GSIS. These effects were partially reversed with MPE or the I-k-B-kinase β (IKK) inhibitor PS1145, coinciding with reduced activation of p65 and p-IκB in the NF-κB pathway. We conclude that MPE may have potential for therapeutic development for β-cell protection.
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In the present study, a homogenous polysaccharide (DFPW) was isolated and purified from the dried rhizome of Drynaria fortunei, and its protective effect against osteoporosis was investigated in ovariectomized (OVX) rats. Histological analysis indicated that oral administration of DFPW (100 and 400 mg/kg) for 12 weeks significantly improved trabecular bone mass, as demonstrated by the increase in trabecular area, trabecular thickness and its number in OVX rats. Furthermore, the decline of bone mineral density and bone mineral content including Ca, P and Mg induced by OVX was reversed by the DFPW administration. This function was achieved by the decreased levels of the bone turnover markers, such as serum ALP, urinary deoxypyridinoline (DPD), Ca and P excretions. Besides, DFPW improved biomechanical parameters (maximum load, energy, Young's, modulus and maximum stress) to strengthen the hardness and strength femoral diaphysis in OVX rats. These results strongly suggested that DFPW might be a hopeful alternative therapeutics to treat postmenopausal osteoporosis.
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For centuries, Curcuma longa (turmeric) was used as a spice in Asian cuisine and as a medicinal herb for treatment of inflammation, pain, wound healing, and digestive disorders, to name a few. Considerable preclinical research found that turmeric and its bioactive curcuminoid polyphenols can affect a variety of chronic conditions. Poor oral bioavailability of these curcuminoids hindered human trials investigating the efficacy of oral turmeric and its curcuminoids in treating various diseases and disorders. However, with the development of absorption-enhanced curcuminoid formulations in the past decade, dozens of clinical studies were conducted examining this spice's actions toward inflammatory conditions and glucose/lipid dysregulation. This narrative review of human trials addresses the scientific evidence for potential health benefits of turmeric and its curcuminoids in the treatment of arthritis, diabetes, and the metabolic syndrome and discusses recommendations for future research.
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Azadirachta indica A. Juss., Meliaceae, or Indian neem is a plant used to treat inûammatory disorders. Total polysaccharide (TPL) and FI (fractioned by ion exchange chromatography) from the seed tegument of A. indica were evaluated in models of acute inflammation (paw edema/peritonitis) using Wistar rats. Paw edema (measured by hydroplethysmometry) was induced s.c. by Λ-carrageenan (300 µg), histamine (100 µg), serotonin (20 µg), compound 48/80 (10 µg), prostaglandin (PGE2 30 µg) or L-arginine (15 µg). Peritonitis (analyzed for leukocyte counts/protein dosage) was induced i.p. by carrageenan (500 mg) or N-formyl-methionyl-leucyl-phenylalanine (fMLP 50 ng). Animals were treated i.v. with TPL (1 mg/kg) or FI (0.01, 0.1, 1 mg/kg) 30 min before stimuli. FI toxicity (at 0.1 mg/kg, i.v. for seven days) was analyzed by the variation of body/organ mass and hematological/biochemical parameters. TPL extraction yielded 1.3%; FI, presenting high carbohydrate and low protein content, at 0.1 mg/kg inhibited paw edema induced by carrageenan (77%), serotonin (54%), PGE2 (69%) and nitric oxide (73%), and the peritonitis elicited by carrageenan (48%) or fMLP (67%), being well tolerated by animals. FI exhibited potent anti-inflammatory activity, revealing to be important active component in traditionally prepared remedies to treat inflammatory states.
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While curcuminoids have been reported to possess diverse biological activities, the anti-inflammatory activity of polar extracts (devoid of curcuminoids) of Curcuma longa (C. longa) has seldom been studied. In this study, we have investigated immune-stimulatory and anti-inflammatory activities of an aqueous based extract of C. longa (NR-INF-02) and its fractions in presence and absence of mitogens. Effects of NR-INF-02 (Turmacin™, Natural Remedies Pvt. Ltd., Bangalore, India) on proliferation, nitric oxide (NO), monocyte chemotactic protein-1 (MCP-1), interleukins (ILs) and prostaglandin (PGE2) levels of mouse splenocytes and mouse macrophage (RAW264.7) cells were determined. NR-INF-02 increased splenocytes number in presence and absence of lipopolysaccharide (LPS) or concanavalin A. Treatment of NR-INF-02 showed a significant increase of NO, IL-2, IL-6, IL-10, IL-12, interferon (IFN) gamma, tumor necrosis factor (TNF) alpha and MCP-1 production in unstimulated mouse splenocytes and mouse macrophages. Interestingly, NR-INF-02 showed potent inhibitory effect towards release of PGE2 and IL-12 levels in LPS stimulated mouse splenocytes. Further, NR-INF-02 was fractionated into polysaccharide fraction (F1) and mother liquor (F2) to study their immune-modulatory effects. F1 was found to be more potent than F2 toward inhibiting PGE2 and IL-12 in LPS stimulated splenocytes. Present findings revealed the novel anti-inflammatory property of NR-INF-02 and its polysaccharide fraction by inhibiting the secretion of IL-12 and PGE2 in vitro.
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Certain non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., rofecoxib [Vioxx]) increase the risk of heart attack and stroke and should be avoided in patients at high risk of cardiovascular events. Rates of cardiovascular disease are high and rising in many low- and middle-income countries. We studied the extent to which evidence on cardiovascular risk with NSAIDs has translated into guidance and sales in 15 countries. Data on the relative risk (RR) of cardiovascular events with individual NSAIDs were derived from meta-analyses of randomised trials and controlled observational studies. Listing of individual NSAIDs on Essential Medicines Lists (EMLs) was obtained from the World Health Organization. NSAID sales or prescription data for 15 low-, middle-, and high-income countries were obtained from Intercontinental Medical Statistics Health (IMS Health) or national prescription pricing audit (in the case of England and Canada). Three drugs (rofecoxib, diclofenac, etoricoxib) ranked consistently highest in terms of cardiovascular risk compared with nonuse. Naproxen was associated with a low risk. Diclofenac was listed on 74 national EMLs, naproxen on just 27. Rofecoxib use was not documented in any country. Diclofenac and etoricoxib accounted for one-third of total NSAID usage across the 15 countries (median 33.2%, range 14.7-58.7%). This proportion did not vary between low- and high-income countries. Diclofenac was by far the most commonly used NSAID, with a market share close to that of the next three most popular drugs combined. Naproxen had an average market share of less than 10%. Listing of NSAIDs on national EMLs should take account of cardiovascular risk, with preference given to low risk drugs. Diclofenac has a risk very similar to rofecoxib, which was withdrawn from worldwide markets owing to cardiovascular toxicity. Diclofenac should be removed from EMLs. Please see later in the article for the Editors' Summary.
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Hedychium spicatum (Ham-ex-Smith), known as Shati in Ayurvedic classics, is documented for the treatment of cough, hiccough, fever and asthma. The present study includes the evaluation of aqueous and ethanolic extracts of the dried rhizome of H. spicatum for anti-histaminic and ulcer-protective activities in guinea pig (GP), anti-inflammatory and analgesic activities in rat and acute toxicity in mouse. The extracts were administered orally, daily as suspension, in 1% carboxymethyl cellulose either for 7 days in GP studies or 60 min before or just before experiment in rats and mice. An initial dose-dependent anti-histaminic action of both the extracts (100, 200 and 400 mg/kg) was performed against histamine-induced bronchospasm in GPs. The 200 mg/ kg dose of aqueous and ethanolic extracts was selected both in GP and rat for further studies. GPs treated with aqueous and ethanolic extracts showed gastric ulcer protection against histamine-induced gastric ulcer compared with the control group. Both the extracts also showed an anti-inflammatory effect against carrageenan-induced paw edema in rats from 1 h onwards, and this was maximum at 3 h. Analgesic effect was determined by using hot plate and tail flick tests in rats, and both the extracts at 200 mg/kg showed a significant increase in the latent period from 30 min onwards till 120 min of their study period. Both the extracts did not show any toxic effect like increased motor activity, salivation, clonic convulsion, coma and death in mice even at the 2000 mg/kg dose (nearly 10 times of the optimal effective dose), indicating the safety of the extracts. The result confirms the indigenous use of this plant in respiratory disorders.
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Curcuma longa Linn. is widely used for the treatment of disorders associated with inflammation and was evaluated for its safety and efficacy in the treatment of painful knee osteoarthritis (OA). This was a randomized, single blind, placebo-controlled trial. Total of 120 patients (37 males and 83 females) with primary knee OA received either placebo (400 mg twice daily) or NR-INF-02 (500 mg twice daily) or glucosamine sulphate (GS) (750 mg twice daily) alone or combination of NR-INF-02 and GS for 42 days. The efficacy was assessed during treatment period, on day 21 and day 42. The decrease in severity of pain symptom and function of affected knee as primary efficacy outcome measure was assessed by Visual Analog Scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scale, respectively. The clinical examination of affected joint was measured by an orthopaedic specialist and using a Clinician Global Impression Change (CGIC) scale. The analysis of post-treatment scores following administration of NR-INF-02 using VAS, WOMAC, and CGIC at each clinical visit showed significant decrease (p < 0.05) compared to placebo. NR-INF-02 treated group showed a significant (p < 0.01) decrease in use of rescue medication, along with clinical and subjective improvement compared to placebo. The tolerability and acceptability profile of NR-INF-02 was better during the trial period. The study demonstrates safety and efficacy of NR-INF-02 as a useful treatment option for patients with primary painful knee OA.
Anti-inflammatory effects of turmeric (Curcuma longa L.) rich in polysaccharides, as well as free of curcuminoids and turmerones were investigated in acute and chronic inflammatory models. Activity against the acute phase of inflammation was evaluated in carrageenan-induced paw edema and xylene-induced ear edema models. The results showed that turmeric extract significantly decreased paw edema volume in the first and third hours after carrageenan injection (P≤0.05). Turmeric extract at all dose levels also significantly inhibited xylene-induced ear edema formation (P≤0.05). Activity against chronic inflammation was also evaluated in cotton pellet-induced granuloma model. Turmeric extract significantly (P≤0.05) decreased the weight of granuloma tissue on cotton pellets in a dose-dependent manner when compared to the vehicle control. Thus, the findings of the study suggest that turmeric extract in effective against both acute and chronic inflammation.
Background: Crocus sativus L. (saffron) is used in folk medicine, for example as an antiedematogenic agent. We aimed to evaluate the antinociceptive and anti-inflammatory activity of saffron extracts in mice.