REVIEW

Search for bioactive natural products from medicinal plantsof Bangladesh

Firoj Ahmed • Samir Kumar Sadhu •

Masami Ishibashi

Received: 5 March 2010 / Accepted: 20 April 2010 / Published online: 6 July 2010

� The Japanese Society of Pharmacognosy and Springer 2010

Abstract In our continuous search for bioactive natural

products from natural resources, we explored medicinal

plants of Bangladesh, targeting cancer-related tumor

necrosis factor-related apoptosis-inducing ligand-signaling

pathway, along with some other biological activities such

as prostaglandin inhibitory activity, 1,1-diphenyl-2-picryl-

hydrazyl free-radical-scavenging activity, and cell growth

inhibitory activity. Along with this, we describe a short

field study on Sundarbans mangrove forests, Bangladesh,

in the review.

Keywords Bangladesh � Sundarbans mangrove forests �TRAIL � Apoptosis

Introduction

In search of bioactive natural products targeting cancer-

related signaling pathways such as tumor necrosis factor

(TNF)-related apoptosis-inducing ligand (TRAIL), Wnt,

and Hedgehog, we explored medicinal plant resources in

Thailand and Bangladesh [1, 2]. Previously, we isolated a

number of bioactive compounds targeting different bio-

logical activities such as prostaglandin (PG) inhibitory

activity, 1,1-diphenyl-2-picrylhydrazyl (DPPH) free-radi-

cal-scavenging activity, and cell growth inhibitory activ-

ity. Bangladesh serves as a source of a wide variety of

medicinal plants, as does a large number of mangroves

from Sundarbans mangrove forests. Medicinal plant

resources of Sundarbans intrigued us greatly, so we

studied the habitat and distribution patterns of mangroves

growing there. Mangroves have long been a source of

astonishment to scientists, including natural product

researchers. This is because a diversified chemical class of

compounds containing different types of biological

activities has been isolated from mangroves [3]. In this

report, we discuss the isolation and characterization of

bioactive compounds from some medicinal plants of

Bangladesh, along with a brief field study on collection

and species identification of mangroves from Sundarbans

mangrove forests, Bangladesh.

Field study

Study area

The field study in Sundarbans mangrove forests was carried

out in November 2008. Sundarbans is the largest single

block of tidal halophytic mangrove forest in the world [4].

The Bengali language name Sundarban can be literally

translated as beautiful jungle or beautiful forest (Sundar

beautiful; ban forest or jungle). The name may have been

derived from the Sundari trees (Heritiera fomes) that are

found in Sundarbans in large numbers. The forest is spread

across areas of Bangladesh and India and covers

10,000 km2, of which about 6,000 are in Bangladesh

(Fig. 1a, b) [5]. It became inscribed as a United Nations

Educational, Scientific, and Cultural Organization (UNE-

SCO) World Heritage Site in 1997. Sundarbans is inter-

sected by a complex network of tidal waterways, mudflats,

and small islands of salt-tolerant mangrove forests.

F. Ahmed � M. Ishibashi (&)

Graduate School of Pharmaceutical Sciences, Chiba University,

1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan

e-mail: mish@p.chiba-u.ac.jp

F. Ahmed � S. K. Sadhu

Pharmacy Discipline, Life Science School, Khulna University,

Khulna 9208, Bangladesh

123

J Nat Med (2010) 64:393–401

DOI 10.1007/s11418-010-0424-7

Sundarbans flora is characterized by the abundance of

H. fomes, Excoecaria agallocha, Ceriops decandra, and

Sonneratia apetala. A total 245 genera and 334 plant

species were recorded in 1903 [6]. Study area included a

number of spots in Sundarbans, such as Supati, Kochikhali,

Katka, Dublar char, Nilkomol, and others. During our visit,

we collected a number of species from Sundarbans.

Salient features of mangroves

Mangrove forests are composed of taxonomically diverse,

salt-tolerant tree and other plant species, which thrive in

intertidal zones of sheltered tropical shores, ‘‘overwash’’

islands, and estuaries. Mangrove trees have specially

adapted aerial and salt-filtering roots and salt-excreting

leaves that enable them to occupy the saline wetlands

where other plant life cannot survive. They are present in

tropical and subtropical areas around the world and are

generally found within 25� north and south of the equator,

even though they can be found as high as 32� in some

northern latitudes. Root system of mangroves is adapted to

the peculiar conditions found in the mangrove forests, such

as still roots in Rhizophora and knee roots in Bruguiera.

Pneumatophores (breathing roots) are profuse in Sonnera-

tia and Avicennia (Fig. 2a, d). Certain mangrove species

can propagate successfully in a marine environment

through viviparous germination, in which the seed germi-

nates while still on the tree and falls during its germinating

condition (Fig. 2b) [7].

Collection and identification

Plants were collected from canal banks and deep forests in

2008 (Fig. 3). After collection, the plants were identified

by Prof. AK Falul Huq, Forestry and Wood Technology

Discipline, Khulna University, Bangladesh, who accom-

panied us on the entire field study. In 2009, the study was

arranged in Chittagong, and we collected a number of

Fig. 1 a Location of

Sundarbans (http://news.bbc.

co.uk); b map of Sundarbans

(http://wwfindia.org)

Fig. 2 a Aerial roots

(pneumatophores); b viviparous

root, and c young seedlings of

Rhizophora sp.; d trees on

Sundarbans mainland

394 J Nat Med (2010) 64:393–401

123

medicinal plants at that time. Also, we plan to perform a

similar study in some other parts of Bangladesh in 2010

and 2011.

Chemical and biological studies on medicinal plants

of Bangladesh

During our search for bioactive natural products from

medicinal plants of Bangladesh, we isolated a number of

novel compounds and some known ones. In this section, we

present the chemical and biological studies performed on

some of the plants, such as Leucas aspera, S. caseolaris,

Aphanamixis polystachya, Saraca asoca, Jasminum gran-

diflorum, Zingiber spectabile, Hoya parasitica, Vallaris

solanaceae, and Sida acuta.

Leucas aspera

L. aspera Link. (Labiatae), known as darkolos or dandokolos

in Bangladesh, is a common aromatic herb and grows

abundantly in Bangladesh and a wide area in south Asia.

Traditionally, the decoction of the whole plant is taken orally

for analgesic–antipyretic, antirheumatic, anti-inflammatory,

and antibacterial treatment, etc., and its paste is applied

topically to inflamed areas. According to the traditional

usage of the plant as an anti-inflammatory and analgesic,

L. aspera was tested for its PG inhibitory and antioxidant

activities. The extract showed both activities, i.e., inhibition

at 30 lg/ml against PGE1- and PGE2-induced contractions

in guinea pig ileum and a DPPH-radical-scavenging effect.

The separation guided by the activities in these dual assay

methods provided compounds 1–25, among which 1–7

and 10–12 were identified as nectandrin B, meso-di-

hydroguaiaretic acid, macelignan, acacetin, apigenin 7-O-

[600-O-(p-coumaroyl)-b-D-glucoside], chrysoeriol, apigenin,

erythro-2-(4-allyl-2,6-dimethoxyphenoxy)-1-(4-hydroxy-

3-methoxyphenyl)propan-1-ol, myristargenol B, and

machilin C, respectively (Fig. 4). Compound 8 was deter-

mined to be (-)-chicanine, the new antipode of the (?)

compound, by spectroscopic methods, including circular

dichroism (CD) and optical rotary dispersion (ORD). Chiral

high-performance liquid chromatography (HPLC) analysis

of compound 9 showed it was a mixture of two enantiomers:

(7R,8R)- and (7S,8S)-licarin A [8, 9].

Sonneratia caseolaris

S. caseolaris Linn. (Sonneratiaceae), locally known as

Choila, is a small tree with oblong or obovate-elliptic

coriaceous leaves and large red flowers, which grows

among mangrove areas flooded by the sea in the Sundar-

bans and Chittagong areas of Bangladesh. Extracts of this

plant are traditionally used as an astringent and antiseptic,

in sprains and swellings, and in arresting hemorrhage.

Based on the traditional usage of this plant, we tested the

extract for antioxidant activity using the DPPH-radical-

scavenging effect on thin-layer chromatography (TLC).

Although fatty acids, hydrocarbons, steroids, pectin, and

sugars have been previously isolated from this plant [10],

by taking the DPPH-radical-scavenging effect as the iso-

lation guide, we isolated a flavone, luteolin (26), and its

7-O-b-glucoside (cynaroside) (27) (Fig. 5). According to

Fig. 3 a Plant collection of

aerial parts from a shrub,

b leaves with small stems from

a tree, and c leaves with small

stems from another tree;

d people returning after

collection

J Nat Med (2010) 64:393–401 395

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the traditional medicinal usage of S. caseolaris, we tested

the extract of S. caseolaris for antioxidant activity using

DPPH-radical-scavenging effect with TLC. Following

activity-oriented separation, two flavonoids, luteolin (26)

and luteolin 7-O-b-glucoside (27), were isolated. Both

compounds were found to possess antioxidant activity [10].

Aphanamixis polystachya

A. polystachya (Wall.) Parker or Amoora rohituka (family:

Meliaceae; local names: Roina, Pitraj, etc.) is a medicinal

plant of Bangladesh. The bark is astringent and is used to

treat spleen and liver diseases, tumors, and abdominal

complaints. Different types of compounds, for example,

limonoids, terpenoids, glycosides, an alkaloid, and a

saponin, have previously been isolated from this plant.

With the objective of isolating components bioactive

against tumors, a methanol (MeOH) extract of the dried

bark, was checked for growth inhibitory activity against

Henrietta Lacks (HeLa) cells and shown to have potent

activity with an IC50 of approximately 50 lg/ml. The

extract was then partitioned successively between hexane,

ethyl acetate (EtOAc) and butanol (BuOH), and water. Of

these, BuOH and n-hexane extracts were potent active

fractions with IC50 of approximately 22 and about 33 lg/

ml, respectively. These two fractions were subjected to a

general separation procedure to isolated compounds 28–31,

along with stigmasterol and oleic and linoleic acids

(Fig. 5) [11].

Saraca asoca

S. asoca (Roxb.) De Wilde or S. indica Linn. (family: Cae-

salpiniaceae; local names: Ashok, Anganapriya, etc.) is a

medicinal plant of Bangladesh whose bark is astringent and

used in menorrhagia, bleeding hemorrhoids, and hemor-

rhagic dysentery. The isolation of tannins, flavonoids, pro-

anthocyanidins, and leucoanthocyanidins were previously

reported from the bark [12]. In our assay method, an MeOH

extract of the dried bark showed potent antioxidant activity

determined by DPPH-radical-scavenging assay. Following

this activity, we isolated eight compounds (32–39) from this

plant (Fig. 6). Of the isolates, five were lignan glycosides,

such as, lyoniside, nudiposide, 5-methoxy-9-b-xylopyrano-

syl-(-)-isolariciresinol, icariside E3, and schizandriside;

and three were flavonoids, namely, (-)-epicatechin, epi-

afzelechin-(4b ? 8)-epicatechin, and procyanidin B2 [12].

Fig. 5 Structures of the compounds isolated from Sonneratia caseo-laris (26 and 27) and Aphanamixis polystachya (28–31)

Fig. 6 Structures of compounds isolated from Saraca asoca (32–39)

Fig. 4 Structures of compounds isolated from Leucas aspera (1–25)

396 J Nat Med (2010) 64:393–401

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Jasminum grandiflorum

J. grandiflorum Linn. (family: Oleaceae; local names:

Jasmine or Jatiful) is a medicinal plant of Bangladesh that

has certain therapeutic properties against various psychi-

atric disorders, skin diseases such as conjunctivitis and

dermatitis, and different types of cancer. Previously, irid-

oid-type compounds secoiridoid glucosides, triterpenes,

flavonoids, lignans, etc., were isolated from this herb [13].

In our continued investigation on traditional medicinal

plants of Bangladesh, we isolated eight compounds

(40–47), including secoiridoid glucosides as 200-epifrax-

amoside and demethyl-200-epifraxamoside, the secoiridoid

jasminanhydride (Fig. 7), together with four previously

known phenolics and a triterpene from this herb. Structures

were elucidated by detailed spectroscopic analysis. Ste-

reochemistry of the compounds was determined by dif-

ferential nuclear Overhauser effect (NOE) experiment [13].

Zingiber spectabile

Z. spectabile (Zingiberaceae), common names: bonada

(Bangla), beehive ginger (English), micro’ fono (Spanish),

Wan-prai-dum (Thai), is a medicinal herb of Bangladesh

primarily found in the Khagrachhari and Bandarban for-

ests. Traditionally, its rhizome is used in cough and asthma

complication and as a germicidal, stimulant, and tonic. It is

reported that the rhizome extract is beneficial in cancer.

Previous investigations on the rhizome reported the pres-

ence of terpinen-4-ol, labda-8(17), 12-diene-15,16-dial,

a-terpineol, a-pinene, b-pinene, limonene, and structurally

related compounds [14]. Aiming at isolation of the com-

ponents responsible for its anticancer property, we carried

out a total phytochemical investigation guided by the cell-

growth inhibitory activity. Nine sesquiterpenes (48–56)

and eight flavonoids (57–64), together with b-sitosterol,

were obtained, all of which were first isolated from this

species (Fig. 8) [14].

Hoya parasitica

H. parasitica Wall. ex Traill or Asclepias parasitica

Wallich ex Hornemann (Asclepiadaceae, local name:

Bayupriya, Porgacha) grows in southeastern Asia, partic-

ularly in the Sundarbans and Chittagong areas in Bangla-

desh. H. parasitica is a parasite creeper with a fragrant

flower whose aerial part is used to treat rheumatism.

A previous phytochemical investigation reported the iso-

lation of dihydrocanaric acid, along with lupeol and lupe-

none, from this plant. However, no biological data have

been reported. As part of our continuing investigation of

traditional medicinal plants of southeastern Asia [3, 4], we

isolated four compounds (65–70) from this herb (Fig. 9).

An androstanoid, hoyasterone (compound 65); a sesqui-

terpene, 15-bulnesolic acid (66); and a phenolic compound,

Fig. 7 Structures of the compounds isolated from Jasminum gran-diflorum (40–47)

Fig. 8 Structures of the compounds isolated from Zingiber spectabile(48–64)

Fig. 9 Structures of the compounds isolated from Hoya parasitica(65–70), Vallaris solanaceae (71–73), and Sida acuta (74–76)

J Nat Med (2010) 64:393–401 397

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1-(4-hydroxy-3-methoxyphenyl)-1-methoxypropan-2-ol (67);

together with a known triterpene, dihydrocanaric acid

(compound 68), were isolated from H. parasitica. Struc-

tures were elucidated by 1D and 2D nuclear magnetic

resonance (NMR) and mass spectroscopic analysis [15].

Vallaris solanaceae

V. solanaceae Kuntze (syn.: V. heynei) (Apocynaceae),

locally known as agarmoni, grows in Bangladesh and in

other Southeast Asian countries. It is a creeper with fra-

grant white flowers traditionally used against ringworms

and skin infections. Previous chemical investigation of its

leaves reported its ability to isolate b-sitosterol, b-amyrin,

ursolic acid, and triterpenes; vallaroside, solanoside, val-

larosolanoside, and acoshimperosid P. In our continuous

investigation on traditional medicinal plants of Bangla-

desh–Asia, we isolated a new cardenolide glycoside,

vallarisoside (71), and a known one, 3b-O-(a-acofriosyl)-

16-anhydrogitoxigenin (72), along with a new glycoside,

benzyl 2-O-b-apiofuranosyl-(1 ? 2)-b-D-glucopyranosyl-

2, 6-dihydroxy-benzoate (73) from this herb (Fig. 9) [16].

Sida acuta

S. acuta Burm. (Malvaceae), locally known as Berela, is a

shrub distributed in all areas of Bangladesh and other trop-

ical countries. Its leaves are traditionally used as a diuretic,

demulscent, etc. Roots are used as a tonic, diaphoretic, and

antipyretic. It was reported for antiplasmodial, antimicro-

bial, analgesic, free-radical-scavenging, and apoptosis-

inducing activities. Previously isolated constituents include

alkaloids, tocoferols, and triterpenoids; sterols poly phenols,

and glycosides. Bioassay guided separation of Sida acuta

whole plants led to the isolation of an alkaloid, cryptolepine

(74); and two kaempferol glycosides (75–76) (Fig. 9) [17].

The PG inhibitory activity

The PG-inhibitory activity of isolates (1–25) was evaluated

by the method using PG-induced contraction in guinea pig

ileum. Compound 1 exhibited inhibition at 2.6 and 8.7 lM

against PG E1- and PG E2-induced contractions, respec-

tively, and 2 was inhibitory at 9.1 lM for both contrac-

tions. Compound 5 only caused inhibition at 5.2 lM

against PG E1-induced contraction but was inactive against

PG E2 at the same concentration. Compound 18 exhibited

the most potent effect at 16 and 48 lM against PG E1- and

PG E2-induced contractions, respectively. Compounds 13

and 17 inhibited both types of contractions at 126 and

76 lM, respectively, whereas 22 showed a less potent

inhibition against PG E1-induced contraction only, at

98 lM [8, 9].

Antioxidant activity

Antioxidant activities were evaluated by DPPH-radical-

scavenging assay. In the case of antioxidant activity on

TLC sprayed with DPPH reagent, all lignans and neo-

lignans 1–3 and 8–12 showed positive spots on TLC,

whereas the flavonoids (4–7) were negative. The IC50

values of 1–3 and 5 and quercetin (positive control)

recorded on a microplate reader with DPPH were 60, 28,

50, 500, and 30 lM, respectively. The IC50 values of

DPPH-radical-scavenging assay for compounds 32–39 and

the positive control quercetin were 104, 85, 44, 75, 55, 50,

55, 40, and 30 lM, respectively [9–12].

Cell-growth inhibitory activity

Compound 48 (zerumbone) was found to be the most

active (IC50 59.6 lM) in cell-growth inhibitory assay

against colon carcinoma SW480 cells. Among the isolated

compounds from H. parasitica, only dihydrocanaric acid

(68) exhibited growth inhibitory activity against both HeLa

and SW480 cells [14, 15].

TRAIL-resistance-overcoming activity

Tumor-necrosis-factor-related apoptosis-inducing ligand

(TRAIL), a member of the TNF superfamily, has emerged

as a promising anticancer agent because of its ability to

selectively kill tumor cells. TRAIL-induced apoptosis ini-

tiated by the death-receptor pathway involves DR

engagement, death-inducing signaling complex (DISC)

formation, proteolytic activation of caspase-8, and, conse-

quently, activation of caspase-3. Proteolytic caspase-8

further activates Bid, which, in turn, translocates to the

mitochondria and activates the mitochondrial pathway.

However, considerable numbers of cancer cells, especially

some highly malignant tumors, are resistant to apoptosis

induction by TRAIL. Resistance to TRAIL can occur at

different points in the signaling pathways of TRAIL-

induced apoptosis. Overcoming TRAIL resistance and

understanding the mechanisms underlying such resistance

are thus very important in anticancer drug discovery [1].

Isolated compounds (71–76) were evaluated for their

activity in overcoming TRAIL resistance in human gastric

adenocarcinoma (AGS) cells. Recently, this cell line has

been widely used as a model system for evaluating cancer

cell apoptosis [16] and is reported to be refractory to

apoptosis induction by TRAIL. To assess the effects of the

isolated compounds, TRAIL, or their combined treatment

on cell viability, AGS cells were treated with the indicated

agents and subjected to fluorometric microculture cyto-

toxicity assay (FMCA) [18, 19]. As shown in Fig. 10a,

treatment with 100 ng/ml TRAIL for 24 h resulted in only

398 J Nat Med (2010) 64:393–401

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a slight decrease in cell viability (89%). Luteolin [20, 21],

used as a positive control, produced about 50% more

inhibition along with TRAIL than the agent alone. Com-

bined treatment with TRAIL and compound 71 at 5, 10,

and 20 lM produced about 32%, 37%, and 31% more

inhibition than the agent alone. These results suggest a

possible synergism between compound 71 and TRAIL.

Combined treatment of AGS cells with 100 ng/ml

TRAIL and 1.25 or 2.5 lM of compound 74 produced

about 32% and 50% more inhibition, respectively, than the

agent alone, suggesting a possible synergism between the

two agents. Cryptolepine (compound 74), reported as a

candidate antitumor agent [22, 23], exhibits potent cyto-

toxic activity against a wide variety of cancer cells,

including human leukemia HL-60 cells [24]. It induced

cell-cycle arrest and apoptosis by activating mitochondrial

release of cytochrome c. Here, we found, for the first time,

its TRAIL-resistance-overcoming activity against AGS

cells (Fig. 10b). To ascertain whether the decrease in cell

viability produced by compound 74 was caused by apop-

totic cell death, we stained the treated cells after 24 h with

Hoechst 33342 reagent. We observed apoptotic nuclei,

with condensed chromatins stained more brightly in the

treated cells than the normal cells (Fig. 11), suggesting that

the cell death was due to apoptosis [25].

We further checked the effect of compound 74 on cas-

pase-3/7 activity in AGS cells to ascertain whether the

induced apoptosis was mediated through caspase activa-

tion. Caspases-3/7 are known as effector caspases, and after

activated by the initiator caspases (caspase-8/9), it induce

apoptosis. We observed that treating AGS cells with

compound 74 in combination with TRAIL (100 ng/ml),

increased caspase-3/7 activity 1.8-, 1.9-, and 2.3-fold, at

1.25, 2.5, and 5 lM, respectively, compared with the

control after 12 h (Fig. 12). The results tend to suggest that

compound 74 sensitized AGS cells to TRAIL-induced

apoptosis through caspase-3/7 activation [26].

Fig. 10 a Effect of compound 71, luteolin (positive control: Lut) and

tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL)

treatment, alone and in combination, on the viability of human

gastric adenocarcinoma (AGS) cells. Cells were seeded in a 96-well

culture plate (6 9 103 cells per well) for 24 h and then treated with

indicated concentrations (lM) of the compounds and/or TRAIL for

24 h. Cell viability was determined by fluorometric microculture

cytotoxicity assay (FMCA). The bar represents the means

[n = 3 ± standard deviation (SD)]. Significance was determined by

Student’s t test; p \ 0.01 (**) vs. control (Con). b Effect of

compound 74, luteolin (positive control: Lut) and TRAIL treatment,

alone and in combination, on the viability of AGS cells. Cells were

seeded in a 96-well culture plate (6 9 103 cells per well) for 24 h and

then treated with indicated concentrations (lM) of the compounds

and/or TRAIL for 24 h. Cell viability was determined by fluorometric

microculture cytotoxicity assay (FMCA). The bar represents the

means (n = 3 ± SD). Significance was determined by Student’s t test

p \ 0.01 (**) vs. control (Con)

Fig. 11 Effect of compound 74 and tumor-necrosis-factor-related

apoptosis-inducing ligand (TRAIL) treatment, alone and in combi-

nation, on apoptosis of human gastric adenocarcinoma cells (AGA).

AGS cells were grown on cell culture dishes and treated as described,

and apoptosis was detected by Hoechst 33342 stain. Representative

photomicrographs from each treatment group showing induction of

apoptosis (bright fluorescence indicated by arrow)

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Conclusion

Mangrove plants may serve as a potential source of bio-

active compounds, but little is known about the chemistry

of natural products of mangroves. We studied the habitat

and distribution of mangroves and collected some species

for further exploration for isolation and characterization of

bioactive compounds from them. In this report, we also

describe our recent findings on our search for bioactive

natural products from some medicinal plants of Bangla-

desh, targeting different biological activities, as, for

example, TRAIL-resistance-overcoming activity, PG

inhibitory activity, DPPH-free-radical-scavenging activity,

and cell-growth inhibitory activity. We were able to isolate

a number of compounds with significant activity.

Acknowledgments We are grateful to Prof. AK Falul Huq, Forestry

and Wood Technology Discipline, Khulna University, Bangladesh,

for his kind effort to guide us throughout the study and identification

of the mangrove plants. We are also grateful to the Tokyo Bio-

chemical Research Foundation (TBRF) who provided Post Doctoral

Fellowship to Dr. Samir K. Sadhu. This work was supported by the

Grant-in-Aid for Scientific Research from the Japan Society for the

Promotion of Science (JSPS).

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