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ABSTRACTS BOSWELLIA SERRATA

Evid Based Complement Alternat Med. 2013;2013:140509. doi: 10.1155/2013/140509. Epub 2013
Mar 6.

Chemistry and biology of essential oils of


genus boswellia.
Hussain H, Al-Harrasi A, Al-Rawahi A, Hussain J.

Source
Department of Biological Sciences and Chemistry, College of Arts and Sciences, University of
Nizwa, Birkat Al-Mouz, 616 Nizwa, Oman ; Department of Chemistry, University of Paderborn,
Warburger Strae 100, 33098 Paderborn, Germany.

Abstract
The properties of Boswellia plants have been exploited for millennia in the traditional medicines of
Africa, China, and especially in the Indian Ayurveda. In Western countries, the advent of synthetic
drugs has obscured the pharmaceutical use of Boswellia, until it was reported that an ethanolic
extract exerts anti-inflammatory and antiarthritic effects. Frankincense was commonly used for
medicinal purposes. This paper aims to provide an overview of current knowledge of the volatile
constituents of frankincense, with explicit consideration concerning the diverse Boswellia species.
Altogether, more than 340 volatiles in Boswellia have been reported in the literature. In particular, a
broad diversity has been found in the qualitative and quantitative composition of the volatiles with
respect to different varieties of Boswellia. A detailed discussion of the various biological activities
of Boswellia frankincense is also presented.
J Nat Prod. 2012 Oct 26;75(10):1675-82. doi: 10.1021/np300009w. Epub 2012 Sep 26.

Effect of phospholipid-based formulations of Boswellia serrata extract


on the solubility, permeability, and absorption of the individual
boswellic acid constituents present.
Hsch J, Gerbeth K, Fricker G, Setzer C, Zirkel J, Rebmann H, Schubert-Zsilavecz M, Abdel-Tawab M.

Source
Central Laboratory of German Pharmacists , Carl-Mannich-Strae 20, 65760 Eschborn, Germany.

Abstract
Boswellia serrata gum resin extracts are used widely for the treatment of inflammatory diseases. However,
very low concentrations in the plasma and brain were observed for the boswellic acids (1-6, the active
constituents of B. serrata). The present study investigated the effect of phospholipids alone and in
combination with common co-surfactants (e.g., Tween 80, vitamin E-TPGS, pluronic f127) on the solubility of
1-6 in physiologically relevant media and on the permeability in the Caco-2 cell model. Because of the high
lipophilicity of 1-6, the permeability experiments were adapted to physiological conditions using modified
fasted state simulated intestinal fluid as apical (donor) medium and 4% bovine serum albumin in the

basolateral (receiver) compartment. A formulation composed of extract/phospholipid/pluronic f127 (1:1:1


w/w/w) increased the solubility of 1-6 up to 54 times compared with the nonformulated extract and exhibited
the highest mass net flux in the permeability tests. The oral administration of this formulation to rats (240
mg/kg) resulted in 26 and 14 times higher plasma levels for 11-keto--boswellic acid (1) and acetyl-11-keto-boswellic acid (2), respectively. In the brain, five times higher levels for 2 compared to the nonformulated
extract were determined 8 h after oral administration
Planta Med. 2006 May;72(6):507-13.

Modulation of Pgp function by boswellic acids.


Weber CC, Reising K, Mller WE, Schubert-Zsilavecz M, Abdel-Tawab M.

Source
Institute of Pharmacology, ZAFES, Biocenter, University of Frankfurt, Germany.

Abstract
Boswellic acids, the main active ingredients of Boswellia serrata, are gaining more and more importance in
the treatment of peritumoural oedema and chronic inflammatory diseases. They may be even considered as
alternative drugs to corticosteroids in reducing cerebral peritumoural oedema. An important focus for drugs
acting in the central nervous system is achieving a high extent of brain penetration. Today there is increasing
evidence for the importance of transporters, especially P-glycoprotein (Pgp), for drug disposition and
resulting clinical response. Pharmacokinetic studies revealed that the concentrations of the potent keto
derivatives, the 11-keto-beta-boswellic acid (KBA) and the acetyl-11-keto-beta-boswellic acid (AKBA), in
proportion to boswellic acids lacking a keto group, like the beta-boswellic acid, are much lower in plasma
than in the orally administered extract. Moreover the brain/plasma ratio for KBA and AKBA determined in
preliminary experiments on rats was only about 0.51 and 0.81, respectively, in spite of their lipophilicity. Until
now little is known about the cerebral pharmacokinetics of boswellic acids and how it may be influenced.
Since many drugs are known to interact with Pgp at the level of the intestine and the blood-brain barrier the
modulatory potencies of the Boswellia serrata extract of H15(R) and the major boswellic acids on the
transport activity of Pgp have been determined in two in vitro assays. A human lymphocytic leukaemia cell
line (VLB cells) expressing Pgp was chosen as model for human Pgp, and porcine brain capillary endothelial
cells (PBCEC cells) were taken as model for the blood-brain barrier using calcein acetoxymethyl ester
(calcein-AM) as Pgp substrate. It was found that the Boswellia extract, as well as the keto-boswellic acids
inhibit the transport activity of Pgp in the micromolecular range in both cell types. No modulation was
observed using those boswellic acids which have no keto group in their structure. The inhibition of Pgp at the
blood-brain barrier by Boswellia extract is probably not relevant for the brain availability of other Pgp
substrates, because of the low plasma levels determined for KBA and AKBA. However the presented data
could not exclude the possibility of drug interactions caused by modulation of Pgp by extracts of Boswellia
serrata on the gastrointestinal level.
Drug Metab Dispos. 2008 Jun;36(6):1135-42. doi: 10.1124/dmd.107.018424. Epub 2008 Mar 20.

Metabolism of boswellic acids in vitro and in vivo.


Krger P, Daneshfar R, Eckert GP, Klein J, Volmer DA, Bahr U, Mller WE, Karas M, Schubert-Zsilavecz M,
Abdel-Tawab M.

Source
Central Laboratory of German Pharmacists, Eschborn, Germany.

Abstract

Boswellia serrata resin dry extract is among the few herbal remedies designated with an orphan drug status
for the treatment of peritumoral brain edema. In addition, boswellic acids (BAs), the main active ingredients
of B. serrata extracts, have potent anti-inflammatory properties, and may represent promising agents for the
treatment of inflammatory diseases. Pharmacokinetic studies, however, revealed poor bioavailability,
especially of 11-keto-beta-boswellic acid (KBA) and 3-acetyl-11-keto-beta-boswellic acid (AKBA), the most
potent BAs. To address the question of whether BAs are extensively metabolized, we determined the
metabolic stability of KBA and AKBA in vitro, investigated the in vitro metabolism of BAs, and compared the
metabolic profiles of KBA and AKBA with those obtained in rats in vivo. In rat liver microsomes and
hepatocytes as well as in human liver microsomes, we found that KBA but not AKBA undergoes extensive
phase I metabolism. Oxidation to hydroxylated metabolites is the principal metabolic route. In vitro, KBA
yielded metabolic profiles similar to those obtained in vivo in rat plasma and liver, whereas no metabolites of
AKBA could be identified in vivo. Furthermore, AKBA is not deacetylated to KBA. This study indicates that
the efficacy of B. serrata extract may be enhanced by increasing the bioavailability of AKBA.
Phytomedicine. 2010 Sep;17(11):862-7. doi: 10.1016/j.phymed.2010.03.003. Epub 2010 Aug 8.

Modulation of the immune system by Boswellia serrata extracts and


boswellic acids.
Ammon HP.

Source
Department of Pharmacology, Institute of Pharmaceutical Sciences, University of Tuebingen, Tuebingen,
Germany. sekretariat.ammon@uni-tuebingen.de

Erratum in

Phytomedicine. 2011 Feb 15;18(4):334.

Abstract
Extracts from the gum resin of Boswellia serrata and some of is constituents including boswellic acids affect
the immune system in different ways. Among the various boswellic acids 11-keto-beta-boswellic acid (KBA)
and acetyl-11-keto-beta-boswellic acid have been observed to be active. However, also other boswellic acids
may exhibit actions in the immune system. In the humoral defence system a mixture of boswellic acis at
higher doses reduced primary antibody titres; on the other hand lower doses enhanced secondary antibody
titres following treatment with sheep erythrocytes. In the cellular defence boswellic acides appear to increase
lymphocyte proliferation whereas higher concentrations are even inhibitory. Moreover, BAs increase
phagocytosis of macrophages. BAs affect the cellular defence system by interaction with production/release
of cytokines. Thus, BAs inhibit activation of NFkappaB which is a product of neutrophile granulocytes.
Consequently a down regulation of TNF-alpha and decrease of IL-1, IL-2, IL-4, IL-6 and IFN-gamma, which
are proinflammatory cytokines by BEs and BAs has been reported. Suppressions of the classic way of the
complement system was found to be due to inhibition of the conversion of C3 into C3a and C3b. However,
which of these pharmacological actions contribute to the therapeutic effects and which is finally the best
dosage of a standardized extract needs further examination. And it is also a question whether or not a single
BA will have the same therapeutic effect as a standardized extract. Among the mediators of inflammatory
reaction, mast cell stabilisation has been described by a BE. Inhibition of prostaglandin synthesis appears to
play only a minor role as far as the anti-inflammatory effect is concerned. On the other hand the inhibitory
action of BAs on 5-LO leading to a decreased production of leukotrienes has received high attention by the
scientific community since a variety of chronic inflammatory diseases is associatied with increased
leukotriene activity. At the end of the cascade of events in the cellular immune system as far as it directs to
various tissues of the body - i.e. autoimmune diseases - formation of oxygen radicals and proteases (for
example elastase) play an important destructive role. Here, BEs as well as BAs have been found to be
inhibitory. From the pharmacological properties of BEs and BAs it is not surprising that positive effects of
BEs in some chronic inflammatory diseases including rheumatoid arthritis, bronchial asthma, osteoarthritis,
ulcerative colitis and Crohn's disease have been reported.

Wien Med Wochenschr. 2002;152(15-16):373-8.

[Boswellic acids (components of frankincense) as the active principle in


treatment of chronic inflammatory diseases].
[Article in German]
Ammon HP.

Source
Lehrstuhl Pharmakologie fr Naturwissenschaftler, Pharmazeutisches Institut der Universitt Tbingen,
Deutschland. sekretariat.ammon@uni-tuebingen.de

Abstract
Preparations from the gum resin of Boswellia serrata have been used as a traditional remedy in Ayurvedic
medicine in India for the treatment of inflammatory diseases. Compounds from the gum with genuine
antiinflammatory effects are pentacyclic triterpenes of the boswellic acid type. Boswellic acids inhibit the
leukotriene biosynthesis in neutrophilic granulocytes by a non-redox, noncompetitive inhibition of 5lipoxygenase. The effect is triggered by boswellic acids binding to the enzyme. Moreover certain boswellic
acids have been described to inhibit elastase in leukocytes, to inhibit proliferation, induce apoptosis and to
inhibit topoisomerases of leukoma- and glioma cell lines. A series of chronic inflammatory diseases are
thought to be perpetuated by leukotrienes. In clinical trials promising results were observed in patients with
rheumatoid arthritis, chronic colitis, ulcerative colitis, Crohn's disease, bronchial asthma und peritumoral
brains edemas.
Planta Med. 2006 Oct;72(12):1100-16.

Boswellic acids in chronic inflammatory diseases.


Ammon HP.

Source
Dept. of Pharmacology, Institute of Pharmaceutical Sciences, University of Tuebingen, Tuebingen, Germany.
sekretariat.ammon@uni-tuebingen.de

Abstract
Oleogum resins from BOSWELLIA species are used in traditional medicine in India and African countries for
the treatment of a variety of diseases. Animal experiments showed anti-inflammatory activity of the extract.
The mechanism of this action is due to some boswellic acids. It is different from that of NSAID and is related
to components of the immune system. The most evident action is the inhibition of 5-lipoxygenase. However,
other factors such as cytokines (interleukins and TNF-alpha) and the complement system are also
candidates. Moreover, leukocyte elastase and oxygen radicals are targets. Clinical studies, so far with pilot
character, suggest efficacy in some autoimmune diseases including rheumatoid arthritis, Crohn's disease,
ulcerative colitis and bronchial asthma. Side effects are not severe when compared to modern drugs used
for the treatment of these diseases.

Lipids Health Dis. 2009 Dec 1;8:51. doi: 10.1186/1476-511X-8-51.

Boswellic acid inhibits expression of acid


sphingomyelinase in intestinal cells.

Zhang Y, Duan RD.

Source
Gastroenterology and Nutrition Lab, Biomedical Center, B11, University of Lund, Lund, Sweden.
yao.zhang@med.lu.se

Abstract

BACKGROUND:
Boswellic acid is a type of triterpenoids with antiinflammatory and antiproliferative properties.
Sphingomyelin metabolism generates multiple lipid signals affecting cell proliferation,
inflammation, and apoptosis. Upregulation of acid sphingomyelinase (SMase) has been found in
several inflammation-related diseases such as inflammatory bowel diseases, atherosclerosis, and
diabetes.

METHODS:
The present study is to examine the effect of 3-acetyl-11-keto-beta-boswellic acids (AKBA), a
potent boswellic acid, on acid SMase activity and expression in intestinal cells. Both transformed
Caco-2 cells and non-transformed Int407 cells were incubated with AKBA. After incubation, the
change of acid SMase activity was assayed biochemically, the enzyme protein was examined by
Western blot, and acid SMase mRNA was quantified by qPCR.

RESULTS:
We found that AKBA decreased acid SMase activity in both intestinal cell lines in dose and time
dependent manners without affecting the secretion of the enzyme to the cell culture medium. The
effect of AKBA was more effective in the fetal bovine serum-free culture medium. Among different
types of boswellic acid, AKBA was the most potent one. The inhibitory effect on acid SMase
activity occurred only in the intact cells but not in cell-free extract in the test tubes. At low
concentration, AKBA only decreased the acid SMase activity but not the quantity of the enzyme
protein. However, at high concentration, AKBA decreased both the mass of acid SMase protein and
the mRNA levels of acid SMase in the cells, as demonstrated by Western blot and qPCR,
respectively. Under the concentrations decreasing acid SMase activity, AKBA significantly
inhibited cell proliferation.

CONCLUSION:
We identified a novel inhibitory effect of boswellic acids on acid SMase expression, which may
have implications in human diseases and health.
Indian J Pharm Sci. 2011 May;73(3):255-61. doi: 10.4103/0250-474X.93507.

Boswellia serrata, a potential


antiinflammatory agent: an overview.

Siddiqui MZ.

Source
Processing and Product Development Division, Indian Institute of Natural Resins and Gums,
Namkum, Ranchi-834 010, India.

Abstract
The resin of Boswellia species has been used as incense in religious and cultural ceremonies and in
medicines since time immemorial. Boswellia serrata (Salai/Salai guggul), is a moderate to large
sized branching tree of family Burseraceae (Genus Boswellia), grows in dry mountainous regions of
India, Northern Africa and Middle East. Oleo gum-resin is tapped from the incision made on the
trunk of the tree and is then stored in specially made bamboo basket for removal of oil content and
getting the resin solidified. After processing, the gum-resin is then graded according to its flavour,
colour, shape and size. In India, the States of Andhra Pradesh, Gujarat, Madhya Pradesh, Jharkhand
and Chhattisgarh are the main source of Boswellia serrata. Regionally, it is also known by different
names. The oleo gum-resins contain 30-60% resin, 5-10% essential oils, which are soluble in the
organic solvents, and the rest is made up of polysaccharides. Gum-resin extracts of Boswellia
serrata have been traditionally used in folk medicine for centuries to treat various chronic
inflammatory diseases. The resinous part of Boswellia serrata possesses monoterpenes, diterpenes,
triterpenes, tetracyclic triterpenic acids and four major pentacyclic triterpenic acids i.e. -boswellic
acid, acetyl--boswellic acid, 11-keto--boswellic acid and acetyl-11-keto--boswellic acid,
responsible for inhibition of pro-inflammatory enzymes. Out of these four boswellic acids, acetyl11-keto--boswellic acid is the most potent inhibitor of 5-lipoxygenase, an enzyme responsible for
inflammation.
Inflamm Bowel Dis. 2011 Feb;17(2):573-82. doi: 10.1002/ibd.21345.

Randomized, placebo-controlled, double-blind trial of Boswellia serrata


in maintaining remission of Crohn's disease: good safety profile but
lack of efficacy.
Holtmeier W, Zeuzem S, Preiss J, Kruis W, Bhm S, Maaser C, Raedler A, Schmidt C, Schnitker J, Schwarz
J, Zeitz M, Caspary W.

Source
Department of Gastroenterology, Diabetes and Internal Medicine, Hospital Porz am Rhein, Cologne,
Germany. W.Holtmeier@khporz.de

Abstract
BACKGROUND:
Complementary therapies are frequently used by patients with inflammatory bowel disease (IBD). The aim of
this study was to evaluate the efficacy and safety of long-term therapy with a new Boswellia serrata extract
(Boswelan, PS0201Bo) in maintaining remission in patients with Crohn's disease (CD).

METHODS:
In 22 German centers a double-blind, placebo-controlled, randomized, parallel study was performed. In all,
108 outpatients with CD in clinical remission were included. Patients were randomized to Boswelan (32
capsules/day; 400 mg each) or placebo for 52 weeks. The primary endpoint was the proportion of patients in
whom remission was maintained throughout the 52 weeks. Secondary endpoints were time to relapse,
changes of Crohn's Disease Activity Index (CDAI), and IBD Questionnaire (IBDQ) scores.
RESULTS:
The trial was prematurely terminated due to insufficient discrimination of drug and placebo with regard to the
primary efficacy endpoint. A total of 82 patients were randomized to Boswelan (n=42) or placebo (n=40).
Sixty-six patients could be analyzed for efficacy. 59.9% of the actively treated patients and 55.3% of the
placebo group stayed in remission (P=0.85). The mean time to diagnosis of relapse was 171 days for the
active group and 185 days for the placebo group (P=0.69). With respect to CDAI, IBDQ, and laboratory
measurements of inflammation, no advantages in favor of active treatment were detected. Regarding safety
concerns, no disadvantages of taking the drug compared to placebo were observed.
CONCLUSIONS:
The trial confirmed good tolerability of a new Boswellia serrata extract, Boswelan, in long-term treatment of
CD. However, superiority versus placebo in maintenance therapy of remission could not be demonstrated.
Z Rheumatol. 1998 Feb;57(1):11-6.

[Is H15 (resin extract of Boswellia serrata, "incense") a useful


supplement to established drug therapy of chronic polyarthritis?
Results of a double-blind pilot study].
[Article in German]
Sander O, Herborn G, Rau R.

Source
Rheumatologische Klinik, Evangelisches Fachkrankenhaus Ratingen.

Abstract
BACKGROUND:
Leukotrienes and prostaglandines are important mediators of inflammation. While prostaglandine synthesis
can be influenced by NSAIDs therapeutical approaches to the 5-lipoxygenase pathway are rare. Resinous
extracts of Boswellia serrata (H15, indish incense), known from traditional ayurvedic medicine, decrease
leukotriene synthesis in vitro. Case reports suggest a clinical role for that drug.
METHODS:
Outpatients with active RA have been enrolled into a multicenter controlled trial. Patients received 9 tablets
of active drug (3600 mg) or placebo daily in addition to their previous therapy. Doses of NSAIDs could be
adjusted on demand. Efficacy parameters, Ritchies Index for swelling and pain, ESR, CRP, pain on VAS and
NSAID dose were documented at baseline and 6 and 12 weeks after initiation. Mean values and medians
were calculated to compare the groups for significant or clinically relevant change from baseline or difference
between both groups at any time point of observation.

RESULTS:
A total of 78 patients were recruited in 4 centers, the data have been published in abstract form. Only 37
patients (verum 18, placebo 19), enrolled in Ratingen were available for detailed efficacy and safety analysis.
All evaluations in these patients were performed by one investigator (G.H.). There was no subjective, clinical
or laboratory parameter showing a significant or clinically relevant change from baseline or difference
between both groups at any time point of observation. The mean NSAID dose reduction reached levels of
5.8% (H15) and 3.1% (placebo). One patient in each group showed a good response in all parameters but 4
patients in each group worsened. The others showed no alteration of their disease.
CONCLUSION:
Treatment with H15 showed no measurable efficacy. Controlled studies including a greater patient
population are necessary to confirm or reject our results.
Clin Biochem. 2010 Jul;43(10-11):887-90. doi: 10.1016/j.clinbiochem.2010.04.061. Epub 2010 Apr 27.

Natural anti-inflammatory products and leukotriene inhibitors as


complementary therapy for bronchial asthma.
Houssen ME, Ragab A, Mesbah A, El-Samanoudy AZ, Othman G, Moustafa AF, Badria FA.

Source
Department of Biochemistry, Faculty of Pharmacy, University of Beni Sueif, Beni Sueif 62514, Egypt.
mahahoussen@yahoo.com

Abstract
OBJECTIVE:
To assess the efficacy of a combination of Boswellia serrata, licorice root (Glycyrrhiza glabra) and Tumeric
root (Curcuma longa) as natural leukotriene inhibitor, antiinflammatory and antioxidant products respectively
in controlling bronchial asthma.
SUBJECTS AND METHODS:
The study comprised 63 patients with bronchial asthma that are further subdivided into two groups .Group 1
receiving oral capsule (combined herb) in a soft-gelatin capsule 3 times daily for 4weeks and group 2
receiving placebo. Plasma leukotriene C(4) (LTC(4))(,) nitric oxide (NO) and malondialdehyde (MDA) levels
were measured and pulmonary function was also assessed in all patients enrolled in the study.
RESULTS:
There was a statistically significant decrease in the plasma levels of LTC(4), (MDA), and NO in target
therapy group when compared with placebo group.
CONCLUSION:
The used extract contained Boswellia serrata, Curcuma longa and Glycyrrhiza has a pronounced effect in
the management of bronchial asthma.
Phytomedicine. 2008 Jun;15(6-7):400-7. doi: 10.1016/j.phymed.2007.11.019. Epub 2008 Jan 28.

Boswellic acids: A leukotriene inhibitor also effective through topical


application in inflammatory disorders.

Singh S, Khajuria A, Taneja SC, Johri RK, Singh J, Qazi GN.

Source
Department of Pharmacology, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi
180001, J&K, India. surjeet58@yahoo.com

Abstract
Boswellic acids (BA), a natural mixture isolated from oleo gum resin of Boswellia serrata comprised of four
major pentacyclic triterpene acids: beta-boswellic acid (the most abundant), 3-acteyl-beta-boswellic acid, 11keto-beta-boswellic acid, and 3-acetyl-11-keto-beta-boswellic acid, is reported to be effective as antiinflammatory, immunomodulatory, anti-tumor, anti-asthmatic and in Chron's disease. It inhibits proinflammatory mediators in the body, specifically leukotrienes via inhibition of 5-lipoxygenase, the key enzyme
of leukotriene synthesis, is the scientifically proved mechanism for its anti-inflammatory/anti-arthritic activity.
All previous work on BA for its biological activity has been done through the systemic application but no preclinical data reported for its anti-inflammatory activity by topical application. We here by report antiinflammatory activity of BA through this route by applying different acute and chronic models of inflammation
i.e., arachidonic acid and croton oil-induced mouse ear edema, carrageenan-induced rats paw edema and
adjuvant-induced developing arthritis in rats. The results of the study revealed that the effect observed
through this route is in accordance to the study conducted with the systemic route, thus establishing that BA
when used through topical application is as effective as through the systemic route.
Bioorg Med Chem Lett. 2007 Jul 1;17(13):3706-11. Epub 2007 Apr 19.

Boswellic acids and glucosamine show synergistic effect in preclinical


anti-inflammatory study in rats.
Singh S, Khajuria A, Taneja SC, Khajuria RK, Singh J, Qazi GN.

Source
Department of Pharmacology, Indian Institute of Integrative Medicine, Canal Road Jammu Tawi, Jammu and
Kashmir 180001, India. surjeet58@yahoo.com <surjeet58@yahoo.com>

Abstract
The present study revealed the synergistic effect of boswellic acid mixture (BA) and glucosamine for antiinflammatory and anti-arthritic activities in rats. Two studies were conducted, that is, acute anti-inflammatory
by carrageenan edema and chronic anti-arthritic by Mycobacterium-induced developing arthritis. Five groups
of animals were included in each of the study: the vehicle control, positive control (ibuprofen 100mg/kg),
boswellic acids (250 mg/kg), glucosamine (250 mg/kg) and a combination of boswellic acids (125 mg/kg) and
glucosamine (125 mg/kg). BA when administered at 250 mg/kg in rats, carrageenan-induced paw edema
and Mycobacterium-induced developing arthritis were significantly inhibited. In comparison to boswellic
acids, glucosamine when administered at 250 mg/kg showed a mild effect in carrageenan-induced edema
and moderate inhibition of paw swelling against developing arthritis. Although the combination of boswellic
acids and glucosamine did not affect the acute inflammation to a greater extent yet a significant anti-arthritic
activity was observed in rats. In conclusion, a synergistic effect was observed in chronic inflammatory
conditions when two chemical entities were administered in combination in preclinical study.
Nat Prod Rep. 2009 Jan;26(1):72-89.

Boswellic acids: a group of medicinally important compounds.


Shah BA, Qazi GN, Taneja SC.

Source

Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, 180001, India.

Abstract
This review, containing over 276 references, covers the progress made in the chemistry and bioactivity of
this important group of triterpenoids. Though initially known for their anti-inflammatory and anti-arthritic
activities through a unique 5-LO inhibition mechanism, boswellic acids have recently attained significance
due to their anti-cancer properties. The phytochemistry and chemical modifications, including mechanism of
action, are discussed.
Agents Actions. 1986 Jun;18(3-4):407-12.

Pharmacology of an extract of salai guggal ex-Boswellia serrata, a new


non-steroidal anti-inflammatory agent.
Singh GB, Atal CK.

Abstract
Pharmacological evaluation of alcoholic extract of salai guggal (AESG) has been carried out in experimental
animals. AESG displayed marked anti-inflammatory activity in carrageenan induced oedema in rats and mice
and dextran oedema in rats. It was equally effective in adrenalectomised rats. In formaldehyde and adjuvant
arthritis, AESG produced prominent anti-arthritic activity but no significant effect was observed in cotton
pellet-induced granuloma test. It inhibited inflammation induced increase in serum transaminase levels and
leucocyte counts but lacked any analgesic or anti-pyretic effects. The gestation period or parturition time in
pregnant rats or onset time of castor oil-induced diarrhoea was unaffected by AESG and no significant effect
was seen on cardiovascular, respiratory and central nervous system functions. No ulcerogenic effects were
found in the rat stomach. The oral and intraperitoneal LD50 was greater than 2 g/Kg in mice and rats.
Agents Actions. 1986 Jun;18(3-4):407-12.

Pharmacology of an extract of salai guggal ex-Boswellia serrata, a new


non-steroidal anti-inflammatory agent.
Singh GB, Atal CK.

Abstract
Pharmacological evaluation of alcoholic extract of salai guggal (AESG) has been carried out in experimental
animals. AESG displayed marked anti-inflammatory activity in carrageenan induced oedema in rats and mice
and dextran oedema in rats. It was equally effective in adrenalectomised rats. In formaldehyde and adjuvant
arthritis, AESG produced prominent anti-arthritic activity but no significant effect was observed in cotton
pellet-induced granuloma test. It inhibited inflammation induced increase in serum transaminase levels and
leucocyte counts but lacked any analgesic or anti-pyretic effects. The gestation period or parturition time in
pregnant rats or onset time of castor oil-induced diarrhoea was unaffected by AESG and no significant effect
was seen on cardiovascular, respiratory and central nervous system functions. No ulcerogenic effects were
found in the rat stomach. The oral and intraperitoneal LD50 was greater than 2 g/Kg in mice and rats.

Clin Diagn Lab Immunol. 2005 May; 12(5): 575580.


doi: 10.1128/CDLI.12.5.575-580.2005
PMCID: PMC1112084

Boswellia carterii Extract Inhibits TH1


Cytokines and Promotes TH2 Cytokines In
Vitro
Marc R. Chevrier,1, Abigail E. Ryan,1 David Y.-W. Lee,2 Ma Zhongze,2 Zhang Wu-Yan,2 and
Charles S. Via1,*
Author information Article notes Copyright and License information
This article has been cited by other articles in PMC.
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ABSTRACT
Traditional herbal formulas used to treat inflammatory arthritis in China and India include
Boswellia carterii or Boswellia serrata. They both contain boswellic acids (BAs) which have been
shown to exhibit anti-inflammatory and antiarthritic properties. This study tests the hypothesis that
mixtures of BAs derived from B. carterii have immunomodulatory properties. B. carterii plant resin
obtained from China was prepared as an ethanol extract, and the presence of seven BAs was
confirmed by column chromatography, high-performance liquid chromatography, and UV laser
desorption/ionization tandem mass spectroscopy. The extract was then tested for its ability to alter
in vitro production of TH1 cytokines (interleukin-2 [IL-2] and gamma interferon) and TH2
cytokines (IL-4 and IL-10) by murine splenocytes. Delivery of the resin extract using ethanol as a
solvent resulted in significant cellular toxicity not seen with the addition of ethanol alone. By
contrast, delivery of the resin extract using a sesame oil solvent resulted in a dose-dependent
inhibition of TH1 cytokines coupled with a dose-dependent potentiation of TH2 cytokines. These
results indicate that a purified mixture of BAs from B. carterii plant resin exhibits carrier-dependent
immunomodulatory properties in vitro.
Complementary and alternative treatments of arthritis have gained popularity because they are
purported to show clinical efficacy with minimal side effects compared to mainstream treatments.
Frankincense, or olibanum, is obtained from the genus Boswellia, family Burseraceae, tree. Its
extracted resin, salai guggal, is produced predominantly by four species, including Boswellia
serrata in India, Boswellia carterii in East Africa and China, Boswellia frereana in Somalia, and
Boswellia sacra in Arabia (
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Destroy user interface control21). The term guggals collectively refers to gum resins. The Boswellia
gum oleoresin is comprised of essential oils, gum, and terpenoids. The Boswellia resin's chemical
structure is similar to that of other pentacyclic triterpenes, which closely resembles that of antiinflammatory steroids. Salai guggal has been shown to exhibit strong immunostimulant activity (
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Destroy user interface control17), and in the Ayurvedic Indian tradition, inflammatory polyarthritis
and other forms of rheumatism have been successfully treated with herbal mixtures containing
Boswellia resins or extracts (
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The active constituents are contained in the extracted Boswellia terpenoid portion and are composed
of boswellic acids (BAs) (
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Destroy user interface control20). The herbal formulas used for treatment vary, with BAs
constituting from 37.5% to 65% of the total formulation (
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Destroy user interface control1). The plant resin from B. carterii is a frequent constituent of
traditional Chinese herbal therapy, whereas BAs from B. serrata are key ingredients in Ayurvedic
treatments for similar disease states (
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Destroy user interface control1). Both species contain BAs reported to have anti-inflammatory
properties (
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Human rheumatoid arthritis has a strong immune-mediated component and is marked by increased
activated levels of TH1 cells and their cytokines, interleukin-2 (IL-2) and gamma interferon (IFN), with fewer immunomodulatory TH2 cells and their cytokines, IL-4 and IL-10 (
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Destroy user interface control11,


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Destroy user interface control18). It is possible, then, that the beneficial effect of boswellins in
inflammatory arthritis may derive in part from immunomodulatory activity in addition to antiinflammatory properties.
In this study, we address the in vitro immunomodulatory capacity of BAs derived from B. carterii.
Moreover, we applied both quantitative chromatographic techniques and laser desorption/ionization
tandem mass spectroscopy to ensure proper characterization and quantification of BAs present in
the preparation and, thereby, proper standardization. Our results support the hypothesis that a
portion of the therapeutic effects of B. carterii-derived BAs could reflect immunomodulation.
Go to:

MATERIALS AND METHODS


Procurement and preparation of crude B. carterii extract.
The B. carterii plant resin was procured and identified by Q. C. Fang at the Institute of Materia
Medica, Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing,
China. Ten kilograms of resin was manually ground into powder and passed through a mesh screen
(#80) and suspended in aqueous ethanol (95%; 20 liters) for 24 h. After filtration, the residue was
resuspended in aqueous ethanol (95%; 20 liters) for an additional 24 h and refiltered. The combined
liquid-phase filtrate was then concentrated to give an initial B. carterii ethanol extract (BCE). Based
on previous experimentation, 20% by weight of this initial BCE consists of total pentacyclic
triterpenic acids. To ensure the presence of a relative proportion of each BA, the following
fractionation methods were used for repetitive quality control of each individual preparation.

Isolation scheme to purify - and -boswellic acids and related analogs from BCE.
The isolation of BAs and derivatives from BCE is summarized in Fig. Fig.1.1. Forty-five grams of
BCE was chromatographed over a 250-g silica gel column using a gradient solvent system
consisting of n-hexane with increasing amounts of ethyl acetate. A total of 120 fractions, 250
ml/fraction, were collected. The following methods were used to subpurify the BAs.

FIG. 1.
Fractionation scheme of BCE. The initial ethanol extract was subjected to SiO2 column
chromatography, and fractions 33 through 68 and 69 through 85 were subpurified by HPLC. Yields
shown are derived from a 60-mg column injection. Yields from fractions ...

(i) Method for - and -boswellic acid acetates.

Fractions 33 through 68 were combined and concentrated. This yielded a 12.2-g residue that was
recrystallized in 200 ml of hot methanol and allowed to precipitate at 2C ( 2) for 12 h; the
precipitate was then mesh filtered. The final mixture yielded 6 g of acetylated - and -BA. This
mixture was further separated by preparative high-performance liquid chromatography (HPLC) (25by 250-mm Varian Prostar HPLC/ODS column,; mobile phase of 100% MeOH; wavelength of 210
nm; flow rate of 7 ml/min; injected amount of 60 mg), yielding 27 mg of acetyl--BA, 22 mg of
acetyl--BA, and 1.8 mg of acetyl-11-dien--BA.

(ii) Method for - and -BAs.


Fractions 69 through 85 were combined and concentrated, yielding a 13.3-g crystalline residue. This
was chromatographed on a 150-g silica gel column chromatograph, eluting with n-hexane-ethyl
acetate (EtOAc; 5:1), to provide 42 fractions (200 ml/fraction). Of these, fractions 7 through 25
were combined and concentrated, yielding an 8.9-g residue. This was dissolved in 200 ml of hot
acetonitrile and precipitated at 2C ( 2) for 12 h; the precipitate was mesh filtered, yielding a
crystalline mixture of 3.0 g of - and -BAs. Preparative HPLC (Varian Prostar HPLC/ODS
column; mobile phase of 100% MeOH; wavelength of 210 nm; flow rate of 6 ml/min; injected
amount of 60 mg) yielded 15 mg of -BA and 20 mg of -BA.

(iii) Method for 11-keto--BA acetate.


Fractions 86 through 98 were combined and concentrated, yielding a 6.8-g residue. This was
chromatographed on a 150-g silica gel column chromatograph, eluting with n-hexane-EtOAc (4:1).
Of the 80 fractions (150 ml/fraction) collected, fractions 30 through 65 were combined and
concentrated, yielding a 4.5-g residue. This was dissolved in 100 ml of hot methanol and
precipitated at 2C ( 2) over 12 h. The precipitate was mesh filtered, yielding 1.8 g of acetyl-11keto--BA.

(iv) Method for 11-keto--BA.


Fractions 99 through 118 were combined and concentrated, yielding a 6.0-g residue. This was
chromatographed on a silica gel (150 g) column chromatograph, eluting with n-hexane-EtOAc
(3:1), and provided 50 fractions (150 ml/fraction). Fractions 15 through 35 from this fourth
chromatography were combined and concentrated to yield a 2.1-g residue. This was dissolved in 50
ml of hot methanol and cooled to 2C ( 2) over 12 h, yielding a final precipitate. The precipitate
was mesh filtered, yielding 0.5 g of 11-keto--BA.

LDI/MS and LDI/MS/MS analysis.


Laser desorption/ionization mass spectrometry (LDI/MS) was performed with sufficient resolution
of MH+, MNa+, and MK+ ions to reveal isotopic distributions. BCE and its BA subextracts were
dissolved in 70% USP ethyl alcohol-30% distilled H2O at 20C and pipetted onto metal sample
platens of UV laser desorption/ionization-time of flight mass spectrometers (Kratos MALDI IV or
AXIMA; Shimadzu Scientific, Manchester, England). During analysis, peaks corresponding to the
predicted molecular mass/charge ratio (m/z) of BAs or their NA+/K+ adducts were gated and
subjected to LDI tandem mass spectrometry (LDI/MS/MS) analysis, revealing characteristic
degradation product ions to confirm their composition.

Preparation of extract for in vitro use.

Pulverized BCE stock was prepared by mortar and pestle and irradiated to promote sterility. On the
day of use, a stock solution prepared using the fine powder was dissolved in autoclaved solvent of
either 100% USP ethanol or sesame oil (SO). Using equivalent amounts of solvent, extract was used
at final concentrations of 10, 50, or 200 g/ml. Controls consisted of unstimulated cells plus solvent
(negative control) and stimulant plus solvent without BCE (positive control).

In vitro generation and measurement of cytokine production.


Normal male C57BL/6 (B6), DBA/2, or B6D2F1 mice were purchased from Jackson Laboratories
(Bar Harbor, ME) and maintained in an animal facility certified by the Association for Assessment
and Accreditation of Laboratory Animal Care. Splenocytes from 6- to 12-week-old mice were
tested for their ability to produce in vitro IL-2, IL-4, IL-10, and IFN- following stimulation with
soluble anti-CD3 or concanavalin A (ConA) as previously described (
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Destroy user interface control19). Briefly, spleen cells (4 106 cells/well) were cultured in 24-well
plates (Costar, McLean, VA) in a total volume of 2 ml of culture medium consisting of RPMI 1640
supplemented with 10% fetal calf serum, antibiotics, 2-mercaptoethanol, nonessential amino acids,
and l-glutamine. Cells were cultured in a 7% CO2-humidified air mixture at 37C. Measurements of
the TH2 cytokines IL-4 and IL-10 were performed in both unstimulated cultures and cultures
stimulated with 10 g/ml (final concentration) of soluble anti-CD3 monoclonal antibody (2C11) (
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Destroy user interface control14). Measurements of TH1 cytokines IFN- and IL-2 were performed
in cultures stimulated with 5 g/ml (final concentration) of ConA. Prior experiments determined
optimal time points for supernatant harvesting to be 24 h for TH1 cytokines or 48 h for TH2
cytokines. Supernatants were frozen at 20C until testing. Cytokine content was determined by
enzyme-linked immunosorbent assay (ELISA) using commercial anticytokine sandwich
monoclonal antibody (BD-Pharmingen, San Diego, CA). Beginning at a dilution of 1:2,
supernatants were tested, and optical density values were converted to U/ml by comparison with
results using recombinant cytokine standards (BD-Pharmingen, San Diego, CA). Supernatant
cytokine assays were performed in duplicate, with results being confirmed in two additional,
independent experiments.

Viability analysis.
Cell viability was assessed by trypan blue exclusion. Results are expressed as the percent of trypan
blue excluding cells (live cells) per total cells counted.

Statistical analysis.
Groups shown in Fig. Fig.55 and and66 were compared by repeated measures analysis of variance.

FIG. 5.
BAs in SO inhibit TH1 cytokine production in vitro. IFN- (A) and IL-2 (B) levels in culture
supernatants were determined by ELISA at 24 h following stimulation with ConA as described in
Materials and Methods. Similar results were seen in two ...

FIG. 6.
BAs in SO promote TH2 cytokine production in vitro. IL-4 (A) and IL-10 (B) levels in culture
supernatants from DBA/2 splenocytes were determined by ELISA at 48 h after stimulation with
anti-CD3 as described in Materials and Methods. Similar results were ...
Go to:

RESULTS
Analysis of BAs in the extract.
The BCE was prepared as described in Materials and Methods and then subjected to further
fractionation. The fractionation scheme and yields are shown in Fig. Fig.1.1. Figure Figure22
depicts a representative analytical HPLC tracing showing the elution of the BAs in BCE. The
identities of the BAs in the initial extract were further confirmed by initial LDI/MS and gating of
appropriate peaks to yield LDI/MS/MS. Figure Figure33 shows an overall mass spectrum of BCE
and summarizes several BA parent ions identified by mass spectrometry. The peaks corresponding
to potential BA molecular ions were gated using a ~30 atomic mass unit (AMU) m/z window to
capture the entire MH+/MNa+ isotopic mass distribution. The entire mass window was analyzed for
spontaneous degradation products in a tandem (LDI/MS/MS) mode to reveal characteristic progeny
ions. Structures of the parent ions were confirmed by progeny ion spectrums. The spectral inset in
Fig. Fig.33 is an example of an LDI/MS/MS spectrum of 11-keto--BA and demonstrates the
characteristic fragmentation observed in this mode. The observed versus expected masses of the
parent BA molecular ions in the initial BCE are summarized in Table Table1.1. Although there are
techniques available to enhance analysis of molecules of <1,500 AMU using exogenous UVadsorbent matrix (
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regarding chemical reactions with the BA under analysis or additional background signal due to the
addition of the UV-absorbent matrices that are typically utilized in matrix-assisted LDI/MS (
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FIG. 2.
Identification of BAs present in the initial B. carterii ethanol extract by HPLC. Shown in the upper
panel is a representative analytical HPLC tracing. The lower panel contains the molecular structure
of the eluted compounds. Compounds (retention time ...

FIG. 3.
Identification of BAs present in the initial B. carterii ethanol extract by laser desorption MS/MS
analysis. Spectra were performed on the BCE and fragmentation ions were determined in MS/MS
(reflectron mode) to confirm their identification by observing ...

TABLE 1.
Observed versus expected masses of boswellic acids present in the initial acid extract (BCE) as
determined by MS/MS analysis

In vitro effects of BCE: cellular toxicity with ethanol but not SO as a solvent.
The BCE was dissolved in either sterile ethanol or sesame oil, and its effect on cell viability in vitro
was assessed using splenocytes from B6, DBA/2, and B6D2F1 mice. Splenocytes were cultured
with three concentrations of BCE (final concentration of 10, 50, or 200 g/ml), and viability was
determined by trypan blue exclusion at 24 h. As shown in Fig. Fig.4,4, when ethanol was used as a
solvent, BCE exhibited 100% toxicity (0% viable cells) at concentrations of 50 g/ml and 200
g/ml for both the DBA/2 and B6D2F1 splenocytes. This profound degree of cellular toxicity was
not seen when SO was used as a solvent or with the addition of ethanol alone (no BCE). Based on
these results, subsequent studies of the immunomodulatory properties of BCE were carried out
using SO as a solvent.

FIG. 4.

BCE in ethanol exhibits cellular toxicity not seen with SO as a carrier or with ethanol alone. Murine
splenocytes from B6, DBA/2, or B6D2F1 mice were cultured in vitro with either ethanol (EtOH)
alone (final concentration, 0.1%), SO alone (final concentration, ...

In vitro effects of BCE: BCE in SO exhibits immunomodulatory activity.


In a dose-response experiment, BCE dissolved in sesame oil (SO-BCE) was tested for its ability to
alter cytokine production of ConA-stimulated splenocytes. Three responder strains were tested: B6
mice, which make a strong TH1 response (
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exhibits a dose-dependent inhibition of the TH1 cytokines IFN- (panel A) and IL-2 (panel B) from
all three strains tested. In vitro detection of IL-4 and IL-10 was possible for TH2 response-prone
DBA/2 mice following anti-CD-3 stimulation (Fig. (Fig.6)6) but not for B6 or B6D2F1 mice (data
not shown). Moreover, the addition of SO-BCE in vitro potentiated TH2 cytokine production by
DBA/2 splenocytes in a dose-dependent fashion; however, cytokine potentiation was lost at the 200
g/ml concentration, a dose at which significant cellular toxicity is evident (Fig. (Fig.4).4). Taken
together, these results indicate that BCE dissolved in sesame oil exhibits immunomodulatory
properties in vitro and promotes a shift in the cytokine production profile away from a TH1
response and toward a TH2 response.
Go to:

DISCUSSION
Alternative medicine treatments frequently incorporate herbal therapies and plant resins from
species of the Boswellia family e.g., B. serrata and B. carterii. Both have anti-inflammatory
properties and contain - and -BAs (
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Destroy user interface control15); however they differ in their proportion of acetylated acids. In this
study, we focused on the less studied B. carterii resin. Herbal therapeutics are typically formulated
with less quality control than commercially prepared pharmacologic agents and may contain
multiple bioactive components (
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Destroy user interface control9). Moreover, B. carterii is widely used in unpurified or minimally
purified extracts. For these reasons, we used both chromatography and mass spectrometry for
specific identification of the BAs present in the initial B. carterii extract. This analysis was aided by
the use of an intrinsic 337-nm UV absorbance, promoting soft desorption and permitting the
production of molecular ions. These relate to the initial species that is present in analyte rather than
fragments. With this ionization strategy, ample parent ions were generated. Progeny fragment ions
could be generated to confirm the parent ion composition. Quality control was optimized by
tracking multiple components within the complex mixture through the combination of direct laser
desorption/ionization coupled with a high-resolution tandem time of flight mass analysis. This
analysis not only identified the BAs present in the initial extract but also ensured the similarity of
separate batches tested in vitro.
The initial BCE dissolved in SO exerted a dose-dependent inhibitory effect on in vitro IFN- and
IL-2 production by splenocytes from B6, DBA/2, and B6D2F1 hybrid mice. The TH2 cytokines IL4 and IL-10 were detected in vitro only from stimulated TH2 response-prone DBA/2 splenocytes (
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Destroy user interface control6). In contrast to the effects on TH1 cytokine production, BCE in SO
did not inhibit IL-4 and IL-10 production and, instead, promoted production of TH2 cytokines at the
two lower BCE concentrations tested. Very little stimulated TH1 or TH2 cytokine was detected at
the highest concentration of BCE-SO (200 g/ml), consistent with the loss of viability seen at this
level (Fig. (Fig.4).4). These data support the conclusion that BCE-SO at concentrations of 10 g/ml
to 50 g/ml is immunomodulatory rather than immunosuppressive or simply toxic, as these
concentrations simultaneously inhibit TH1 cytokine production and promote TH2 cytokine
production.
Lastly, we observed that BCE combined with ethanol exhibits significant cellular toxicity that was
not seen when it was combined with SO or when ethanol alone was used. We can only speculate as
to the mechanism for this differential toxicity, and it very likely may reflect the different kinetics of
drug release from the two carriers, resulting in toxic accumulations of BCE with the ethanol solvent
and slower release from the SO solvent. Alternatively, BCE may exhibit a toxic synergy with
ethanol that is not seen with SO. It is not possible to directly extrapolate the concentrations used in
these in vitro studies to those achieved in humans following oral ingestion of Boswellia resins;
nevertheless, these data raise the question as to whether coingestion of alcohol might promote toxic
properties of orally ingested boswellin-containing herbal preparations. Our results not only support
the need for standardization of dosage and delivery of phytopharmaceuticals but also underscore the
possibility of unexpected, adverse effects.

Go to:

ACKNOWLEDGMENTS
This work was supported by Public Health Service grant AT00084 from the National Center for
Complementary and Alternative Medicine. M. R. Chevrier is a recipient of an Engelicheff
Fellowship award from the Maryland Chapter of the Arthritis Foundation.
Go to:

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