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FITOTERAPIA - Es - Fumaria - Bioq 6 - Todas As Especies
FITOTERAPIA - Es - Fumaria - Bioq 6 - Todas As Especies
PII: S0367-326X(20)30279-3
DOI: https://doi.org/10.1016/j.fitote.2020.104697
Reference: FITOTE 104697
Please cite this article as: R. Zhang, Q. Guo, E.J. Kennelly, et al., Diverse alkaloids and
biological activities of Fumaria (Papaveraceae): An ethnomedicinal group, Fitoterapia
(2019), https://doi.org/10.1016/j.fitote.2020.104697
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ethnomedicinal group
Ruifei Zhanga,b, Qiang Guoc, Edward J. Kennellya,d,e, Chunlin Longa,f*, Xingyun Chaib*
a
College of Life and Environmental Sciences, Minzu University of China, Beijing 100081, China
b
Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica,
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c
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences,
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Peking University, Beijing 100191, China
d
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Department of Biological Sciences, Lehman College, City University of New York, Bronx, NY
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10468, USA
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e
PhD Program in Biology, Biochemistry, and Chemistry, The Graduate Center, City University of
f
Key Laboratory of Ethnomedicine (Minzu University of China), Ministry of Education, Beijing
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100081, China
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*
Correspondence to:
Chunlin Long, long@mail.kib.ac.cn;
Xingyun Chai, xingyunchai2020@yeah.net
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Graphical abstract
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Abbreviations
AChE: acetylcholinesterase; ALT: alanine transaminase; ALP: alkaline phosphatase; AST: aspartate
GPx: glutathione peroxidase; MDA: malondialdehyde; o-CA: o-coumaric acid; p-CA: p-coumaric
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Abstract
Fumaria species, commonly known as fumitory or earth smoke, are considered weeds in many
regions. However, several Fumaria species have long been used in folk medicine, such as F.
capreolata L., F. densiflora DC., F. indica (Hausskn.) Pugsley, F. officinalis L., F. parviflora Lam.,
Fumaria species have been investigated. Phytochemical studies on Fumaria species revealed the
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protoberberines, and spirobenzylisoquinolines (SBIs) are the major alkaloids in the genus Fumaria.
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The plants biosynthesize a diverse group of biologically active isoquinoline alkaloids, and these
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may help to explain the use of various Fumaria species in folk medicine. Pharmacological studies
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revealed a broad spectrum of bioactivities such as hepatoprotective, anti-inflammatory,
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antimicrobial, antioxidant, and antitumor activities. We found 159 articles published from 1969–
2019 by searching the keyword “Fumaria” using databases such as SciFinder, Google Scholar, and
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PubMed. Based on our reading of these papers, Fumaria species appear to be a source of bioactive
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pharmacokinetics, clinical efficacy, quality control, and toxicology are discussed in this review.
alkaloid
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1. Introduction
The genus Fumaria L., belonging to the poppy family (Papaveraceae), possesses about 60
species. The majority of them are slightly floppy, delicate, hairless annuals with finely divided
leaves and small, tubular, red to pink or whitish flowers [1,2]. There are many synonyms for
Fumaria species with one source listing 386 names [3–5]. Fumaria species are named fumitory,
earth smoke, fumes, or wax dolls, alluding to the smoke-like odor and other morphological
characters [6]. The botanical identification of Fumaria species is difficult due to the interspecific
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hybridization and changes in the herbarium specimens during drying [7]. The native range of
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Fumaria species is from Europe to central Asia and North Africa. These countries include the U.K.,
Turkey, Iran, Pakistan, India, and Afghanistan [6,8,9], and two species in the west of China [10].
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The ethnobotany, phytochemistry, and pharmacology of about 24 Fumaria species have been
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investigated. Although they are often regarded as weeds [6], several of them have long been used in
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vaillantii. These herbs have been used medicinally in folk as antihypertensive, diuretic,
Recent studies revealed that the bioactivities of Fumaria species, such as hepatoprotective,
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mainly due to the isoquinoline alkaloids. How do these structurally diverse alkaloids correlate with
different biological targets? We critically examine whether the ethnomedicinal uses of Fumaria
No comprehensive review on the genus Fumaria has been performed to date. However, we
have reviewed the pharmacology of other Papaveraceae alkaloids, including Bocconieae [15],
Corydalis [16], Dactylicapnos [17] Hypecoum [18], and Meconopsis [19], and this extensive
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knowledge base has helped to inform our current review. This Fumaria review examines the
ethnobotany, phytochemistry, and pharmacology of the species by focusing on the diverse alkaloids
In 1753, Linnaeus established the genus Fumaria in his book Species Plantarum. He derived
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the name from the Latin fumus terrae, which means the smoke of the earth [6]. Fumaria species
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have been called earth smoke, deriving from an early European legend that fumitory was created by
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vapor rising from the earth [2]. Other common names for Fumaria species include beggary,
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fume-of-the-earth, fumiterre, fumusterre, God‟s fingers and thumbs, snapdragon, and wax dolls [11].
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Despite their delicate appearance, Fumaria taxa are often regarded as noxious weeds capable of
strangling entire crop fields and grow well on nutrient-deficient soils as their popular name beggary
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implies [20]. Fumaria species have been associated with witchcraft and superstition in Europe from
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the 5th century AD. The leaves were burned for their smoke, which was believed to possess the
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power to expel and protect against evil spirits and spells [2,21]. Fumaria officinalis has been used
in Europe to curdle milk, and its flowers were once used to make a yellow dye for wool [2].
Several Fumaria species have long been used in folk medicine, including F. capreolata, F.
densiflora, F. indica, F. officinalis, F. parviflora, and F. vaillantii. They are traditionally used as an
antihypertensive, digestive, diuretic, hepatoprotection, laxative, and tonic, and to treat arthritis,
gallstones, and skin rashes [11–14]. The whole plant of Fumaria species has a medicinal application
as a blood purifier and cosmetics, and the leaves are considered to be the most active part [12].
Among these medicinal species, F. indica, F. officinalis, and F. parviflora are most popularly used.
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Fumaria indica is one of the most commonly used herbs in Ayurvedic, Unani, and other
traditional medicine systems in South Asia [22]. It is commonly known as “Pitpapra” in India, and
as “Shahtra papra” in Pakistan. Its medicinal values are often mentioned in classical Ayurvedic texts
like Charak Samhita, Dhanvantari Nighantu, and Bhava Prakash. In ethnomedicinal systems of
India and Pakistan, F. indica is commonly used for its anthelmintic, diuretic, diaphoretic, laxative,
cholagogue, stomachic, and sedative activities [23–28]. It is also used to purify blood in liver
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In Europe, the use of F. officinalis as medicine began in the late Middle Ages, although it was
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known since antiquity. In 17th century Europe it was considered good for the eyes [29]. The juice
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from F. officinalis leaves was decocted or distilled and added to syrups and essences, to treat liver
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disorders, urolithiasis, gout, yellow jaundice, plagues and pestilence, and skin diseases [2].
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Furthermore, dried Fumaria seed powder along with water and rose honey and as employed for
melancholia. Also, smoking the dried leaves, in the manner of tobacco, was used to treat head
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disorders.
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Herba, and it is an ingredient of preparations used mainly for gastrointestinal and biliary tract
disorders [29]. But various folk traditions throughout Europe ascribed to it a multitude of uses:
infections. In Sicily, it was used to treat skin blemishes, and in Britain into the modern era as an
eyewash to treat conjunctivitis [29]. In North America, during the late 19th century, the fresh green
leaves were prescribed for their tonic properties [2]. The flowers and tops were also macerated in
wine for the treatment of dyspepsia. Since 1963 F. officinalis has been marketed as an herbal
medicine in France [29]. Fumaria products in France and Spain are marketed as a digestive aid, in
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Austria it is sold for the treatment of dyskinesia of the biliary duct, and in Germany it is sold as an
herbal tea.
3. Chemical constituents
Phytochemical studies on Fumaria species have revealed their chemical components, including
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amino acids [30–33]. As a member of the Papaveraceae family, which is famous for abundant and
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unique alkaloids [15–19], the genus Fumaria possesses a variety of alkaloids mainly consisting of
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benzylisoquinolines, as shown in Figure 1.
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Figure 1 Possible biosynthesis pathway for isoquinoline alkaloids in Fumaria species based on the work by Beaudoin and Facchini [109].
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3.1 Alkaloids
A detailed inventory of 135 alkaloids isolated from Fumaria species during 1969–2019 is listed
in Table 1, including protoberberines and berberines (I, 1–24), benzylisoquinolines (II, 25–34), SBIs
(III, 35–49), classical PTIs (IV, 50–65), secophthalideisoquinolines (V, 66–89), indenobenzazepines
(VI, 90–95), protopines (VII, 96–101), benzophenanthridines (VIII, 102–108), aporphines (IX,
109–117), and others (X, 118–135). The structures of these compounds are shown in Figure 2.
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Table 1 Alkaloids isolated from Fumaria species.
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No Name (synonym) Class Parts of the plant Species (references)
1 (+)-Stylopine I Aerial parts -p F. vaillantii Loisel. (34)
2 (+)-Scoulerine I /1) F. officinalis L. (35)
3 (−)-Sinactine I / F. officinalis (36,37), F. macrocarpa Parl.
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(38)
4 (+)-Tetrahydropalmatine I Aerial parts F. bastardii Boreau (39)
5 (−)-Cheilanthifoline I Aerial parts F. vaillantii (40)
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No Name (synonym) Class Parts of the plant Species (references)
11 Coptisine I Aerial parts F. agraria (3), F. capreolata (3,44,45), F.
densiflora DC. (56–58), F. judaica (59), F.
kralikii (46), F. muralis Sond. ex W.D.J. Koch
(3), F. officinalis (3), F. parviflora (3,46), F.
schrammii (60), F. sepium (43), F. vaillantii
(3)
Cell extract F. capreolata (53)
Twigs and leaves F. parviflora (47)
/ F. indica (61), F. macrocarpa (38)
12 Berberine I Aerial parts F. kralikii (46)
Twigs and leaves F. indica (22)
13 Palmatine I Aerial parts F. densiflora (56,58), F. parviflora (3)
14 Dehydrocheilanthifoline I Cell extract F. capreolata (53)
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/ F. indica (22,62), F. parviflora (63,64)
15 Protoberberine I Aerial parts F. bastardii (14,), F. capreolata (14,)
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16 Coptisine chloride I / F. indica (22,62)
17 Berberine iodide I Leaves -p F. indica (65)
18 (−)-Canadine I Aerial parts F. kralikii (46)
19 (S)-cis-N-Methylstylopine I Aerial parts F. agraria (3), F. capreolata (3), F. densiflora
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(3), F. muralis (3), F. officinalis (3), F.
parviflora (3), F. vaillantii (3)
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iodide
24 N-Methyl-5-hydroxystylop I Aerial parts F. densiflora (67)
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ine chloride
25 Fuyuziphine II / F. indica (22,25,68)
26 (+)-Coclaurine II / F. indica (61), F. parviflora (63), F. vaillantii
(40,69)
27 (−)-Norjuziphine II Aerial parts F. vaillantii (40), F. densiflora (67)
28 Fumarizine II Aerial parts F. indica (22)
29 Ledecorine II / F. vaillantii (40,69)
30 (+)-Juziphine II Aerial parts F. bastardii (39), F. vaillantii (40)
31 (+)-Reticuline II Cell extract F. capreolata (53)
32 N-Methylcoclaurine II Cell extract F. capreolata (53)
33 Fumaflorine II Aerial parts F. densiflora (56,57)
34 Fumaflorine methyl ester II Aerial parts F. densiflora (56,57)
35 (−)-Norfumaritine III Leaves F. kralikii (70)
2)
36 Densiflorine III Aerial parts F. densiflora (58), F. sepium (43)
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No Name (synonym) Class Parts of the plant Species (references)
37 (+)-Fumariline III Aerial parts F. agraria (3,43), F. bastardii (14,39), F.
capreolata (3,14, 71), F. densiflora (3,57), F.
faurei (Pugsley) M. Linden (71), F.
macrocarpa (72), F. muralis (3), F. officinalis
(3,71), F. parviflora (3,46,71), F. petteri
Rchb. (71), F. sepium (71), F. vaillantii (3,40)
Flowers and fruits F. rostellata Knaf (73)
Leaves F. muralis (74)
Twigs and leaves F. parviflora (47)
Seeds F. indica (22,75,76)
Twigs and leaves F. capreolata (41)
/ F. schrammii (52)
38 Dihydrofumariline III Aerial parts F. bastardii (14), F. parviflora (46), F. petteri
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(71), F. schrammii (60)
/ F. officinalis (37)
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39 (+)-Parfumine III Aerial parts F. agraria (3,43,71), F. bastardii (71), F.
(fumarilicine) -p capreolata (3,71), F. densiflora (3,57,71), F.
faurei (71), F. indica (22,77), F. judaica (59),
F. macrocarpa (72), F. muralis (3), F.
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officinalis (3,71), F. parviflora (46,71), F.
petteri (71), F. schrammii (60), F. sepium
(43,71), F. vaillantii (3,40,78)
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No Name (synonym) Class Parts of the plant Species (references)
44 (–)-Fumarophycine III Aerial parts F. agraria (3), F. bastardii (14), F. capreolata
(3,14, 71), F. densiflora (3,57), F. faurei (71),
F. kralikii (46), F. muralis (3), F. officinalis
(3,71), F. petteri (71), F. vaillantii (3)
Leaves F. muralis (74)
/ F. parviflora (31)
45 (−)-O-Methylfumarophyci III Aerial parts F. bastardii (39), F. densiflora (3), F. kralikii
ne (46), F. muralis (3), F. officinalis (3), F.
vaillantii (3)
46 Raddeanine III Aerial parts F. indica (22,27)
47 (−)-Fumaritine N-oxide III Aerial parts F. indica (22,77), F. sepium (43)
F. kralikii (46,79), F. officinalis (37)
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48 (+)-Papracinine III Aerial parts F. indica (22,77)
49 (−)-Fumaricine N-oxide III Aerial parts F. densiflora (67)
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50 (+)-Bicuculline IV Aerial parts F. bastardii (39), F. vaillantii (40,84)
Twigs and leaves
-p F. barnolae (42,64), F. capreolata (41)
/ F. asepala (49), F. bracteosa Pomel (85), F.
indica (86), F. parviflora (41)
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51 (+)-Corlumine IV / F. officinalis (36,87)
52 (+)-Papraine IV / F. indica (22,88)
(+)-Corlumidine IV Aerial parts F. parviflora (89)
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54 (−)-Corledine IV Aerial parts F. parviflora (89), F. vaillantii (40,84)
55 (+)-Egenine IV Aerial parts F. vaillantii (84)
(−)-Corlumine
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/ F. parviflora (63)
72 Narlumicine V Stems F. indica (22,92)
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73 Adlumidiceine V Aerial parts F. capreolata (3), F. densiflora (56,68), F.
-p kralikii (46), F. officinalis (3), F. parviflora
(3,46), F. schrammii (60), F. vaillantii (3,40)
Twigs and leaves F. parviflora (47)
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74 Adlumiceine V Aerial parts F. agraria (3), F. capreolata (3), F. officinalis
(3), F. parviflora (3), F. schrammii (60), F.
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vaillantii (3)
75 N-Methylhydrasteine V Aerial parts F. vaillantii (40)
/ F. densiflora (91), F. officinalis (37), F.
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parviflora (64)
76 Adlumiceine methyl ester V Aerial parts F. vaillantii (78)
77 N-Methylhydrastine V Aerial parts F. vaillantii (78)
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methyl ester
78 Narceimine V Leaves F. indica (66)
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95 Lahorine VI / F. parviflora (34,63)
96 Protopine VII Aerial parts F. agraria (3,71), F. bastardii (60), F.
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capreolata (3,71), F. densiflora (3,71), F.
-p faurei (71), F. judaica (59), F. kralikii (46), F.
muralis (3), F. officinalis (3,71), F. parviflora
(3,71), F. petteri (71), F. schrammii (52), F.
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sepium (43,71), F. vaillantii (3,40)
Cell extract F. capreolata (53)
Flowers and fruits F. rostellata (73)
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97 Cryptopine (cryptocavine) VII Aerial parts F. agraria (3), F. capreolata (3), F. densiflora
(3,71), F. faurei (71), F. indica (22,27), F.
kralikii (46), F. muralis (3), F. officinalis
(3,71), F. parviflora (3,71), F. petteri (71), F.
schrammii (60), F. vaillantii (3)
Flowers and fruits F. rostellata (73)
/ F. asepala (45,49), F. macrocarpa (38), F.
schleicheri (80)
98 β-Allocryptopine VII / F. capreolata (44,45), F. judaica (51)
99 Izmirine VII / F. parviflora (103)
100 Vaillantine VII Roots F. vaillantii (90)
101 Pseudoprotopine VII / F. indica (55)
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No Name (synonym) Class Parts of the plant Species (references)
102 Dihydrosanguinarine VIII Aerial parts F. agraria (43,71), F. bastardii (71), F.
capreolata (71), F. densiflora (71), F. faurei
(71), F. macrosepala (71), F. officinalis (71),
F. parviflora (71), F. petteri (71), F. sepium
(71), F. vaillantii (40)
103 Oxysanguinarine VIII Aerial parts F. vaillantii (40), F. parviflora (46)
Seeds F. indica (22)
104 (−)-8-Methoxydihydrosang VIII Aerial parts F. vaillantii (40)
uinarine Seeds F. indica (22)
105 8-Acetonyldihydrosanguin VIII Aerial parts F. vaillantii (40)
arine
106 Sanguinarine VIII Aerial parts F. capreolata (45), F. parviflora (46), F.
schrammii (60)
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Twigs and leaves F. barnolae (41), F. capreolata (41)
Cell extract F. capreolata (53)
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/ F. asepala (45,49), F. indica (61), F. vaillantii
-p (40)
107 Chelerythrine VIII Aerial parts F. schrammii (60)
108 Norsanguinarine VIII Aerial parts F. vaillantii (40)
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Seeds F. indica (54,66)
/ F. indica (75)
109 (+)-Isoboldine IX Aerial parts F. agraria (43), F. vaillantii (40)
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134 Densiflorine2) X / F. densiflora (106)
135 Choline X Cell extract F. capreolata (53)
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1)
No data collected; 2) Homonym.
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Figure 2 Continued
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Figure 2 Continued
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3.1.1 Protoberbines and berberines
Protoberbine and berberine alkaloids, consisting of 24 members, are a large group of alkaloids
from Fumaria species. These compounds are important intermediates for the biosynthesis of
alkaloids in the genus Fumaria (Figure 1). Protopines are known to be formed by oxidative ring
salts are likely to be the biogenetic precursors of SBIs [79]. However, there are yet no C-13
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studies on these compounds showed that the quaternary ammonium salts, an alkyl substituent at
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C-13, and a methylenedioxy group at C-3 and C-4 enhanced antibacterial activity [9]; the size of
functional groups located at C-8 and C-13 and the oxygenated substituents and their location at A
-p
and D rings are relevant to the antiviral activity [107,108].
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3.1.2 Benzylisoquinolines
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Ten benzylisoquinoline alkaloids have been isolated and identified from the genus Fumaria
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(Table 1). Benzylisoquinolines are the basic skeleton of the alkaloids from Fumaria species. For
example, (S)-reticuline (31) is an essential biogenetic processor for many alkaloids such as
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berberine (12), protoberberine (15), protopine (96), sanguinarine (106), corytuberine (111), and
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salutaridinol (132) [109–111]. However, few studies were conducted on the biosynthesis pathway of
unique benzylisoquinoline alkaloids from Fumaria species, such as fumaflorine (33) and its methyl
ester (34). Compounds 33 and 34, isolated from the aerial parts of F. densiflora, possess an unusual
carbonyl group located at C-1 and a carboxyl group at C-8 [56,57]. Fuyuziphine (25), isolated and
identified from the whole plant of F. indica [25], has an inhibitory activity to the spore germination
of some plant pathogenic fungi [68]. Nevertheless, these investigations provide only preliminary
information about benzylisoquinoline in the genus Fumaria. More studies on bioactivity screening
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3.1.3 Spirobenzylisoquinolines
SBI alkaloids are almost exclusively found in the genera Fumaria and Corydalis [106], including
15 analogs reported in Fumaria species. SBIs isolated from Fumaria species usually bear only one
oxygenated substituent in the form of a hydroxyl, an acetate, or a ketone located at C-8. In contrast,
those found in Corydalis species usually have two oxygenated substituents located at C-8 and C-13
in ring C [79]. An exception among these SBI alkaloids is raddeanine (46), which occurs in the
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aerial parts of F. indica, bearing two hydroxyl groups both at C-8 and C-13 [22,27]. The biogenetic
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precursor of SBIs may be a C-13 methylated dihydroprotoberberine N-metho salt. However, such an
-p
analog has not been isolated from Fumaria species up to now [79]. (+)-Parviflorine (41), isolated
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from F. parviflora, is the first glycosidic SBI, which corresponds to (+)-parfurnine-β-D-glucoside
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[81]. There are a pair of epimers for dihydrofumariline (38), 38A has the signal δH 4.82 ppm for the
hydrogen at C-8, and 38B has a signal at δ 5.52 for the hydrogen at C-8 trans to the N-methyl group
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[37]. (−)-Norfumaritine (35) is the second N-norspiroisoquinoline which has no N-methyl found in
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nature, and the first is (+)-lederine [70]. Moreover, several SBIs are unstable. A tautomeric form of
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fumariline (37) and three tautomeric structures of parfumine (39) were found in F. indica [86,112].
Compound 37 also showed potential central nervous system depression effects in rats, producing
hypnosis [76].
alkaloids. Unlike most protoberberine alkaloids which usually possess the S-configuration at C-1,
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PTIs in Fumaria species (50–65) do not show stereochemical preference at either C-1 or C-8 [42],
although protoberberines are believed to be the biogenetic processor of PTI [113]. (+)-Egenine (55),
the first natural PTI hemiacetal, was isolated from F. vaillantii and indicated to be an intermediate
in the conversion of a berberine alkaloid into (+)-bicuculline (50) [84]. Compound 50 is a major
constituent in several Fumaria species such as F. asepala [49], F. barnolae [42,64], F. bastardii [39],
F. bracteosa [85], F. capreolata [41], F. indica [86], F. parviflora [41], and F. vaillantii [40,84].
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central nervous system [85], and its enantiomer (–)-bicuculline (57) showed in vitro antiviral potent
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in HepG2.2.15, a hepatitis-B virus (HBV)-expressing cell line [114].
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3.1.5 Secophthalideisoquinolines
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Secophthalideisoquinoline alkaloids from the genus Fumaria, having a seco-ring B, include enol
lactones (66–72), keto acids (73–77), diketo acids (78–82), and ene-lactams (83–89) subgroups
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[115]. The ene-lactams subgroup is also called narceineimides. Inspection of the structures of
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Fuamria species, it suggests that the secophthalideisoquinolines are essential intermediates in the
metabolic sequence [105]. A Hofmann elimination could supply classical PTIs with an open ring,
such as 75. Then, 75 or closely related alkaloids such as 84, undergoing oxidative cleavage,
originated a unique amino acid fumariflorine (121). Although Z- and E- 83 were isolated and
Photoirradiation of either the Z- or the E-isomers could provide the other isomer [40]. Adlumiceine
methyl ester (76), N-methylhydrastine methyl ester (77), and parfumine (39) were tested in PC3 and
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3.1.6 Indenobentazepines
Lahoramine (94) and lahorine (95), the first members of indenobenzazepines group alkaloids, are
most probably derived from SBI [34]. It is known that Fumaria species can convert
benzylisoquinolines into protoberberines, which in turn are the probable precursors of SBI [99].
Bulgaramine (91) occupies a central position in the biogenetic scheme linking SBIs with
indenobentazepines. In the plant, the ketonic SBI alkaloid parfumidine (40) may reduce to the
of
alcohol fumaricine (43), which could supply the aziridinium cation. Proton loss from aziridinium
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cation with fission of the aziridinium ring may yield 91, which can undergo oxidation and
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aromatization to lahoramine (94) [99]. Moreover, fumarofine (90), fumaritridine (92), and
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fumaritrine (93), first isolated from F. rostellata and wrongly identified as SBI, were later revised as
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indenobenzazepines [98,100].
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3.1.7 Protopines
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Although there are only six protopine-type alkaloids (96–101) in Fumaria, they are found in most
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of the studied species, indicating they are one of the major groups of alkaloids in this genus. For
example, protopine (96) was isolated from 22 of the 24 investigated Fumaria species. The
pharmacology of 96 has been investigated, and it protected oxidative stress-induced cell from death
activities [116]. It was also studied for its muscle relaxant, hydrocholeretic and antiviral effects
[76,117], revealing the mechanism associated with inhibiting calcium, sodium, and potassium
channels [76]. Toxicological study on 96 showed that it was devoid of any acute toxicity up to a
dose of 50 mg/kg (i.p.) in rats [112]. Besides, the biosynthesis of 96 in F. rostellata and F. officinalis
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cell suspensions was investigated. F. rostellata 5FRL14 cell suspension was selected as the best
producer [118]. The achieved volumetric yield was 49.6 mg/L/day, and the system productivity
3.1.8 Benzophenanthridines
of
various pharmacological properties such as antitumor, antimicrobial, and anti-inflammatory
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activities [119]. Sanguinarine (106), a representative member of QBAs occurred in different tissues
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of F. asepala [45,49], F. barnolae [41], F. capreolata [45], F. indica [61], F. parviflora [46], F.
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schrammii [60], and F. vaillantii [40], showed antioxidant and antiplatelet activities to induce the
lP
keratinocyte cells, AGS human gastric cancer cells, and MDA-231 human breast cancer cells
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[14,73,120,121].
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3.1.9 Aporphines
Aporphines (109–116), another medicinally important group of natural alkaloids, possess nine
analogs isolated from nine Fumaria species including F. agraria [3], F. barnolae [41] F. capreolata
[41], F. densiflora [3,57], F. indica [22,77], F. muralis [3], F. officinalis [3], F. parviflora [53], F.
vaillantii [3,40]. Five of these aporphines were isolated from F. agrarian. It was reported that the
occurrence of aporphines from F. agraria is unusual in the genus Fumaria [43]. Nevertheless, this
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Fumariflorine (121) is appreciably different in structural features from other typical PTIs. It
was considered as the first representative of a new but small group of isoquinoline alkaloids,
namely the O-(β-dimethylamino-ethyl) benzoic acids. Fumariflorine ethyl ester (122) isolated from
F. parviflora was probably an artifact, due to the ethyl esters are uncommon among alkaloids and
ethanol was used during the isolation process [64,105]. Four members of morphinandienone-type
alkaloids (129–132) occurred in Fumaria species. Rhoeagenine (133), isolated from the leaves and
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twigs of F. parviflora, was the first rhoeadine alkaloid isolated from Fumaria species [63]. The
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rhoeadine-type alkaloids are biogenetic derivatives of protopines. Densiflorine (134), a unique
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seco-SBI alkaloid, was isolated from F. densiflora in 1984 [106].
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Quantitative analyses of many alkaloids from Fumaira species have also been widely studied.
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Although there have been 135 alkaloids isolated from Fumaria, their total yield per species is
typically less than 1% w/w [14]. For example, the total quinolizidine contents were 0.43% for F.
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capreolata and 0.52% for F. bastardii. Total alkaloids, 0.88% for F. sepium and 0.83% for F.
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agraria, were obtained from the aerial parts of these species [43]. In F. macrocarpa, a mixture of
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alkaloids (0.78%) was obtained, and the major compound was 96 [40]. Furthermore, based on a gas
chromatography-mass spectrometry analysis of alkaloid contents in ten Fumaria species (F. agraria,
parviflora, F. petteri subsp. calcarata, and F. sepium), they were classified into three groups [71].
stylopine (1, 6, racemic or scalemic mixture), which is the biogenetic precursor of 96, and 96 is the
main alkaloid (66–79% in total alkaloid) in these species. Species in group II (F. densiflora, F.
faurei, F. officinalis, F. parviflora, and F. petteri subsp. calcarata), with 96 as the major alkaloid,
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(3) which is the biogenetic processor of 97. While the presence of stylopine was particularly
significant in group I, SBI type alkaloids were present in both groups I and II but were particularly
abundant in group II. A rather different alkaloid profile was observed for group III (F. macrosepala).
Along with bicuculline (50, 57, racemic or scalemic mixture) and adlumine (61, 62, racemic or
scalemic mixture), the PTI alkaloids in F. macrosepala account for more than 65% of the total
tertiary bases, while these analogs are not abundant in other Fumaria species.
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3.2 Other chemical constituents
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Phytochemical investigations revealed the presence of various non-alkaloid constituents:
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steroids, e.g. β-sitosterol, stigmasterol, and campesterol [26]; organic acids, e.g. citric, coumaric,
lP
ferulic, fumaric, malic, 3-hydroxybenzoic, protocatechuic, and caffeic acid (and its methyl ester) [3];
esters, likely methyl caffeate and a phthalic acid ester [14]. Moreover, non-alkaloid constituents
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against M. incognita, was isolated from the n-hexane fraction of the F. parviflora roots [122].
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Fumaric acid and its conjugates were reported to have hepatoprotective, antipruritic, antioxidative,
and anti-inflammatory activities. Fumarates may also modulate the central nervous system function
[123]. F. indica was found to contain 0.45% of free fumaric acid and 0.35% of fumaric acid
conjugates (dimethyl fumarate) [117]. Phenolic acids of 5 Fumaria species (F. densiflora, F. kralikii,
F. officinalis subsp. cilicica (Hausskn.) Lidén, F. parviflora, and F. rostellata) were quantified by
high-performance liquid chromatography. o-Coumaric acid (o-CA, 14.23 mg/g) and p-coumaric
acid (p-CA, 12.44 mg/g) were the dominant phenolic acids in F. cilicica, trans-cinnamic acids (4.32
mg/g) and caffeic acids (3.71 mg/g) in F. densiflora, o-CA (6.35 mg/g) and p-CA (5.44 mg/g) in F.
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kralikii, o-CA (8.48 mg/g) and p-CA (8.80 mg/g) in F. rostellata, and caffeic acid (5.18 mg/g) was
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triol-3,2-n-di-octadecanoyl-1-n-octadeca-9‟,12‟-dienoate, and n-tetradecanyl
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n-octadec-9,12-dienoate [126]. Jameel and colleagues reported seven compounds from the aerial
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parts of F. parviflora [31], including (5αH,11αH)-8-oxo-homoiridolide named fumaria
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homoiridolide; n-docosanyl-2-O-β-D-glucopyranosyl salicylate, a phenolic ester glycoside,
lP
2-methyl-6-hydroxymethylenedodecan-10-oyl-12,15-olide14-O-β-D-xylopyranoside, a
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α-D-glucopyranosyl-(2→1‟)-α-D-glucopyranoside, an α-D-diglucoside.
Although kaempferol is found in many species in the Papaveraceae, Fumaria species make
unique to Fumaria species, when compared with other closely aligned genera, and thus are useful
chemotaxonomic markers [127]. The total flavonoid contents of F. cilicica, F. densiflora, F. kralikii,
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In general, Fumaria species show a wide diversity of chemical structures, especially with regards
to the isoquinoline alkaloids. SBIs are unique components in the genus Fumaria, producing
aporphines, and morphinandienones are small groups of alkaloids in the genus Fumaria, they are
also major components and enrich the structural diversity. Nevertheless, the chiral carbons in SBI
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and PTI alkaloids make it difficult to identify the absolute configurations. The stereochemistry of
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some compounds such as 71, 72, 87, and 88 need to be further studied. The biosynthesis and
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biological assays of unique isoquinolines in Fumaria species are also necessary.
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4. Pharmacological effects
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hepatocarcinogenesis rat model treated with N-nitrosodiethylamine (200 mg/kg, i.p.) and CCl4 (3
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mL/kg/week, i.h., 6 weeks), by suppressing the tumor burden and reversing the levels of certain
marker hepatic cancer enzymes that [130]. F. indica extracts (200 and 400 mg/kg/day, p.o., for 20
weeks) raised the body weight, with values of 212.0 and 238.0 g, respectively. While final
bodyweight of the rats in the model group and positive control group (silymarin, 200 mg/kg/day)
were 172.0 and 240.0 g, respectively. At the same time, the rat liver weight was reduced by the
treatment with F. indica extracts (8.03 g for 200 mg/kg/day and 7.51 g for 400 mg/kg/day) and
silymarin (7.31 g, 200 mg/kg/day), comparing with the model group (9.82 g). F. indica extracts also
reversed the levels of liver cancer markers such as aspartate transaminase (AST), alanine
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transaminase (ALT), alkaline phosphatase (ALP), γ-glutamyl transferase, total bilirubin level, α-feto
the active substance in a 50% ethanol-aqueous extract of F. indica, subfractions including hexane,
chloroform, and butanol fractions (100 and 400 mg/kg/day) were tested for a hepatoprotective effect
against D-galactosamine-induced liver damage [131]. The butanol fraction, in which 96 was
quantified as a major compound (0.2 mg/g), was found to be the most effective. Compound 96 at a
dose of 10–20 mg/kg (p.o.) was equally effective as the standard drug silymarin (25 mg/kg, p.o.).
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Moreover, in the anesthetized dog, 96 at the dose of 5 mg/kg (i.v.) produced a 2.5-fold rise in bile
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flow at 1 h after drug administration [112]. In normal rat hepatocytes, monomethyl fumarate, a
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non-alkaloid compound isolated from F. indica, showed a dose-dependent (10–100 μg/mL)
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hepatoprotection against toxicity induced by thioacetamide (20 μg/mL). In rats, monomethyl
lP
fumarate at a dose of 50 mg/kg (p.o.) protected against hepatic injury induced by CCl4 (1.25 mL/kg),
paracetamol (3 g/kg), and rifampicin (1 g/kg), with an equivalent effect as the standard drug
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silymarin (100 mg/kg, p.o.). A toxicological study showed that monomethyl fumarate has no
ur
toxicity up to the dose of 1 mg/mL in vitro and up to 50 mg/kg (p.o.) in rats [61]. In general, both
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crude extracts and phytochemicals from F. indica showed in vitro and in vivo hepatoprotective
effects against chemical-induced liver injury. Thus, these studies provide evidence for the
ethnomedicinal uses of Fumaria species for hepatoprotection. Nevertheless, a single dose was used
in some studies, thus making it difficult to know if there is a dose-dependent activity. More
further studies.
Ethanol-aqueous (1:1) extract from the whole plant of F. parviflora, with 96 and fumaric acid as
major compounds, protected from the nimesulide-induced injury both in vitro and in vivo [132,133].
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F. parviflora (2 mg/mL) protected primary cultured rat hepatocytes from apoptosis caused by
nimesulide (500 μM) [133]. In a further in vivo study, F. parviflora extract (200 mg/kg/day, p.o., for
5 days) showed a protective effect in rats fed with nimesulide (80 mg/kg/day, p.o., 5 days) [132].
release, caspase-9 and -3 activities, and DNA fragmentation. The pharmacological mechanism of
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another in vivo pharmacological study [134], pretreatment of mice with F. parviflora extract (500
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mg/kg, p.o.) reduced the paracetamol-induced (1 g/kg, p.o.) death rate from 100% to 50%,
-p
prolonged the sleep time induced by pentobarbital (75 mg/kg, i.p.), and increased
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strychnine-induced lethality via drug interaction. Pretreatment of rats with F. parviflora extract (500
lP
mg/kg, p.o.) prevented the paracetamol-induced (640 mg/kg, p.o.) increases of serum enzymes
levels such as ALP, glutamate oxaloacetate transaminase, and glutamate pyruvate transaminases.
na
However, it was unable to prevent the CCl4-induced rise in serum enzyme levels. The protective
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parviflora provide primary evidence for the traditional use of Fumaria species. However, the
hepatoprotective effects of the crude extract are not potent. Further, activity-guided fractionation
Hepatoprotective effects of the 80% aqueous-ethanol extracts of F. asepala and F. vaillantii (500
mg/kg, p.o.) were studied using the CCl4-induced hepatotoxicity model (2.5 mL/kg, p.o.) in rats. F.
vaillantii extracts prevented the elevation of levels of plasma malondialdehyde (MDA), liver
homogenate MDA, and enzyme levels (ALT and AST) at 29.7, 33.7, 66.9, and 60.8%, respectively
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[135]. Histopathological studies demonstrated that liver injury induced by CCl4 was reduced by the
acute administration of F. vaillantii extract. However, the reduction was not observed in the F.
asepala group. This investigation afforded preliminary data for the hepatoprotection of F. vaillantii.
More doses of this folk medicine should be evaluated in future studies. Both the methanol extracts
hepatocytes [57]. The alkaloids showed a significant cytoprotective effect even at the lowest
concentration of 1.0 mM, while the phenolic fraction exhibited no cytoprotective effect. Chloroform
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and ethyl acetate fractions of F. cilicica 85% aqueous-ethanol extract had also been evaluated for its
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hepatoprotective effect against CCl4-induced liver injury in rats, however, showed no positive
-p
activity [128].
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One major ethnomedicinal uses of Fumaria species is purifying blood in liver obstruction [28]. In
lP
officinalis, F. parviflora, and F. vaillantii had been evaluated for their hepatoprotective effects
na
against chemical toxicant-induced liver injury. Among them, F. asepala and F. cilicica showed no
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positive activities. While F. indica and F. parviflora, which are traditionally used to treat liver
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diseases in India and Pakistan folk medicine, are widely studied and show hepatoprotective
potential. There are also alkaloids and non-alkaloids, such as 96 and monomethyl fumarate
Disc-plate tests showed that more than 20 isoquinoline alkaloids from Fumaria species in Turkey
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concentration of 1 mg/mL [136]. Among the examined isoquinoline derivatives, PTIs and
tetrahydroprotoberberines are most effective, and the activity of protopines is similar to that of
epidermidis, Escherichia coli, Candida albicans, and Aspergillus niger, with a GI50 value of 5.35
μg/mL and MIC values of 250, 250, 500, and 250 μg/mL, respectively [138].
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4.2.2 Antifungal Activity
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Fuyuziphine (24) affected the spore germination of the 13 fungal species [68]. After 24 h
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incubation, Alternaria brassicicola, A. solanidid, Colletotrichum falcatum, C. gloeosporioides,
lP
Curvularia lunata, C. maculans, and Oidium erysiphoides did not germinate at a concentration of
3.19 μM; Curvularia lunata, Oidium erysiphoides, Alternaria brassicicola and A. solaniwere were
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inhibited at 2.39 μM. Germination of most of the fungi was significantly inhibited at 0.32–2.39 μM.
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Berberine iodide (17) (0–2 mg/mL), an alkaloid salt isolated from the leaves of F. indica, inhibited
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Penicillium species, and some plant pathogenic and saprophytic fungi [65]. Complete inhibition
concentration of 1.5 mg/mL. Albugo candida and Alternaria species were not affected. Protopines,
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Several Fumaria species have been used to treat malaria and other parasitic diseases in the
traditional system of medicine in India, Iran, Pakistan, and Turkey [124]. Ethanol extracts (0.81 and
Turkey were evaluated using the parasites Plasmodium falciparum and Trypanosoma
(41.65%) exerted antiplasmodial activity against P. falciparum, compared with the positive control
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artemisinin (99.70%). F. densiflora extract also showed moderate antitrypanosomal activity
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(55.40%) against T. bruceirhodesiense, as compared to the standard drug melarsoprol (99.50%).
-p
This investigation supported the ethnomedicinal uses of F. densiflora for treating malaria.
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Nevertheless, this experiment had only two doses, making it difficult to know if there is truly a
lP
dose-dependent effect. More detailed in vitro and in vivo experiments are needed.
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The roots and stem of F. parviflora extracted with four different solvents (n-hexane, ethyl acetate,
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chloroform, and methanol) showed nematicidal effects on in vitro egg hatching and in planta
mortality of Meloidogyne incognita juveniles at 50.0 mg/mL and 3000 mg/kg, respectively
[122,139]. Notably, the inhibition against egg hatching and mortality of M. incognita juveniles were
significantly increased (100%) by the most active extract, n-hexane extract of F. parviflora root.
Oral administration of 50% ethanol-aqueous extract of F. indica (100, 200, and 400 mg/kg, p.o.)
dose-dependently inhibited the inflammation in both acute and chronic rat models [26]. The 400
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mg/kg administration of F. indica produced 42.2% and 42.1% inhibition to the paw edema in rats
after 3 h treatment with carrageenan and histamine, respectively. Phenylbutazone (100 mg/kg, p.o.)
was used as a positive control, producing 44.1% and 43.2% inhibition to the paw edema in rats after
3 h treatment with carrageenan and histamine, respectively. F. indica extract (400 mg/kg/day, 7 days)
showed a 38.9% reduction in granuloma mass in a chronic condition, compared with the 40.1%
reduction afforded by standard drug phenylbutazone (100 mg/kg, p.o.). Moreover, pre-treatment
with the F. indica extract (100, 200, and 400 mg/kg, p.o.) produced 6.6–67.7% protection in
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mechanical injury, 33.9–125.1% protection in thermal induced pain, and 22.2–73.9% protection in
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the acetic acid-induced writhing test. Acetylsalicylic acid (25 mg/kg, i.p.) was used as the control,
-p
blocking the writhing response by 63.1% [26]. In another study, the anti-inflammatory activity of
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fumaric acid (1.25, 2.50, and 5.00 mg/kg/day, for 7 days, p.o.) and the ethanol extract of F. indica
lP
(100, 200, and 400 mg/kg/day, for 7 days, p.o.) was observed in carrageenan-induced edema and
cotton pellet granuloma [140]. No analgesic activity at the lowest tested dose (1.25mg/kg/day) of
na
fumaric acid was observed in the acetic acid writhing test. While all tested dose levels of F. indica
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Preparations of F. capreolata total alkaloids (12.5, 25, 50, and 100 𝜇g/mL) from the aerial parts,
an ethnomedicine used in North Africa for its gastrointestinal and anti-inflammatory activities,
dose-dependently inhibited the LPS-induced production of nitric oxide and IL-6 in RAW264.7
factors such as IL-6, IL-1β, iNOS, TNF-α, and COX-2, without affecting the viability of RAW264.7
cells. F. capreolata extract (100, 250, and 500 mg/kg, p.o.) reduced acetic acid-induced writhes and
F. indica and F. capreolata, two folk medicines traditionally used to treat gastric disorders and
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inflammation, showed anti-inflammatory and antinociceptive activities both in vitro and in vivo.
and biochemical studies may help to determine active phytochemicals and explore pharmacological
mechanisms.
The total alkaloid fraction of F. agraria aerial parts contains 41.6% protopine (96), while a basic
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subfraction contains 60.7% [104]. Both of these fractions showed antiproliferative activities against
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MCF-7 breast cancer cells, with IC50 values of 47.8 μg/mL and 17.6 μg/mL, respectively. In cancer
-p
cells, QBAs interact with DNA, induce apoptosis and cell cycle arrest, affect the cytoskeleton, and
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target important members of the signaling pathways [119]. Slaninová et al. studied sanguinarine
lP
(106) and chelerythrine (107), the best-known members of QBAs, for their in vitro anticancer
activities in numerous cancer cell lines. Compounds 106 and 107 induced apoptosis in more than
na
half of the tested cancer cell lines with IC50 values ranging at 0.3–7.3 μM and 0.4–25.0 μM,
ur
respectively [119]. It was suggested that 106 induced apoptosis in human immortalized HaCaT
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keratinocytes through an up-regulation of apoptotic proteins including Bax, Bak, and Bid,
factor-1, and enzymes in caspases family such as caspase-3, -7, -8, and -9 [129]. Moreover,
treatment with 106 (0.1–2.0 μM, for 24 h) on HaCaT cells resulted in a dose-dependent increase in
Bax level, a concomitant decrease at Bcl-2 level, and an increase at Bax/Bcl-2 ratio [129]. The
apoptosis of MDA-231 human breast cancer cells induced by 106 was blocked by ectopic
expression of Bcl-2 and cFLIPs [121]. However, the cell death induced by a combination of 106
and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was not blocked by the
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overexpression of Bcl-2 or Akt. Due to sub-lethal doses of 106 sensitized MDA-231 cells to
TRAIL-mediated apoptosis. Results indicated that combination therapy with 106 and TRAIL might
offer a good strategy for the treatment of various human tumors which are resistant to
chemotherapy or TRAIL treatment alone. Fumaria species are not ethnomedicinally used to treat
cancers. And few studies are investigating the antitumor activities of crude extracts from Fumaria
species. However, Fumaria species that contain medicinally valuable alkaloids may be a botanical
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4.5 Antioxidant activity
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The 50% ethanol-aqueous extract of F. parviflora modulated antioxidant enzymes mRNA
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expression and reduced lipid peroxidation against nimesulide-induced toxicity in rats [132].
lP
Pre-administration with F. parviflora (200 mg/kg/day, p.o., for 5 days) up-regulated the levels of
superoxide dismutase (SOD) and glutathione peroxidase (GPx) mRNA expression to 86% and 64%,
na
(55%), comparing with the model group treated with nimesulide. In another study, ethanol extract
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of F. parviflora leaves (200 mg/kg/day, p.o., for 70 days) elevated the content of SOD and GPx in
rat testicles, suggesting it ameliorated oxidative stress by decreasing lipid peroxidation and
activating antioxidant enzymes in the lead acetate-treated rats [142]. The 50% ethanol-aqueous
extract of F. indica increased the levels of SOD, catalase, and glutathione, and decreased the
formation of MDA in the rat brain [123]. Inhibitory effects of F. indica extract (100, 200, and 400
mg/kg/day, for 16 days) against MDA production in the incubated brain homogenates were in a
dose-dependent manner.
Scavenging and anti-lipoperoxidant activity of the main alkaloids (44, 45, and 96) and phenolic
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officinalis, F. parviflora, and F. vaillantii were tested [143]. All alkaloid isolates showed higher
antioxidant activity against tBH-induced lipoperoxidation than phenolic acids. On the other hand,
(DPPH) radical than the alkaloids. Moreover, 44 and caffeic acid were the most active constituents.
In another study, the phenolic constituents and antioxidant activities of extracts of five species,
including F. kralikii, F. officinalis, F. rostellata, F. schrammii, and F. thuretii Boiss. were examined
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[144]. The total phenolic content and antioxidant activity were the highest in F. officinalis, with
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quercetin (0.49 ± 0.03 mg/g), p-CA (1.10 ± 0.03 mg/g), and ferulic acid (2.35 ± 0.04 mg/g) as the
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major compounds. Ethanol extracts of four Fumaria species, including F. cilicica, F. densiflora, F.
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kralikii, and F. parviflora were partitioned into petroleum ether, chloroform, ethyl acetate, and
lP
methanol fractions [128]. Their antioxidant activities were estimated by DPPH radical scavenging
and xanthine oxidase inhibition assays at a concentration of 1000 μg/mL. As a result, the
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chloroform and ethyl acetate fractions of F. cilicica were the most effective. Alkaloid extracts of F.
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bastardii and F. capreolata both showed antioxidant activities, especially as radical scavengers
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[145]. F. bastardii and F. capreolata alkaloids exhibited inhibition of lipid peroxidation of linoleic
acid emulsion in a dose-dependent manner at 100, 300, and 500 µg/mL. Ethanol extract of F.
vaillantii showed potent antioxidant activity, including H2O2 decomposition and scavenging DPPH
radical, nitric oxide, and superoxide [146]. The 80% aqueous-methanol extract of F. parviflora
exerted DPPH radical scavenging activity with an EC50 value of 0.60 mg/mL and ferric reducing
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thuretii, and F. vaillantii have been reported to have antioxidant properties via different mechanisms
Given F. indica is traditionally used to treat constipation and diarrhea, an 80% aqueous-ethanol
extract of the whole plant was studied in vitro for its spasmogenic and spasmolytic effects [145]. F.
indica extract (1.0–5.0 mg/mL) caused a moderate degree of atropine-sensitive spasmogenic effect
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in guinea-pig ileum. In spontaneously contracting rabbit jejunum, F. indica extract (0.03–0.3
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mg/mL) caused a mild spasmogenic effect, followed by relaxation at higher doses. Activity-directed
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fractionation revealed that the spasmolytic effect was concentrated in its petroleum ether fraction. It
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caused dose-dependent (0.003–0.1 mg/mL) relaxation of the spontaneous and K+-induced
lP
contraction, thus showing 10-fold more potency than the F. indica crude extract. The
dichloromethane fraction showed activity equivalent to the crude extract, causing a dose-dependent
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(0.01–0.3 mg/mL) spasmogenic effect followed by complete relaxation at a higher dose of 0.5
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mg/mL. The ethyl acetate fraction was devoid of any spasmogenic effects but caused a
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the aqueous fraction possessed weak spasmolytic and spasmogenic effects. The calcium channel
blocking effect was confirmed when pre-treatment of the tissues with the F. indica crude extract
(0.1–1.0 mg/mL) produced a dose-dependent shift in the Ca2+ dose-response curves to the right
[148]. In another similar study, the 70% aqueous-methanol extract of F. parviflora protected against
diarrhea caused by castor oil in rats and mice [149]. F. parviflora caused 40% and 80% protection
against castor oil-induced diarrhea in rats at respective doses of 100 and 300 mg/kg. Whereas equal
protection was observed in mice at higher doses of 300 and 1000 mg/kg. The bronchodilator effect
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of F. parviflora was observed with an ED50 value of 5.32 mg/kg, compared with the reference drug
aminophylline with an ED50 value of 8.76 μM. In vitro studies showed that these activities might be
In these studies, F. indica and F. parviflora, two ethnomedicines traditionally used to treat
abdominal asthma, constipation, cramps, and diarrhea in Greco-Arab (Unani) traditional medical
system in India, were confirmed to have an ethnopharmacological basis. However, the active
substances of these folk medicines are not yet completely understood. Further
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phytopharmacological studies are necessary.
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4.7 Other pharmacological activities
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4.7.1 Antiplatelet activity
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F. vaillantii completely inhibited platelet aggregation caused by arachidonic acid and collagen
vaillantii resulted in the isolation of 96. Elsewhere, sanguinarine (106), which occurs in many
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Fumaria species, has been used as an antiseptic mouth rinse and a toothpaste additive to reduce
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dental plaque and gingival inflammation [150]. Compound 106 inhibited platelet aggregation
induced by arachidonic acid, collagen, U46619, and sub-threshold concentration of thrombin (0.05
U/mL), with IC50 values of 8.3, 7.7, 8.6, and 4.4 μM, respectively. Its antiplatelet effect is correlated
Although only a few studies examined the antiplatelet activity of F. vaillantii and alkaloids in
Fumaria species, they do provide preliminary data that is beneficial to further exploration.
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diabetes in several countries such as Iran, Pakistan, and Turkey. It showed a hypoglycemic effect on
streptozotocin-induced type-2 diabetic rats, with no effects on blood glucose levels in normal rats
[151]. This study confirmed that F. parviflora extracts (125 and 250 mg/kg/day, for 2 weeks)
controlled the levels of blood glucose under 100 mg/dl in diabetic rats. However, there was no
significant difference between the blood glucose levels in diabetic rats treated with 125 and 250
mg/kg/day. This study has limitations because there were only two doses of F. parviflora extract
tested. More rigorous pharmacological studies and biological-guided fractionation may lead to
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promising hypoglycemic agents. However, the current studies do provide some justification for the
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traditional use of F. parviflora as antidiabetic medicine.
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4.7.3 Anti-anxiety activity
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type of anxiolytic [22,152]. The 50% ethanol-aqueous extract of F. indica whole plant (100, 200,
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and 400 mg/kg/day, p.o., for 7 days) showed dose-dependent anti-anxiety effects in a battery of rat
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models consisting of open-field, elevated plus and zero maze, social interaction, and novelty
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induced feeding tests [152]. Anti-anxiety effects of F. indica extract at 400 mg/kg/day in all tests
were qualitatively similar to those of the reference drug lorazepam (5 mg/kg, p.o.). TNF-α, IL-1β,
and IL-10 were reversed by F. indica extract at all the tested concentrations (100, 200, and 400
mg/kg/day). (+)-Fumariline (37) (10, 20, 35, and 50 mg/kg, i.p.), an SBI alkaloid isolated from F.
indica seeds, produced moderate sedation in rats [76]. The 30 min cumulative act photometer
recording of spontaneous motor activity in the control and drug-treated group was 312 and 106,
respectively. While there was no loss of equilibrium or the righting reflex, and the gait of rats
remained normal even at the highest dose of 50 mg/kg. Compound 37 did not produce any adverse
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effects on respiration, heart rate, urination, or defecation in mice up to a dose of 100 mg/kg, i.p.
These studies provided preliminary information on the central nervous system-depression activity
of F. indica and its major alkaloid. However, unlike the crude extract of F. indica, the anti-anxiety
activity of 37 was not potent. A bioactivity-guided fractionation may help reveal active substances.
HepG2.2.15, an HBV-expressing cell line, was used to determine the antiviral activities of 18
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isoquinolines isolated from 16 Fumaria species [114]. As a result, 15 compounds showed potent
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antiviral activities. (–)-Fumarophycine (44) (IC50 = 67.7 nM, CC50 = 33 μM) and (−)-bicuculline (57)
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(IC50 = 97.0 nM, CC50 = 29 μM) were 250- and 150-fold more potent, respectively, than tenofovir
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(IC50 = 1800 nM, CC50 = 3.6 μM) in reducing the level of HBsAg, and more than 10-fold less toxic
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than tenofovir. Tests on the cellular secretory process supported the hypothesis that these
compounds inhibit virus release. Moreover, compound 44 resulted in a ten-fold increase in TNF-α,
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indicating a potential antiviral mechanism related to inflammatory mediators such as TNF-α [114].
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This study has identified promising compounds with in vitro anti-HBV activity. However, few in
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vivo pharmacology and clinic efficacy of these compounds have been studied. Both RNA-virus
Parainfluenza (PI-3) in Vero cells and DNA-virus Herpes simplex in Madine-Darby bovine kidney
cells were employed for antiviral assessment of isoquinoline alkaloids isolated from Fumaria
species [107]. (–)-Fumarophycine (44), 96, β-allocryptopine (98), and bulbocapnine (114) inhibited
PI-3 at minimum inhibition concentrations of 2, 1, 8, and 4 µg/mL, respectively, compared with the
standard drug oseltamivir (< 0.25 µg/mL). However, in PI-3 infected Vero cells, they also possess
cytotoxicity, with a maximum non-toxic concentration of 32 µg/mL. In the studies mentioned above,
44, an SBI alkaloid, showed potent antiviral activity against HBV and PI-3. Compound 44 and its
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indica had been evaluated in rats [153]. Administration of F. indica extract at doses of 100 and 200
mg/kg inhibited the pylorus ligation-induced ulcer in rats with percentages of 59.8% and 77.6%,
respectively, compared with the standard drug ranitidine (78.7%) at a dose of 50 mg/kg. The
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volume of gastric secretion reduced by F. indica was comparable to ranitidine. F. indica extract (200
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mg/kg) and ranitidine increased the pH of gastric juice from 3.67 to 4.35 and 4.40, respectively. F.
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indica extract (200 mg/kg) exhibited 68.63% gastroprotection in the ethanol-induced ulcer model,
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as compared to the standard drug ranitidine (71.81 %). Moreover, F. indica extract (200 mg/kg)
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increased the glutathione level by preventing free radical-induced injury in rats [153]. The
herbal formulation for the management of hypochlorhydria and related iron deficiency [154]. These
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studies provide an initial pharmacological basis for the traditional uses of F. indica and F. vaillantii.
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However, more in vitro and in vivo pharmacological studies are necessary to verify these traditional
In a randomized, double-blind, and placebo-controlled study, 44 patients with hand eczema were
cream to hand (twice a day, for 4 weeks) [155]. As a result, compared with the placebo control, F.
parviflora extract produced an improvement in patients with all types of hand eczema, such as
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allergic contact dermatitis, atopic dermatitis, irritant contact dermatitis, and pompholyx. Only one
patient had side effects, such as erythema. This clinical study provided an important
pharmacological basis for the traditional use of F. parviflora for treating skin diseases. Further
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Alkaloid extracts of ten Fumaria species (F. asepala, F. capreolata, F. cilicica, F. densiflora, F.
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judaica, F. kralikii, F. macrocarpa, F. parviflora, F. petteri subsp. thuretii, and F. vaillantii) showed
in vitro acetylcholinesterase (AChE) inhibitory activities at 1 mg/mL [156]. All the extracts
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displayed an inhibitory activity, ranging between 85.0% and 96.9%, while the standard drug
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galanthamine (1mg/mL) showed a 48.8% inhibition. In addition to the above Fumaria species, F.
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ranging between 75.4% and 99.3% [157]. Alkaloid fraction of F. vaillantii, having 94.2% inhibitory
activity, was separated by column chromatography, leading to 70 fractions [156]. Most of their
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AChE inhibitory activities ranged between 74.6% and 89.3%. The alkaloids and their AChE
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inhibitory activities are as follows: canadine (18) (56.8%), fumarophycine (44) (37.9%), protopine
(96) (80.5%), bulbocapnine (114) (65.2%), and corydaldine (126) (17.1%). Moreover, the inhibitory
activity may also be due to the synergistic interaction among diverse alkaloids. These studies
provided preliminary data for the cholinesterase inhibitory activity of Fumaria species.
cytochrome P450 (CYP) 3A4 (IC50 < 1 μM), and suppresses CYP enzymes 1A2, 2B6, 2C9, 2C19,
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2D6 with IC50 values between 10 and 100 μM [158]. Compound 96 and allocryptopine (98)
inhibited CYP enzymes 1A1, 1A2, 2C8, 2D6, 3A4, and CYP 2B6 with IC50 values ranging from 1
to 100 μM [158]. In another investigation, both 96 and 98 increased CYP 1A mRNA levels starting
from 25 to 10 μM but did not induce CYP 1A activity in HepG2 cells [116].
5. Toxicological studies
Most of the toxicological studies of Fumaria species have shown that these herbal medicines
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exhibited few adverse effects. For example, no mortality or abnormal behavior was observed in the
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acute toxicity study in mice treated with 50% ethanol-aqueous extract of F. indica (1, 2.5, and 5
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g/kg, p.o.) [23]. In the sub-chronic toxicity study, rats administrated with F. indica extract (100 and
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400 mg/kg/day, p.o. for 30 days) did not exhibit any significant change in body weight, daily food,
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and water intake. Hematological and biochemical parameters were normal, and the
histopathological study revealed the typical architecture of the kidney and liver in rats treated with F.
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indica extract. Another study also reported that the ethanol extract of F. indica was safe up to 2 g/kg,
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with no mortality or change in behavioral patterns [153]. Elsewhere, cytotoxic effects in shrimp
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were evaluated using ethanol, chloroform, and n-hexane extracts of F. indica, which at a
concentration of 1.0 mg/mL showed inhibition values of 56.6%, 90.0%, and 93.3%, respectively
[30]. Another in vitro assay using the THP-1 human monocytic cell line indicated that F. indica (50
and 100 μg/mL) did not show any toxic effect; on the contrary, it promoted the growth of cells after
24 h of treatment [117]. Treatment with alkaloid extract of F. capreolata (0.2, 1, and 2 g/kg, p.o.)
did not cause any mortality, and no remarkable changes in general appearance were observed in
mice [159]. Hemolysis of the erythrocytes was not observed at any dilution of extracts. The
cytotoxicity assay revealed that there was no adverse toxicity of n-octacosan-7β-ol, a non-alkaloid
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n-Hexane and ethyl acetate extracts of F. densiflora and n-hexane extract of F. officinalis had an
LC50 value lower than 1000 μg/mL, while water extract did not exhibit cytotoxic activity [13]. The
studies mentioned above showed that both cytotoxic and phytotoxic effects of n-hexane extracts of
Fumaria species are more significant than other Fumaria extracts. It deserves further studies to
observe if there are specific toxic components of concern for human health in Fumaria n-hexane
extracts.
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In summary, these studies provide primary toxicological information of F. capreolata, F.
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densiflora, F. indica, F. officinalis, and F. parviflora. However, this represents only five of the 24
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Fumaria species that have been studied. The toxicology of most species in this genus is not clear,
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although many of them have been used in folk medicine for generations. More in vivo studies
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should be a focus on the toxicology of these medicinally important Fumaria species and alkaloids
since people are already using them as drugs and dietary supplements.
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Fumaria species are widely distributed in many countries, with abundant biomass, and have
long been used as ethnomedicines. Several species such as F. densiflora, F. indica, F. officinalis, F.
parviflora, and F. vaillantii are well-known ethnomedicines in the south and west Asia and Europe.
Previous ethnobotanical studies showed that they are used in a similar manner, including
sedative, and tonic [23–29]. The ethnobotany, phytochemistry, pharmacology, and toxicology of 24
The principal unique chemical constituents in Fumaria are SBI and PTI alkaloids. SBIs (35–49)
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are found almost exclusively in the genera Fumaria and Corydalis [106]. PTIs (50–89) are the
largest group of alkaloids in Fumaria species, playing an essential role in the structural diversity of
isoquinoline alkaloids. These diverse natural alkaloids and their biosynthesis pathways are
important research topics of Fumaria species. There are many alkaloids possessing carboxyl groups
or occurring as quaternary alkaloid salts in the Papaveraceae family, which results in a challenge to
isolate them from aqueous extracts. As chromatographic technology improves nowadays, further
isolation of these aqueous extracts may throw light on the discovery that leads to novel drugs.
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However, Fumaria species also produce many non-alkaloids, and the synergistic effects of alkaloids
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and non-alkaloids on complex diseases deserve further study.
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Moreover, crude extracts and compounds from Fumaria species exhibited a variety of
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pharmacological activities. Protopine and QBA alkaloids have been studied for their antitumor
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critically examined for their ethnomedicinal uses in hepatoprotection. The antidiabetic, antidiarrheal,
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traditional uses of Fumaria species. Toxicological studies of several Fumaria species have been
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conducted, and most of these investigations showed that these folk medicines exhibited no adverse
effects. Although there are many papers describing the bioactivity of crude extracts of Fumaria
species, few purified constituents have been studied in detail for their mechanism of action and
safety. Bioactivity-guided fractionation and biochemical studies may help to identify active
Ethnomedicines are important sources of drugs and dietary supplements in many developing
and developed countries. Ethnopharmacological studies on the genera Chelidonium, Corydalis, and
Papaver in the Papaveraceae family afforded many well-known drugs, including chelerythrine,
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botanical source of unique isoquinoline alkaloids that may become important drugs. Ironically,
Fumaria species are commonly regarded as weeds due to their wide distribution and rich resources.
It would be helpful for people to know that these which often regarded weeds are actually important
medicinal plants. Unlike the related Papaver (poppy) species, the genus Fumaria has a knowledge
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Acknowledgments -p
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This work was supported by grants from the National Natural Science Foundation of China
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Jiansheng Fresh Herb Medicine R & D Foundation (JSYY-20190101-043), and the China
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Conflict of interests
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