The genus Stephania - Dr. DS Kothari Postdoctoral Fellowship ...

Journal of Ethnopharmacology 132 (2010) 369–383
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Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jethpharm
Review
The genus Stephania (Menispermaceae): Chemical and pharmacological
perspectives
Deepak Kumar Semwal a,∗ , Ruchi Badoni b , Ravindra Semwal c , Sudhir Kumar Kothiyal b ,
Gur Jas Preet Singh a , Usha Rawat b
a Department of Chemistry, Punjab University, Sector-14, Chandigarh 160014, Punjab, India
b Department of Chemistry, University of Garhwal, Srinagar 246174, Uttarakhand, India
c Faculty of Pharmacy, Dehradun Institute of Technology, Dehradun 248009, Uttarakhand, India
article
info
abstract
Article history:
Received 13 June 2010
Received in revised form 22 August 2010
Accepted 22 August 2010
Available online 27 August 2010
Key words:
Stephania species
S. cepharantha
S. glabra
S. japonica
S. venosa
Berberines
Antiproliferative
Hyperglycemia
The plants of the genus Stephania (Menispermaceae) are widely distributed, and have long been used
in folk medicine for the treatment of various ailments such as asthma, tuberculosis, dysentery, hyperglycemia,
malaria, cancer and fever. Over 150 alkaloids together with flavonoids, lignans, steroids,
terpenoids and coumarins have been identified in the genus, and many of these have been evaluated
for biological activity. This review presents comprehensive information on the chemistry and pharmacology
of the genus together with the traditional uses of many of its plants. In addition, this review
discusses the structure–activity relationship of different compounds as well as recent developments and
the scope for future research in this aspect.
© 2010 Elsevier Ireland Ltd. All rights reserved.
Contents
1. Introduction .......................................................................................................................................... 370
2. Traditional uses ...................................................................................................................................... 370
3. Chemical constituents ............................................................................................................................... 371
3.1. Stephania abyssinica Walp. ................................................................................................................... 371
3.2. Stephania aculeata F. M. Bailey ............................................................................................................... 371
3.3. Stephania bancroftii F. M. Bailey .............................................................................................................. 371
3.4. Stephania brachyandra Diels .................................................................................................................. 371
3.5. Stephania cepharantha Hayata ................................................................................................................ 371
3.6. Stephania dinklagei Diels ..................................................................................................................... 372
3.7. Stephania delovayi Diels ...................................................................................................................... 372
3.8. Stephania elegans Hook.f. & Thoms. .......................................................................................................... 372
3.9. Stephania erecta Craib ........................................................................................................................ 373
3.10. Stephania excentrica H.S.Lo................................................................................................................. 373
3.11. Stephania glabra (Roxb.) Miers .............................................................................................................. 373
3.12. Stephania hernandifolia (Willd.) Walp. ...................................................................................................... 373
3.13. Stephania intermedia H.S.Lo................................................................................................................ 374
3.14. Stephania japonica (Thunb.) Miers .......................................................................................................... 374
3.15. Stephania longa Lour ........................................................................................................................ 374
3.16. Stephania miyiensis S.Y.Zhao&H.S.Lo.................................................................................................... 374
∗ Corresponding author. Tel.: +91 9412947995.
E-mail address: dr dks.1983@yahoo.co.in (D.K. Semwal).
0378-8741/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.jep.2010.08.047

370 D.K. Semwal et al. / Journal of Ethnopharmacology 132 (2010) 369–383
3.17. Stephania pierrei Diels ....................................................................................................................... 375
3.18. Stephania gracilenta Miers .................................................................................................................. 375
3.19. Stephania rotunda Lour. ..................................................................................................................... 375
3.20. Stephania sasakii Hayata .................................................................................................................... 375
3.21. Stephania sinica Diels........................................................................................................................ 375
3.22. Stephania suberosa L. L. Forman ............................................................................................................. 375
3.23. Stephania succifera H. S. Lo & Y. Tsoong ..................................................................................................... 375
3.24. Stephania sutchuenensis H.S.Lo............................................................................................................. 376
3.25. Stephania tetrandra S. Moore ................................................................................................................ 376
3.26. Stephania venosa (Blume) Spreng. .......................................................................................................... 376
4. Biological activities................................................................................................................................... 376
4.1. Anti-malarial activity ......................................................................................................................... 376
4.2. Antimicrobial activity ........................................................................................................................ 376
4.3. Anthelmintic activity ......................................................................................................................... 377
4.4. Anti-viral activity ............................................................................................................................. 377
4.5. Anti-proliferative/anti-cancer activity ....................................................................................................... 377
4.6. Antipsychotic activity ........................................................................................................................ 377
4.7. Apoptosis inducing effect .................................................................................................................... 377
4.8. Multidrug resistance reversing activity ...................................................................................................... 377
4.9. Anti-inflammatory and analgesic activity ................................................................................................... 378
4.10. Immunomodulating activity ................................................................................................................ 378
4.11. Antifibrotic effect ........................................................................................................................... 378
4.12. Anti-hyperglycemic effect .................................................................................................................. 378
4.13. Ca 2+ channel blocking activity .............................................................................................................. 378
4.14. Acetylcholinesterase (AChE) inhibitory activity ............................................................................................ 379
4.15. Vasodilating and hypotensive activities .................................................................................................... 379
4.16. Inhibition of antinociceptive effect ......................................................................................................... 379
4.17. Acute hemodynamic effect ................................................................................................................. 379
4.18. Histamine release inhibition activity ....................................................................................................... 379
4.19. Antioxidant activity ......................................................................................................................... 379
4.20. Miscellaneous uses .......................................................................................................................... 379
4.21. Toxic effects ................................................................................................................................. 380
5. Future perspectives and conclusion ................................................................................................................. 380
Acknowledgements .................................................................................................................................. 380
References ........................................................................................................................................... 380
1. Introduction
The genus Stephania belongs to family Menispermaceae, a large
family of about 65 genera and 350 species, distributed in warmer
parts of the world. The members of this family are mostly herbs
or shrubs but rarely trees. The plants of the genus Stephania are
slender climbers with peltate and membranous leaves. The flowers
are umbelliform cymes while inflorescence are axillary and arising
from old leafless stem. These plants have recognized medicinal values
and traditionally have been used for the treatment of asthma,
tuberculosis, dysentery, hyperglycemia, cancer, fever, intestinal
complaints, sleep disturbances and inflammation (Chopra et al.,
1958; Gaur, 1999; Kirtikar and Basu, 2004).
Over the last five decades, an extensive amount of chemical
work has been done on many of these plants because of their traditional
uses which are of interest to researchers. These plants are
major sources of bioactive alkaloids such as morphines, hasubanalactams,
hasubanans, aporphines and berberines. The majority
of the chemical work has been reported on S. tetrandra S. Moore,
S. cepharantha Hayata, S. glabra (Roxb.) Miers, S. japonica (Thunb.)
Miers and S. venosa (Blume) Spreng, and more than 70 alkaloids
along with other minor constituents have been reported from these
five species alone. Many of these plants are known for their distinct
biological importance including antitumor and emetine type
activity (Kuroda et al., 1976; Gupta et al., 1980).
In past decade, Chinese-herb nephropathy, a progressive interstitial
nephropathy has been observed among women in Belgium
after the intake of weight-reducing pills containing S. tetrandra
S. Moore. Phytochemical analyses of these pills resulted in the
identification of aristolochic acids (responsible for nephropathy)
instead of tetrandrine (responsible for weight reduction), confirming
the replacement of S. tetrandra (han fangji) by Aristolochia
fangchi (guang fangji/fangchi). These are different plants and the
chemical composition also different. Similarity in the nomenclature
of both these plants was only reason behind the substitution
(Vanherweghem et al., 1993; Debelle et al., 2002; Mosihuzzaman
and Choudhary, 2008).
This study is an attempt to compile an up-to-date and comprehensive
review of the genus Stephania that covers its traditional
medicinal uses, chemistry and pharmacology. Many plants of this
genus are pharmacologically known but chemically unknown and
vice-versa. Therefore, the scope of future research in this aspect is
also discussed here.
2. Traditional uses
In traditional medicine, most of the plants of the genus Stephania
have been used to treat a wide variety of ailments such as dysentery,
pyrexia, tuberculosis, diarrhea, dyspepsia, urinary diseases,
abdominal ills, asthma, ascariasis, dysmenorrhea, indigestion,
wounds, head-ache, sore-breasts and leprosy. The rhizome extract
of S. glabra (Roxb.) Miers has long been used as antidysenteric,
antipyretic, antiasthamatic and antituberculosis agent (Chopra et
al., 1958; Kirtikar and Basu, 2004). The aqueous concoction of the
powders of the dried rhizome of S. glabra (Roxb.) Miers and aerial
root of Trichosanthes multiloba are used as an anthelmintic against
intestinal worms in Meghalaya (Northeast India) (Das et al., 2004).
S. venosa (Blume) Spreng is often used as a bitter tonic (Pharadai et
al., 1985). The stems of S. dinklagei Diels possess vermifuge, aphrodisiac,
analgesic and sedative effects whereas the leaves has been

D.K. Semwal et al. / Journal of Ethnopharmacology 132 (2010) 369–383 371
used to treat infertility in the female and impotence in the male. The
roots of S. hernandifolia (Willd.) Walp. were used in fever, diarrhea,
dyspepsia and urinary diseases (Chopra et al., 1958). S. rotunda Lour.
has been used to treat pulmonary consumption, dysentery, fever,
abdominal ills (tubers), asthma (tubers and stems), ascariasis, dysmenorrhea
(stems), indigestion, wounds, head-ache, sore-breasts
(leaves) and leprosy (flowers) (Chopra et al., 1958; Burkill, 1966;
Phaet-thanesuara, 1967; Khasiphand and Suksah, 1968; Perry,
1980). The root of S. tetrandra S. Moore have been used in hepatofibrogenic
disease (Chen et al., 2005), it also used as diuretic,
antiphlogistic, antirheumatic (Joshi et al., 2008), antipyretic and
analgesic in China for centuries (Achike and Kwan, 2002). S. cepharantha
Hayata has been used to treat many acute and chronic diseases,
including venomous snakebites in Japan (Kimoto et al., 1997).
In Bangladesh, the vines of S. japonica (Thunb.) Miers were used for
leucorrhoea, presence of semen in urine, burning sensations during
urination by Chakma and Tonchonga tribes (Hossan et al., 2010).
3.3. Stephania bancroftii F. M. Bailey
(−)-Tetrahydropalmatine (5), (−)-stephanine (6), (−)-crebanine
(7), ayuthianine (8), (+)-sebiferine and (+)-stepharine (9)
(Blanchfield et al., 1993, 2003; Bartley et al., 1994).
3. Chemical constituents
The reported data showed that alkaloids are the main and
common phytochemicals of the genus Stephania. More than
200 alkaloids have been isolated from this genus together
with flavonoids, lignans, steroids, terpenoids and coumarins. The
reported phytochemicals from different plants of the genus are
given as following.
3.4. Stephania brachyandra Diels
Sinoacutine, stephanine (6), crebanine (7) and (−)-dicentrine
(10) (Shulin et al., 1992).
3.1. Stephania abyssinica Walp.
4 ′ -O-methylstephavanine (1) and stephavanine (2) (Dagne et
al., 1993).
3.5. Stephania cepharantha Hayata
3.2. Stephania aculeata F. M. Bailey
7-Hydroxyaporphine, (+)-laudanidine (3) and (−)-amurine (4)
(Blanchfield et al., 1993, 2003).
Stephaoxocanine, stephaoxocanidine, romorphinane, cepharanthine,
cepharanoline, steponine, isotetrandrine, berbamine,
stecepharine, dehydroreticuline (11), magnoflorine, menisperine,
oblongine, cyclanoline, cis-N-methylcapaurine, sinomenine,
cephamerphinanine, D-glucopyranoside, 2 ′ -N-methylisotetrandrine,
N-methyl stesakine chloride (12), stesakine 9-O--Dglucoside
(13), N-methylasimilobine-2-O--D-glucopyranoside
(14), cephamonine, aromoline, zippelianine, cepharamine, aknadinine
(15), aknadicine (16), cephatonine, (−)-cycleanine (28),
obamegine, berbamine, isocorydine, anolobine, cotypalline,
stepharine (9), (+)-reticuline (17), obaberine, homoaromoline,
fangchinoline, tetrandrine (18), cephamuline (Deng et al., 1992;
Nakamura et al., 1992; Sugimoto et al., 1993, 1988; Kashiwaba et
al., 1996, 1997, 2000, 1998, 1994; Nakaoji et al., 1997; Tanahashi
et al., 2000), berbamine and aromorine (Akasu et al., 1976).

372 D.K. Semwal et al. / Journal of Ethnopharmacology 132 (2010) 369–383
3.6. Stephania dinklagei Diels
Liriodenine (19), dicentrinone (20), (+)-corydine (21), (+)-
idocorydine, (−)-roemerine, N-methylliriodendronine (22),
2-O,N-dimethylliriodendronine (23), aloe-emodin (24), isocorydine,
aporphines, atheroospermidine, tephalagine and
dehydrostephalagine (Dwuma et al., 1980; Camacho et al.,
2000; Goren et al., 2003).
3.7. Stephania delovayi Diels
Stephodeline (Il’inskaya et al., 1973), 16-oxodelavayine
(Il’inskaya et al., 1972), delavayine (25) (Fadeeva et al., 1971a) and
isostephodeline (Perel’son et al., 1975).
3.8. Stephania elegans Hook.f. & Thoms.
Epihernandolinol (26), N-methylcorydalmine (27), hasubanonin,
aknadinin (15), cyclanoline, magnoflorine, isotetrandrine,
isochondodendrine and cycleanine (28) (Singh et al., 1981).

D.K. Semwal et al. / Journal of Ethnopharmacology 132 (2010) 369–383 373
3.9. Stephania erecta Craib
Cepharanthine, (+)-2-N-methyltelobine (29), (+)-1,2-
dehydrotelobine (30), (+)-2-nor-isotetrandrine, (+)-isotetrandrine,
(+)-2-nor-thalrugosine, (+)-thalrugosine, (+)-homoaromoline,
(+)-stephibaberine, (+)-dephnandrine, (+)-2-nor-cepharanthine,
(+)-nor-obaberine, (+)-obaberine (Likhitwitayawuid et al., 1993b;
Tamez et al., 2005).
3.11. Stephania glabra (Roxb.) Miers
(+)-Pronuciferine (33), gindarine, gindaricine, gindarinine,
hyndarine, magnoflorine, N-thyloxystephanine,
N-methylhydoxystepharine, remerine, stephararine, cycleanine
(28), rotundine, capaurine (34), corydalmine (35), stepholidine
(36), stepharine (9), protoberberine, palmatine (37), dehydrocorydalmine
(38), jatrorrhizine (39), stepharanine (40), columbamine
(41), N-desmethycycleanine (42), corynoxidine (43) (Chaudhary
and Siddiqui, 1950; Chaudhary et al., 1952; Chopra et al., 1956;
Cava et al., 1964, 1968; Kin et al., 1965; Robinovich et al., 1965;
Shchelchkova et al., 1965; Doskotch et al., 1967; Dhar et al.,
1968; Thu and Nuhn, 1971; Khanna et al., 1972; Patra et al.,
1980; Bhakuni and Gupta, 1982; Bhakuni, 1984; Mahatma et
al., 1987; Anonymous, 1989; Rastogi and Mehrotra, 1991; Duke,
1992; Das et al., 2004), 11-hydroxypalmatine (44) (Semwal et al.,
2010b), glabradine (45) and gindarudine (46) (Semwal and Rawat,
2009a,b).
3.10. Stephania excentrica H. S. Lo
Excentricine (31), N-methylexcentricine (32), roemerine, 4-
demethylhasubanonine, oxoputerine, oxoanolobine, isoboldine,
homoaromoline, (+)-coclaurine and sinococuline (Deng and Zhao,
1997; Miu et al., 1998).
3.12. Stephania hernandifolia (Willd.) Walp.
(+)-3 ′ ,4 ′ -Dihydrostephasubine (47), (+)-epistephanine (48),
(+)-stephasubine (49) (Patra et al., 1988), l-quercitol, isotrilobine,
-sitosterol, aknadine, aknadinine (15), 4-demethylhasubanonine,
dl-tetrandrine, fangchinoline (50), d-tetrandrine (18), d-
isochondrodendrine, aknadicine (16) (Chopra et al., 1956; Moza,
1960; Kupchan et al., 1961; Kunitomo et al., 1966, 1967, 1969;
Moza and Basu, 1966; Moza and Bose, 1967; Kupchan et al.,
1968; Moza et al., 1968; Moza et al., 1970; Anonymous, 1994),
hernandoline (Fadeeva et al., 1967), hernandine (Il’inskaya et al.,
1971), hernandolinol (Fadeeva et al., 1970), methylhernandine
(Fadeeva et al., 1971b), 3-O-demethylhernandifoline (51)(Fadeeva
et al., 1972) and hernandifoline (Fesenko et al., 1971).

374 D.K. Semwal et al. / Journal of Ethnopharmacology 132 (2010) 369–383
3.13. Stephania intermedia H. S. Lo
(−)-Stepholidine (36) (Xin et al., 1992; Ellenbroek et al., 2006).
3.14. Stephania japonica (Thunb.) Miers
16-Oxohasubonine, aknadicine (16), aknadine, 16-oxoprotometaphanine,
aknadinine (15), cyclanoline, cycleanine (28),
d-fangchinoline (50), oxostephabenine (52), stephabenine
(53), lanuginosine (54), epistephanine, dehydroepistephanine,
d-tetrandrine (18), trilobine, epistephamiersine, insularine,
hasubanonine, hernandoline, obamegine, homoepistephanine,
steponine, stephasunoline, oxostephasunoline (55), homostephanoline,
hypoepistephanine, isochondrodendrine, oxostephamiersine,
isotrilobine, l-quercitol, metaphanine, n-nor-1,
2-dehydroepistephanine, oxostephanine, plastoquinone, protostephanaberrine,
prometaphanine, stepinonine, stebisimine,
oxostephasunodine, stephanaberrine, stephanine (6), prostephanaberrine
(56), stephamiersine, stephanoline, stepholine,
stepisimine, viburnitol, protostephanine (57), oxoepistephamiersine
(58), oxostephamiersine, stephadiamine (Inubushi and Ibuka,
1977; Matsui and Watanabe, 1984; Matsui et al., 1984, 1973,
1982a,b; Matsui et al., 1975; Kondo et al., 1983; Taga et al., 1984;
Yamamura and Matsui, 1985; Matsui and Yamamura, 1986; Duke,
1992; Hall and Chang, 1997) and bebeerine (59) (Hullatti and
Sharada, 2010).
3.15. Stephania longa Lour
Longitherine (60), stephabyssine, stephaboline (Deng and Zhao,
1993), isostephaboline, stephalonines A-I, norprostephabyssine
(61), isoprostephabyssine (62), isoprostephabyssine and isolonganone
(Zhang and Yue, 2005).
3.16. Stephania miyiensis S. Y. Zhao & H. S. Lo
Tetrahydropalmatine (5), stepharine (9), corydalmine (35), jatrorrhizine
(39), stepharanine (40) and 4-O-demethyljatrorrhizine
(63) (Anonymous, 1999).

D.K. Semwal et al. / Journal of Ethnopharmacology 132 (2010) 369–383 375
3.20. Stephania sasakii Hayata
Obaberine, thalrugosine, aknadinine (15), secocepharanthine,
aknadilactam (70) and O-methylpunjabine (Moza et al., 1970;
Kunitomo, 1985).
3.17. Stephania pierrei Diels
(−)-Asimilobine (64), (−)-asimilobine 2-O--D-glucoside,
(−)-anonaine, (−)-isolaureline, (−)-xylopine, (−)-roemeroline,
(−)-dicentrine (10), (−)-nordicentrine, (−)-phanostenine,
cassythicine, magnoflorine, (−)-tetrahydropalmatine (5),
(−)-capaurine (34), (−)-thaicanine, (−)-corydalmine (35),
(−)-N-methyltetrahydropalmatine (65), (−)-xylopinine,
(−)-tetrahydrostephabine, (+)-reticuline (17), (+)-codamine, (±)-
oblongine, (−)-delavaine and (−)-salutaridine (Likhitwitayawuid
et al., 1993a; Angerhofer et al., 1999).
3.21. Stephania sinica Diels
Cepharanthine (69), runanine (71) and -sitosterol (Min et al.,
1985).
3.18. Stephania gracilenta Miers
Sinoacutine, isosinoacutine (66), magnoflorine and papaverine
(67) (Khosa et al., 1987).
3.22. Stephania suberosa L. L. Forman
3.19. Stephania rotunda Lour.
Cepharamine (68), cycleanine (28), (+)-stepharine (9), (−)-
tetrahydropalmatine (5)(Chopra et al., 1958; Burkill, 1966; Tomita
et al., 1966; Tomita and Kozuka, 1966, 1967; Phaet-thanesuara,
1967; Perry, 1980; Kozuka et al., 1985; Luger et al., 1998), coclaurine,
dehassiline, stepholidine (36), corynoxidine (43) (Thuy et
al., 2006), stepharotudine (Hung et al., 2010), cepharanthine (69),
fangchinoline (50)(Gulcin et al., 2010), 5-hydroxy-6,7-dimethoxy-
3,4-dihydroisoquinolin-1(2H)-one, thaicanine 4-O--D-glucoside
and (−)-thaicanine N-oxide (4-hydroxycorynoxidine) (Thuy et al.,
2005).
(+)-Cepharanthine (69), (+)-2-norcepharanthine (72),
(+)-cepharanthine 2 ′ --N-oxide, (+)-stephasubine, (+)-
norstephasubine, stephasubimine (73) (Patra et al., 1986),
(−)-tetrahydrostephabine, (−)-kikemanine, (−)-stephabinamine,
tephabine, stephnubine, (−)-discretine, 8-oxypseudopalmatine,
(−)-tetrahydropalmatrubine, (−)-stepholidine (36), (−)-
capaurimine, pseudopalmatine, (−)-coreximine, stephaphylline
(−)-ctytenchine, (−)-xylopinine and nordelavaine (Patra et al.,
1987; Patra, 1987).
3.23. Stephania succifera H. S. Lo & Y. Tsoong
Cepharanone D, N-formyl-asimilobine, N-formyl-annonain
(Yang et al., 2010a,b), crebanine (7), crebanine-N-oxide, dehydrocrebanine,
tetrahydropalmatine (5), schefferine, asimilobine (Xue
et al., 1986), 7-oxodehydrocaaverine, 7-oxocrebanine and aristololactam
I (Yang et al., 2010a,b).

376 D.K. Semwal et al. / Journal of Ethnopharmacology 132 (2010) 369–383
3.24. Stephania sutchuenensis H. S. Lo
1-Nitroaknadinine (74) and aknadinine (15)(Wang et al., 1994).
3.25. Stephania tetrandra S. Moore
Stephadione (75), oxonantenine (76), cassameridine, nantenine,
cassythicine, corydione, aristolochic acid I and II, fangchinoline
A-D (Chen and Chen, 1935; Chen et al., 1937; Si et al., 1992; Zhu
and Philipson, 1996; Kwan et al., 1996; Kim et al., 1997; Ogino et
al., 1998b; Wong, 1998; Kim et al., 1999; Nan et al., 2000; Liang
et al., 2002; Tsutsumi et al., 2003; Fang et al., 2005; Chiou et al.,
2006), fenfangjine A-C (Ogino et al., 1998a), stephaflavone A and
B(Si et al., 2001), fangchinoline (50), tetrandrine (18) (Lijin et al.,
2009), 2-N-methyltetrandrine and (+)-2-N-merhylfangchinoline
(77) (Deng et al., 1990).
well as aqueous extract (SA) and dichloromethane extracts (SD1
and SD2) from S. rotunda Lour. were tested against Plasmodium falciparum
W2 in vitro. DN, CN and SD1 were the most active against W2
with IC 50 values of 0.36, 0.61 M and 0.7 g/mL, respectively. Their
IC 50 values on human monocytic THP1 cells were 10.8, 10.3 M
and >250 g/mL, respectively. CN, SD1 and SA were selected for in
vivo antimalarial testing against Plasmodium berghei in mice. The
results of SD1 and SA at a dose of 150 mg/kg showed a decrease of
89 and 74% of parasitaemia by intra-peritoneal injection and 62.5
and 46.5% of parasitaemia by oral administration, respectively. The
results for CN at a dose of 10 mg/kg showed a decrease of 47% of
parasitaemia by intra-peritoneal injection and 50% of parasitaemia
by oral administration. Drug interaction of chloroquine (CL) and
major alkaloids indicates that CN–CL and TN–XN associations
are synergistic (Chea et al., 2007). The bisbenzylisoquinoline
alkaloids from S. erecta Craib and tetrahydroprotoberberine alkaloids
from S. pierrei Diels showed anti-malarial activity against
the D6 (ED, 1540 ng/mL) and W2 (ED, 3130 ng/mL) strains of
Plasmodium falciparm having ED values of 950 and 470 ng/mL
in the D6 and W2 strains, respectively. The antimalarial activity
of S. pierrei Diels was attributed to the nonquaternary aporphine
alkaloids and the tetrahydroprotoberberines possessing a
phenolic functionality. None of the isolates showed a degree of
selectivity comparable to that of antimalarial drugs such as chloroquine,
quinine, mefloquine, and artemisinin (Likhitwitayawuid
et al., 1993a,b). Six compounds from S. dinklagei Diels
3.26. Stephania venosa (Blume) Spreng.
(−)-O-acetylsukhodianine (78), kamaline, oxoaporphin,
oxostephanosine (79), (−)-crebanine (7), dehydrocrebanine,
(+)-N-carboxamidostepharine (80), (−)-kikemanine,
(−)-tetrahydropalmatine (5), (−)-stepharinosine (81), (+)-
stepharine (9), liriodenine (19), (−)-O-methylstepharinosine,
oxocrebanine, dehydrostephanine, (−)-ushinsunine, oxostephanine,
(−)-sukhodiamine, (−)-sukhodianine--N-oxide,
(−)-stephadiolamine--N-oxide (Guinaudeau et al., 1981, 1982;
Pharadai et al., 1985; Charles et al., 1987; Banerji et al., 1994;
Likhitwitayawuid et al., 1999), stepharanine, cyclanoline and
N-methyl stepholidine (Ingkaninan et al., 2006).
including, two zwitterionic oxoaporphine alkaloids [Nmethylliriodendronine
(22) and 2-O,N-dimethylliriodendronine
(23)], two oxoaporphine alkaloids [liriodenine (19) and dicentrinone
(20)], one aporphine alkaloid [corydine (21)] and one
anthraquinone [aloe-emodine (24)] were tested for antiprotozoal
and cytotoxic activity in vitro. N-methylliriodendronine was most
active against Leishmania donovani amastigotes (IC 50 = 36.1 M).
Liriodenine showed the highest activity against L. donovani, and
P. falciparum with IC 50 values of 26.16 and 15 M, respectively.
Aloe-emodin (24) was the only compound active (IC 50 =14M)
against T.b. brucei (Camacho et al., 2000). The aqueous extract of
leaves of S. abyssinica Walp. showed significant anti-plasmodial
activity in vitro against chloroquine sensitive and resistant laboratory
adapted strains of P. falciparum with IC 50 values >30 gmL −1
(Muregi et al., 2004).
4.2. Antimicrobial activity
4. Biological activities
4.1. Anti-malarial activity
Four major alkaloids dehydroroemerine (DN), tetrahydropalmatine
(TN) (5), xylopinine (XN) and cepharanthine (CN) (69) as
A hasubanalactam alkaloid, glabradine (45) isolated from the
tubers of S. glabra (Roxb.) Miers was evaluated for antimicrobial
activity against Staphylococcus aureus, S. mutans, Microsporum
gypseum, M. canis and Trichophyton rubrum and displayed potent
antimicrobial activity superior to those of novobiocin and erythromycin
with IZD values of 19–27 cm (Semwal and Rawat,
2009a,b). An ethanolic extract was also evaluated for its antimicrobial
activity against five bacterial species (S. aureus, S. mutans, S.
epidermidis, Escherichia coli and Klebsiella pneumonia) and six fungal
species (Aspergillus niger, A. fumigatus, Penicillum citranum, M. gypseum,
M. canis and T. rubrum) and found to be active against most

D.K. Semwal et al. / Journal of Ethnopharmacology 132 (2010) 369–383 377
of the tested microorganisms with MIC range of 50–100 g/mL
(Semwal et al., 2009). The methanolic root extract of S. japonica
(Thunb.) Miers showed significant in vitro activity together with
Cissampelos pareira and Cyclea peltata (Hullatti and Sharada, 2007).
Cepharanone D, N-formyl-asimilobine and N-formylannonain isolated
from S. succifera H. S. Lo & Y. Tsoong showed significant
antimicrobial activity in vitro (Yang et al., 2010a,b).
4.3. Anthelmintic activity
The alcoholic extract of the dried rhizome of S. glabra (Roxb.)
Miers was tested against various helminth parasites, i.e. nematode
(Heterakis gallinarum, Ascaridia galli, Ancylostoma ceylanicum and
Ascaris suum), cestode (Raillietina echinobothrida) and trematode
(Fasciolopsis buski) in dosages ranging between 25 and 100 mg/mL
in 0.9% phosphate buffered saline (PBS, pH 7.2) at 38 ± 1 ◦ C. The
controls, kept in PBS, survived for an average 22 h (trematode),
72 h (cestode) and 55 > 380 h (nematodes). The results showed pronounced
effect on the cestode and trematode, i.e. a dose-dependent
gradual decline in physical motility was observed in R. echinobothrida
and F. buski (Das et al., 2004).
4.4. Anti-viral activity
The antiviral activity of methanolic extract of S. cepharantha
Hayata tubers, its chloroform soluble fraction (alkaloid fraction)
and the major alkaloid FK-3000 were investigated in BALB/c mice
cutaneously infected with HSV-1 strain 7401H. At oral doses of
125 and 250 mg/kg body weight, the methanol extract significantly
delayed skin lesions on score 2 (vesicles in the local region), limited
the development of further lesions on score 6 (mild zosteriform
lesion) and prolonged the mean survival time of HSV-1 infected
mice. After administration of the alkaloid fraction at doses of 25
and 50 mg/kg or FK-3000 at 10 and 25 mg/kg, similar results were
obtained. Although the alkaloid improved the survival of infected
mice, it had a narrow therapeutic index (Nawawi et al., 2001; Liu
et al., 2004; Zhang et al., 2005).
4.5. Anti-proliferative/anti-cancer activity
Four alkaloids (dl-tetrandrine, fangchinoline (50), d-tetrandrine
and d-isochondrodendrine) isolated from S. hernandifolia (Willd.)
Walp. showed significant cytotoxicity against human carcinoma
of the nasopharynx carried in tissue culture (KB), and that dltetradrine
and d-tetrandrine showed significant inhibitory activity
in vivo against the Walker 256 intramuscular carcinosarcoma in the
rat (Kupchan et al., 1968). Ethanolic extract of S. venosa (Blume)
Spreng. bulb was tested for antiproliferative activity against SKBR3
human breast adenocarcinoma cell line using MTT assay and
showed activity in potential range for further investigation on cancer
cells (Moongkarndi et al., 2004). Aporphine alkaloid isolated
from S. venosa (Blume) Spreng. exhibited antiproliferation activity
on SKOV3 human ovarian cancer cell line using MTT assay.
Aporphine showed strong inhibition activity with an ED 50 value
of 6 g/mL (Montririttigri et al., 2008). Four bisbenzylisoquinoline
alkaloids (cepharanthine (69), cepharanoline, isotetrandrine
and berbamine) from S. cepharantha Hayata showed significant
effects on proliferation of culture cell from the murine skin in
the range of 0.01–0.1 g/mL (Nakaoji et al., 1997). Cepharanthine
(CN) inhibits tumor promotion after topical application
in two-stage carcinogenesis in mouse skin. Epidermal ornithine
decarboxylase activities inhibited by topical application of CN,
with 5 mg/mouse) and mezerein (5 mg/mouse) were found to
be inhibited by topical application of CN, with a ED 50 values of
1.2 mM and 1.4 mM, respectively. A diet containing 0.005% CN
slightly suppressed the two-stage promotion of skin tumors by
twice-weekly applications of 2.5 Mg TPA for 2 weeks (first stage)
followed by twice-weekly applications of 2.5 Mg mezerein for
23 weeks (second stage) in ICR mice following initiation by 50
Mg 7,12-dimethylbenz[a]anthracene. Oral administration of CN
inhibits the tumor promotion in two-stage carcinogenesis in mouse
skin (Yasukawa et al., 1991). S. tetrandra S. Moore demonstrated
antiproliferative and proapoptotic activities in a rat hepatic stellate
cell line, HSC-T6 (Chor et al., 2005). The extract, as well as
two aporphine alkaloids, (−)-asimilobine-2-O--D-glucoside and
(−)-nordicentrine from S. pierrei Diels, and (+)-2-N-methyltelobine
from S. errecta Craib showed potent cytotoxic activity against
the KB (ED 50 3.6 g/mL) and P-388 (ED 50 0.8 g/mL) cell systems.
It was found that the cytotoxicity of S. pierrei Diels was
mainly due to the presence of the aporphine alkaloids containing
the 1,2-methylenedioxy group (Likhitwitayawuid et al., 1993a,b;
Angerhofer et al., 1999). Five compounds (7-oxodehydrocaaverine,
7-oxocrebanine, dehydrocrebanine, crebanine and aristololactam
I) from the tuber of S. succifera H. S. Lo & Y. Tsoong were evaluated
for their cytotoxic activity by MTT assay. Dehydrocrebanine
and crebanine showed inhibitory activity towards chronic myelogenous
leukemia (K562), human gastric carcinoma (SGC-7901)
and human hepatoma (SMMC-7721) cell lines (Yang et al., 2010a,b).
Aqueous extract of S. venosa (Blume) Spreng. tubers was studied for
cytotoxic activity on human peripheral blood mononuclear cells
(PBMCs) and showed activity with IC 50 value of 300 mg/mL. The
effect of the extract on apoptotic induction was also evaluated at the
concentration of 300 mg/mL on PMBCs from healthy subjects and
from cervical cancer patients and significantly induced apoptosis of
the PBMCs from both healthy subjects and from the patients. The
antiproliferative effect was also evaluated on the cells from healthy
subjects and demonstrated activity with IC 50 value of 40 mg/mL
(Sueblinvong et al., 2007).
4.6. Antipsychotic activity
(−)-Stepholidine (SPD) isolated from S. intermedia H. S. Lo, which
binds to the dopamine D 1 and D 2 like receptors has been evaluated
for its antipsychotic effects in animal models. The effects of
SPD, clozapine and haloperidol in increasing forelimb and hindlimb
retraction time in the paw test and in reversing the apomorphine
and MK801-induced disruption of prepulse inhibition was investigated.
In the paw test, clozapine and SPD increased the hind limb
retraction time. In the prepulse inhibition paradigm, all three drugs
reverse the apomorphine-induced disruption in prepulse inhibition,
while none of the drugs could reverse the MK801-induced
disruption. SPD even slightly, but significantly potentiated the
effects of MK801 (Ellenbroek et al., 2006).
4.7. Apoptosis inducing effect
Apoptosis inducing effect of tetrandrine (TN), a bisbenzylisoquinoline
alkaloid derived from S. tetrandra S. Moore on activated
hepatic stellate cells of rat has been examined. The hepatic stellate
cells transformed by Simian virus 4 (T-HSC/CL-6) to overcome
the limitations inherent in studying primary cultures of hepatic
stellate cells. TN treatment at doses of 25 and 50 g/mL for
12 h induced apoptosis as confirmed by DNA fragmentation and
increased sub-G1 DNA content. TN also induced the activation
of capase-3 protease and subsequent proteolytic cleavage of poly
(ADP-ribose) polymerase (Zhao et al., 2004).
4.8. Multidrug resistance reversing activity
An alkaloidal extract of the vines of S. japonica (Thunb.) Miers
showed multidrug resistance reversing activity as demonstrated
by the bicinchoninic acid assay. Insotrilobine and trilobine from

378 D.K. Semwal et al. / Journal of Ethnopharmacology 132 (2010) 369–383
the plant were shown to be as active as verapamil (standard)
in reversing doxorubicin resistance in human breast cancer cells
(MCF-7 cells). Isotrilobine has MDR-reversing activity comparable
to verapamil at concentrations less than the ED 20 of isotrilobine
on MCF-7/ADR cells. Trilobine has low activity with a slope of 28
as compared with slopes of 211 and 232 for isotrilobine and verapamil,
respectively. The greater efficacy of isotrilobine to trilobine
appears to be a result of the methyl group at N-2 ′ . This is the only
structural difference between the two compounds and suggests
that a tertiary amine is preferred at this position to a secondary
amine. The slightly increased lipophilicity induced by the addition
of another methyl group may also contribute to the increased
activity (Hall and Chang, 1997).
4.9. Anti-inflammatory and analgesic activity
To investigate the anti-inflammatory effects of S. tetrandra
S. Moore in vitro and in vivo, its effects on the production of
IL-6 and inflammatory mediators were analyzed. When human
monocytes/macrophages (stimulated with silica) were treated
with 0.1–10 g/mL the plant, the production of IL-6 was inhibited
up to 50%. It also suppressed the production of IL-6 by
alveolar macrophages. In addition, it inhibited the release of
superoxide anion and hydrogen peroxide from human monocytes/macrophages.
To assess the anti-fibrosis effects of S. tetrandra,
its effects on in vivo experimental inflammatory models were evaluated.
In the experimental silicosis model, IL-6 activities in the
sera and in the culture supernatants of pulmonary fibroblasts were
also inhibited by it. In vitro and in vivo treatment with S. tetrandra
reduced collagen production by rat lung fibroblasts and lung
tissue. It also reduced the levels of serum GOT and GPT in the
rat cirrhosis model induced by CCl 4 , and was effective in reducing
hepatic fibrosis and nodular formation (Kang et al., 1996). The antiinflammatory
constituents, tetrandrine (18) and fangchinoline (50)
from S. tetrandra have been shown to decrease IL-1beta, IL-6, IL-8
and TNF-alpha as well as decrease leukotriene and prostaglandin
generation. Furthermore, tetrandrine has been shown to inhibit the
production of TNF-alpha and IL-6 by microglial cells (Teh et al.,
1990; Xue et al., 2008). The combined analgesic effect of aconitum
(Ac) and S. tetrandra (St) was found superior to that of Ac and St
when used alone. The combined Ac-St showed remarkable analgesic
activity within 3 h (p < 0.01) in rabbits and mice models (Li et
al., 2000).
4.10. Immunomodulating activity
S. tetrandra S. Moore has been used to treat autoimmune
diseases such as rheumatoid arthritis and systemic lupus erythe
matosus. Tetrandrine (18) has potential immunomodulating
and anti-inflammatory effects. T-lymphocytes play a critical
role as autoactive and pathogenic population in autoimmune
and inflammatory diseases. Some experimental data showed
that, through down-regulating the protein kinase C (PKC) signaling,
interleukin-2 secretion and the expression of the T
cell activation antigen (CD71), tetrandrine inhibited phorbol
12-myristate 13-acetate (PMA)+ionomycin-induced T cell proliferation
dependent on interleukin-2 receptor chain and CD69,
such an action was unrelated to Ca 2+ channel blockade (Ho
et al., 1999). Tetrandrine (0.1–10 ML −1 ) significantly inhibited
neutrophil-monocyte chemotactic factor-1 upregulation and
adhesion to fibrinogen induced by N-formyl-methionyl-leucylphenylalanine
and PMA. Tetrandrine at 0.1–100 ML −1 caused
dose and time-dependent loss of cell viability of mouse peritoneal
macrophages, guinea-pig alveolar macrophages and mouse
macrophage-like J774 cells, reduced production of oxygen free
radical, down-regulated synthesis and release of some proinflammatory
cytokines (Pang and Hoult, 1997; Shen et al.,
1999).
4.11. Antifibrotic effect
Antifibrotic effect of a methanol extract from S. tetrandra S.
Moore on experimental liver fibrosis has been investigated. Liver
fibrosis was induced by bile duct ligation and scission (BDL/S) in
rats. In BDL/S rats, activity levels of aspirate transaminase, alanine
transaminase, alkaline phosphatase, concentration of total
bilirubin in serum, and 100 mg/kg/day or 200 mg/kg/day, (p.o. for
4 weeks) in BDL/S rats reduced the serum aspirate transaminase,
alanine transaminase, alkaline phosphatase activity levels significantly
(p < 0.01) (Nan et al., 2000).
4.12. Anti-hyperglycemic effect
The ethanolic extract of the tubers of S. glabra (Roxb.) Miers
was evaluated for its hyperglycemic effects against alloxan-induced
diabetic and significantly decreased the blood sugar level in experimental
animals (Semwal et al., 2010a). A palmatine derivative,
11-hydroxypalmatine (44) isolated from this plant was also evaluated
for its anti-hyperglycemic activity. The test compound was
administered at doses of 25, 50, and 100 mg/kg, p.o., 36 h after
alloxan injection (60 mg/kg, i.v.). The alloxan-induced diabetic mice
showed significant reduction in blood glucose after treatment with
the test compound by 52% as compared to the positive control
glibenclamide (54%) and the diabetic control (27%) (Semwal et al.,
2010b). S. tetrandra S. Moore roots increases the blood insulin level
and reduces the blood glucose level in streptozotocin diabetic mice.
Actions of bisbenzylisoquinoline alkaloids isolated from the plant
were investigated in the hyperglycemia of diabetic mice. A main
bisbenzylisoquinoline alkaloid fangchinolin (0.3–3 mg/kg) significantly
reduced blood glucose level of the diabetic mice. The effect
of fangchinoline was 3.9 fold greater than that of water extract
(Tsutsumi et al., 2003). S. tetrandra has a direct effect on the retinal
capillary of posterior ocular region and suppressed neovascularization
of retinal capillary in streptozotocin diabetic rats through
the activation of tetrandrine (Liang et al., 2002). The oral administration
of ethanol and aqueous extract (400 mg/kg body weight) of
powdered corm of S. hernandifolia significantly (p < 0.05) decreased
the blood glucose of normal and Streptozotocin-induced diabetic
rats up to 12 h. Glibenclamide was used as a standard drug at a dose
of 0.25 mg/kg (Sharma et al., 2010).
4.13. Ca 2+ channel blocking activity
Abnormal Ca 2+ signaling and elevated concentration of intracellular
free Ca 2+ are the basic pathophysiological events involved
in various diseases. As a Ca 2+ antagonist, tetrandrine (S. tetrandra)
can inhibit extracellular Ca 2+ entry, int ervene in the distribution
of intracellular Ca 2+ , maintain intracellular Ca 2+ homeostasis, and
then disrupt the pathological processes. As shown in whole cell
patch-clamp recordings, tetrandrine blocked bovine chromaffin
cells voltage-operated Ca 2+ channel current in a time and concentration
dependently manner. In rat phaeochromocytoma PC 12
cells, 100 mol L −1 tetrandrine abolished high K + (30 mmol L −1 )
-induced sustained increase in cytoplasmic Ca 2+ concentration,
inhibited bombesin-induced inositol triphosphate accumulation in
NIH/3T3 fibroblast and abolished Ca 2+ entry (Takemura et al., 1996).
Tetrandrine can affect cardiovascular electrophysiologic properties
by inhibit the contractility, ±dt/dp max , and automaticity of
myocardium, prolong the FRP, and exert concentration-dependent
negative inotropic and chronotropic effects without altering cardiac
excitability. Tetrandrine directly blocks both T-type and L-type
calcium current in ventricular cells and vascular smooth muscle

D.K. Semwal et al. / Journal of Ethnopharmacology 132 (2010) 369–383 379
cells, but it does not shift the I–V relationship curve of I Ca . All its
effects would be beneficial in the treatment of angina, arrhythmias,
and other cardiovascular disorders. It also directly inhibits
the activity of BK Ca channel in endothelial cell line and also inhibits
Ca 2+ -release-activated channels in vessel endothelial cells, which
might significantly contribute to the change of endothelial cell
activity (Qian, 2002; Yao and Jiang, 2002).
4.14. Acetylcholinesterase (AChE) inhibitory activity
Three quaternary protoberberine alkaloids, stepharanine,
cyclanoline and N-methyl stepholidine from S. venosa (Blume)
Spreng. tuber expressed inhibitory activity on AChE with IC 50 values
of 14.10, 9.23 and 31.30 M, respectively. The AChE inhibitory
(potential drugs for Alzheimer’s disease) activity of these compounds
was compared with those of the related compounds,
palmatine, jatrorrhizine and berberine, as well as with tertiary protoberberine
alkaloids, stepholidine and corydalmine isolated from
the same plant. The results suggest that the positive charge at the
nitrogen of the tetrahydroisoquinoline portion, steric substitution
at the nitrogen, planarity of the molecule or substitutions at C-2,
-3, -9, and -10 affect the AChE inhibitory activity of protoberberine
alkaloids (Ingkaninan et al., 2006). The ethanolic extract of roots
along with the alkaloids isolated from S. rotunda Lour. showed significant
AChE inhibitory activity (in vitro) using a rat cortex AChE
enzyme (Hung et al., 2010).
4.15. Vasodilating and hypotensive activities
Comparative studies of the effects of tetrandrine (TN) and
fangchinoline (FN), two major components of the Radix of S.
tetrandra S. Moore, on vasodilations and on calcium movement
in vascular smooth muscle, and studies of hypotensive effects
on stroke-prone spontaneously hypertensive rats (SHRSP) were
performed. TN and FN inhibited high K + (65.4 mM) and induced
sustained contraction in the rat aorta smooth muscle strips. IC 50
values for TN and FN were 0.27 ± 0.05 M and 9.53 ± 1.57 m,
respectively, and this inhibition was antagonized by increasing
the Ca 2+ concentration in the medium. The IC 50 of TN
for norepinephrine (NE)-induced contraction (0.86 ± 0.04 g) was
3.08 ± 0.05 m, and the IC 50 of FN for NE-induced contraction
(0.88 ± 0.07 g) was 14.20 ± 0.40 M. At the molecular level, radiolabelled
45 Ca 2+ uptake tests revealed that TN and FN also inhibited
high K + (65.4 mM) and 1 M NE-stimulated Ca 2+ influx in rat aorta
strips at the maximal concentration was needed to inhibit the
contraction. TN (3 mg/kg) and FN (30 mg/kg) administered by i.v.
bolus injection also lowered the mean arterial pressure (MAP) significantly
during the period of observation in conscious SHRSP,
respectively. These results showed that TN was more potent than
FN in blocking calcium channels and antihypertensive activity. The
compounds were also shown to have hypotensive effects on stroke
prone spontaneously hypertensive rats (Kim et al., 1997).
4.16. Inhibition of antinociceptive effect
Fangchinoline (FN), a non-specific calcium antagonist, from S.
tetrandra S. Moore showed antagonistic activity on morphineinduced
antinociception in mice. It has been found that FN (IP)
attenuated morphine (SC)-induced antinociception in a dosedependent
manner with significant effect at doses of 30 and
60 mg/kg body wt (IP) in the tail-flick test but not the tailpinch
tests. This antagonism was abolished by pretreatment
with a serotonin precursor, 5-hydroxytryptophan (5-HTP, IP),
but not by pretreatment with a noradrenaline precursor, L-
dihydroxyphenylalanine (L-DOPA, IP) in the tail-flick test. The
serotonergic pathway may be involved in the antagonism of
morphine-induced antinociception by FN and, in agreement with
other reports, also indicates the possible dissociation of the morphine
analgesic effect from its tolerance-development mechanism
(Fang et al., 2005).
4.17. Acute hemodynamic effect
Acute hemodynamic effect of tetrandrine, isolated from S.
tetrandra was assessed in anesthetized cirrhotic rats. Tetrandrine
decreases of PVP and MAP, the maximum percentage reduction of
PVP after drug was 5.4 ± 1.0%, 9.2 ± 0.8% and 23.7 ± 1.2% of base
line, respectively, for the doses given 2.0, 6.6 and 20.0 mg/kg. Total
peripheral resistance was also reduced by the drug (Huang et al.,
1999).
4.18. Histamine release inhibition activity
Bisbenzylisoquinoline alkaloids from S. cepharantha Hayata
roots and tubers were tested for histamine release inhibition
assay. The order of the potency of inhibitory effect was ranked
as homoaromoline, aromoline, isotetrandrine, cepharanthine (69),
fangchinoline (50), obaberine and tetrandrine (Nakamura et al.,
1992).
4.19. Antioxidant activity
Fangchinoline (50) and cepharanthine (69) isolated from S.
rotunda Lour. performing different in vitro antioxidant assays,
including 1,1-diphenyl-2-picryl-hydrazyl (DPPH) free radical
scavenging, 2,2 ′ -azino-bis(3-ethylbenzthiazoline-6-sulfonic acid)
(ABTS) radical scavenging, N,N-dimethyl-p-phenylenediamine
dihydrochloride (DMPD) radical scavenging, superoxide anion
(O 2 •− ) radical scavenging, hydrogen peroxide scavenging, total
antioxidant activity, reducing power, and ferrous ion (Fe 2+ ) chelating
activities. Cepharanthine and fangchinoline showed 94.6 and
93.3% inhibition on lipid peroxidation of linoleic acid emulsion
at 30 g/mL concentration, respectively. On the other hand,
butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),
-tocopherol, and trolox indicated inhibitions of 83.3, 92.2, 72.4,
and 81.3% on peroxidation of linoleic acid emulsion at the same
concentration (30 g/mL), respectively (Gulcin et al., 2010). The
ethanol and aqueous extracts (400 mg/kg body weight) of powdered
corm of S. hernandifolia (Willd.) Walp. strongly scavenged
DPPH radicals with IC 50 values of 265.33 and 217.90 g/mL, respectively
in vitro whereas the superoxide radical were scavenged with
IC 50 values of 526.87 and 440.89 g/mL, respectively. Ascorbic acid,
a natural antioxidant, was used as positive control (Sharma et al.,
2010).
4.20. Miscellaneous uses
Tetrandrine (TN) from the root of S. tetrandra S Moore has been
used to treat silicosis. Except for its antiinflammatory, antifibrogenetic,
immunomodulating effects and antioxidant effects, TN
shows antiallergic effects, inhibitory effects on pulmonary vessels
and airway smooth muscle contraction, and platelet aggregation
via its nonspecific calcium channel antagonism that suggested its
potential in the treatment of asthma, pulmonary hypertension and
chronic obstructive pulmonary disease (Xie et al., 2002). TN has
been used to treat silicosis, autoimmune disorders, and hypertension
in Mainland China for decades. The accumulated studies
both in vitro and in vivo reveal that it preserves a wide variety
of immunosuppressive effects. Importantly, the TN-mediated
immunosuppressive mechanisms are evidently different from
some known DMARDs. The synergistic effects have also been
demonstrated between TN and other DMARDs like FK506 and

380 D.K. Semwal et al. / Journal of Ethnopharmacology 132 (2010) 369–383
cyclosporin. TN is a very potential candidate to be considered as one
of DMARDs in the treatment of autoimmune diseases, especially
rheumatoid arthritis (Lai, 2002). The stem extract of S. cepharantha
Hayata (SC) was evaluated for its toxicity, bacteriostatic, antiphlogistic
and antalgic activity. For toxicity, SC administered to mice by
i.v. and i.p. routes in solution in physiological serum (water containing
9 g/L of NaCl) is well tolerated and LD 0 (maximum non-lethal
dose) was found higher than 500 mg/kg. SC exhibits a bacteriostatic
activity against Gram (+) and Gram (−) bacteria. For instance
the MIC values are 2 mg/mL on Staphylococcus aureus London and
44 mg/mL on a strain of Proteus. The antiphlogistic activity of SC
was studied on female rats by using phenylbutazone as a positive
control and inhibits in a statistically significant manner the development
of the carrageen oedema at 100 mg/kg, the action being
maximum 3 h after administration. The antalgic activity was carried
out by i.p. administration of SC and aspirin (standard) to male
mice of 0.2 mL of an aqueous solution of acetic acid (30 g/L) and
showed significant results (Debat et al., 1980). Two aporphine alkaloids,
corydine (21) and atherospermidine isolated from ethanolic
extract of the stems of S. dinklagei Diels showed DNA damaging
activity (Goren et al., 2003). Levo-tetrahydropalmatine (l-THP), an
alkaloid constituent found in many plants of genus Stephania produced
a rightward and downward shift in the dose–response curve
for cocaine self-administration and attenuated cocaine-induced
reinstatement. l-THP also reduced food-reinforced responding and
locomotor activity (Mantsch et al., 2007). The effects of a leaf extract
of S. hernandifolia on testicular activities in albino rats at the dose
of 2 g or 4 g of leaves/mL distilled water/100 g body weight/day
for 28 days was studied. Treatment with both doses resulted in
significant reduction in relative weight in the testis, the seminal
vesicles, the prostate, and the epididymis without any significant
change in the liver and kidney weight. The extract reduced the
activities of testicular androgenic key enzymes and plasma level of
testosterone along with inhibition of spermatogenesis without any
induction of hepatic and renal toxicity (Ghosh et al., 2002; Jana et al.,
2003).
4.21. Toxic effects
Apart from various medicinal uses, rare plants of the genus
Stephania have been reported for their acute toxic effects. The
oral administration of aqueous extract of wet and dry root tuber
of Stephania cepharantha Hayata showed acute toxicity with LD 50
value of 41.4 g/kg and 22.9 g/kg, respectively (Chen et al., 1999). S.
cephalantha Hayata (root tubers) and S. epigaea H.S. Lo (root tubers)
have been recognized as toxic plants in China (Huai et al., 2010). S.
sinica (an shu ling) was shown to have hepatotoxicity (Haller et al.,
2002).
5. Future perspectives and conclusion
Although, an extensive amount of research work has been done
on some plants of this genus to date, but a large number of species
are still chemically and/or pharmacologically unknown such as
S. brevipes Craib, S. tomentella Forman, S. glandulifera Miers and
S. capitata (Blume) Spreng. Consequently, a broad field of future
research remains possible in which the isolation of new active principles
from these species would be of great scientific merit. The
alkaloids are of particular interest as many are highly potent bioactives
and perhaps responsible for most of activities shown by
the plants of this genus. However, the mechanism of their action
is still unknown. Hence, a detailed study is required to understand
the structure–activity relationship of these constituents. As literature
showed, many plant extracts having cytotoxic activity, hence,
the particular constituent responsible for the activity may be isolated
for further process. In addition, some plant extracts were only
screened for their preliminary in vitro activities, so, the advance
clinical trial of them deserves to be further investigated. Herein,
we described the possible applications in clinical research but further
investigations on phytochemical discovery and subsequent
screening are needed for opening new opportunities to develop
pharmaceuticals based on Stephania constituents.
Acknowledgements
This work was financially supported by UGC New Delhi under
the Dr. D.S. Kothari Post Doctoral Fellowship Scheme. The authors
pay their sincere thanks to editor and referees of the journal, for
their valuable suggestions to improve this article.
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