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Ethnobotany, phytochemistry and
pharmacological properties of
Fagopyri Dibotryis Rhizoma: A
review
Qi Geng
†
, Bin Liu
†
, Zhiwen Cao, Li Li, Peipei Lu, Lin Lin, Lan Yan and
Cheng Lu*
Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing,
China
Fagopyri Dibotryis Rhizoma (FDR) is an effective Chinese herbal medicine with a
long history of use in China. FDR is effective in heat clearing and detoxifying,
promotion of blood circulation, relieving carbuncles, dispelling wind, and
removing dampness. Its seeds also have high nutritional value, are rich in
protein, and contain a variety of mineral elements and vitamins. Therefore, FDR
is considered a natural product with medical and economic benefits, and its
chemical composition and pharmacological activity are of interest to scientists.
The current review provides an overview of the available scientific information on
FDR, particularly its botany, chemical constituents, and pharmacological activities.
Various sources of valid and comprehensive relevant information were consulted,
including the China National Knowledge Infrastructure, Web of Science, and
PubMed. Among the keywords used were “Fagopyri Dibotryis Rhizoma”,
“botanical features”,“chemical composition”, and “pharmacological activity”in
combination. Various ailments are treated with FDR, such as diabetes, tumor, sore
throat, headache, indigestion, abdominal distension, dysentery, boils, carbuncles,
and rheumatism. FDR is rich in organic acids, tannins, flavonoids, steroids, and
triterpenoids. Experiments performed in vitro and in vivo showed that FDR extracts
or fractions had a wide range of pharmacological activities, including antitumor,
anti-inflammatory, immunomodulatory, antioxidant, antimicrobial, and
antidiabetic. The current review provides an integrative perspective on the
botany, phytochemistry and pharmacological activities of FDR. FDR may be
used as a medicine and food. Based on its chemical composition and
pharmacological effects, the main active ingredients of FDR are organic acids,
tannins, and flavonoids, and it has obvious antitumor pharmacological activity
against a variety of malignant tumors. Therefore, FDR is worthy of further study
and application as a potential antitumor drug.
KEYWORDS
Fagopyri Dibotryis Rhizoma, ethnobotany, application, phytochemistry, pharmacology
1 Introduction
Chinese herbal medicine plays a crucial role in the prevention and treatment of diseases
as a drug resource for the traditional medical system and as an important raw material for
chemical drugs, international botanicals, and the food industry. A significant amount of
evidence suggests that medicinal plants may be used to treat a variety of diseases and for the
OPEN ACCESS
EDITED BY
Somasundaram Arumugam,
National Institute of Pharmaceutical
Education and Research, Kolkata, India
REVIEWED BY
Carlos L. Cespedes-Acuña,
University of Bío-Bío, Chile
Laiba Arshad,
Forman Christian College, Pakistan
*CORRESPONDENCE
Cheng Lu,
lv_cheng0816@163.com
†
These authors have contributed equally
to this work
SPECIALTY SECTION
This article was submitted to
Ethnopharmacology,
a section of the journal
Frontiers in Pharmacology
RECEIVED 11 November 2022
ACCEPTED 20 February 2023
PUBLISHED 06 March 2023
CITATION
Geng Q, Liu B, Cao Z, Li L, Lu P, Lin L, Yan L
and Lu C (2023), Ethnobotany,
phytochemistry and pharmacological
properties of Fagopyri Dibotryis Rhizoma:
A review.
Front. Pharmacol. 14:1095554.
doi: 10.3389/fphar.2023.1095554
COPYRIGHT
© 2023 Geng, Liu, Cao, Li, Lu, Lin, Yan and
Lu. This is an open-access article
distributed under the terms of the
Creative Commons Attribution License
(CC BY). The use, distribution or
reproduction in other forums is
permitted, provided the original author(s)
and the copyright owner(s) are credited
and that the original publication in this
journal is cited, in accordance with
accepted academic practice. No use,
distribution or reproduction is permitted
which does not comply with these terms.
Frontiers in Pharmacology frontiersin.org01
TYPE Review
PUBLISHED 06 March 2023
DOI 10.3389/fphar.2023.1095554
discovery of novel pharmacologically active molecules. The
phytochemicals identified from medicinal plants have provided
promising lead compounds for effective new drugs (Ríos and
Recio, 2005;Batiha et al., 2019a;Batiha et al., 2020;El-Saber
et al., 2020). Medicinal plants have gained wider acceptance in
recent years due to the perception that they are natural products and
less likely to induce side effects than their synthetic counterparts
(Abushouk et al., 2017a;Abushouk et al., 2017b). Various medicinal
plants possess anti-inflammatory, antibacterial, antitumor, antiviral,
and other activities (Bakkali et al., 2008). Herbal extracts and
pharmacologically active molecules extracted from different plant
species that were previously used in traditional medicine have
received much attention (Essawi and Srour, 2000;Batiha et al.,
2019b;Beshbishy et al., 2019).
Fagopyrum dibotrys (D. Don) Hara is a perennial herb of the
genus Fagopyrum in the family Polygonaceae,anditiswidely
distributed in the Sichuan Basin, the hills of Guangdong and
Guangxi, and the Yunnan-Guizhou Plateau in China and
Thailand, Nepal, India and other countries (Peng et al., 1996).
The dried rhizome is often used as medicine and food because it
effectively clears heat, removes toxins, drains pus, removes blood
stasis and invigorates the spleen to strengthen the stomach. For
several thousand years in China, Fagopyri Dibotryis Rhizoma
(FDR) has been widely used as a folk medicine to cure forms of
chronic bronchitis, lung cancer, sore throat, rheumatic disease,
dysentery, and enteritis (Chan, 2003a;Jing et al., 2016;Zhao et al.,
2018). The medicinal properties of FDR are attracting the
attention of an increasing number of academics due to its
tremendous medicinal value. FDR components have been
extensively examined, and an increasing number of
compounds have been identified and isolated. A variety of
components have been identified in FDR, including organic
acids, tannins, flavonoids, steroids, and triterpenoids (Shao
et al., 2005;Cao et al., 2019). FDR also has a broad spectrum
of pharmacological effects, including antitumor, antimicrobial,
anti-inflammatory, antioxidant, and immunomodulatory effects
(Chan, 2003b;Shen, 2013;Wang et al., 2017).
FDR has a variety of chemical components and diverse
pharmacological activities, and it is a highly valuable medicinal
resource plant for development. Many studies recently investigated
the botany, phytochemistry and pharmacology of FDR and found
that organic acids, tannins, and flavonoids were the most
important active components underlying the broad-spectrum
antitumor, anti-inflammatory, and other effects (Li et al., 2019).
However, comprehensive and up-to-date information on FDR is
lacking. Therefore, the current review summarizes recent progress
on the phytoconstituents, chemical components and
pharmacological activity of FDR, especially the organic acids,
tannins and flavonoids that inhibit tumors and the specific
mechanisms of these effects, and adds its botanical
characteristics and clinical applications. Various published data
of valid and comprehensive relevant information were consulted,
including the China National Knowledge Infrastructure, Web of
Science, and PubMed. Among the keywords used were “Fagopyri
Dibotryis Rhizoma”,“botanical features”,“chemical composition”,
and “pharmacological activity”in combination. This review
provides references for the further development and use of FDR
in traditional Chinese medicine.
2 Botanical characterization and
application
2.1 Botanical characterization
Fagopyrum dibotrys (D. Don) Hara is a perennial herb that is
native to eastern, central and southwestern China, India, Nepal,
Vietnam, Thailand, and other countries. The habitat of Fagopyrum
dibotrys (D. Don) Hara is 250–3,200 m above sea level in valley
wetlands and hillside forests. The rhizomes are black‒brown, stout,
and ligneous, and the stems are long and erect, green, or brownish,
40–100 cm high, branched, striate, and glabrous. The petiole is
2–10 cm, and the leaf blade is triangular at 4-12 × 3–11 cm. Both
surfaces are papillate, the base is nearly hastate, the leaf margin is
entire, and the apex is acuminate. The ocrea is brown, 5–10 mm,
membranous, and oblique, and the apex is truncate, not ciliate.
Plants have terminal, axillary or corymbose inflorescence. Bracts are
ovate-lanceolate, ca. 3 mm, with membranous margins, and an acute
apex, each 4-flowered and rarely 6-flowered. Pedicels are in equaling
bracts that articulate at the middle. Perianth are white, and tepals are
narrowly elliptical, ca. 2.5 mm. Stamens are included. The styles are
free, and stigmas are much longer than the persistent perianth,
capitate, and opaque. During April-August, the chenes are blackish
brown, dull, broadly ovoid, 6–8 mm long, trigonous, sometimes
narrowly winged, with smooth to repandous angles, and an acute
apex (Editorial Committee of Chinese Flora, 1998).
2.2 Application
The anti-inflammatory and antiseptic effects of FDR may be used to
treat a variety of respiratory diseases. FDR tablets combined with
tiotropium bromide powder nebulizer exhibited clinical efficacy and
high safety, and it effectively improved the acute exacerbation of COPD
patients with clinical symptoms and blood gas analysis indicators and
reduced the inflammatory response (Li et al., 2022). FDR capsules
combined with salmeterol ticapone inhalation powder nebulizer for the
treatment of bronchial asthma in children had good results, and it
effectively relieved clinical symptoms, improved lung and immune
functions, regulated serum inflammatory factor levels, and had a good
safety profile (Wei et al., 2022). FDR capsules significantly reduced the
acute exacerbation of asthma patients’serum EOS and IgE levels,
reduced the respiratory inflammatory response, improved the
patient’s lung ventilation function and the clinical symptoms of
patients, which are worthy of clinical promotion (Feng et al., 2021).
The anti-inflammatory, analgesic and antibacterial
pharmacological effects of FDR significantly improved the
symptoms of infectious diseases of the intestinal tract. FDR
tablets combined with cefdinir dispersible tablets effectively
improved the symptoms of acute bacterial dysentery patients
with diarrhea, purulent stools and other symptoms and reduced
the level of serum inflammatory indicators (Zhang and Li, 2019).
3 Phytochemistry
Various parts of FDR have yielded more than 100 compounds,
including organic acids, tannins, flavonoids, steroids, and
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TABLE 1 Phytochemical constituents of FDR.
No. Chemical component Plant Part Chemistry Chemical
Formula
Chemical Structures Biological activity
1 (-)-Epicatechin-3-O-gallate acid
ester
Rhizome Organic acids C
22
H
18
O
10
Anti-inflammatory
Antioxidant
2 Gallic acid Rhizome Organic acids C₇H₆O₅Antitumor
Antimicrobial
Antioxidant
3 Protocatechuic acid Rhizome Organic acids C
7
H
6
O
4
Anti-inflammatory
Antimicrobial
4 3,4-Dihydroxy benzamide Rhizome Organic acids C
7
H
7
O
3
Anti-inflammatory
Antimicrobial
5 Monopalmitin Rhizome Organic acids C
19
H
38
O
4
Immunomodulatory
6 Protocatechuic acid methyl ester Rhizome Organic acids C
8
H
8
O
4
Antioxidant
7 Tans-p-hy-droxy cinnamic
methyl ester
Rhizome Organic acids C
10
H
10
O
3
Antitumor
Antimicrobial
8 3,5-Dimethoxy benzene carbonic
acid-4-O-glucoside
Rhizome Organic acids C
12
H
18
O
3
Anti-inflammatory
9 Ferulic acid Rhizome Organic acids C
10
H
10
O
4
Antioxidant
Antimicrobial
Anti-viral
10 Syringic acid Rhizome Organic acids C
9
H
10
O
5
Antimicrobial
11 p-Hydroxyl-benzaldehyde Rhizome Organic acids C
7
H
6
O
2
Anti-inflammatory
Antimicrobial
12 Succinic acid Rhizome Organic acids C
4
H
6
O
4
Antimicrobial
Immunomodulatory
13 Luteolin Rhizome Flavonoids C
15
H
10
O
6
Anti-inflammatory
(Continued on following page)
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TABLE 1 (Continued) Phytochemical constituents of FDR.
No. Chemical component Plant Part Chemistry Chemical
Formula
Chemical Structures Biological activity
14 (-)-Epicatechin Rhizome Flavonoids C
15
H
14
O
6
Antitumor
Anti-inflammatory
15 3-Galloyl (-) epicatechin Rhizome Flavonoids C
22
H
18
O
10
Antitumor
Antioxidant
Anti-inflammatory
16 Dimeric procyanidin Rhizome Flavonoids C
45
H
38
O
18
Anti-inflammatory
Antimicrobial
Immunomodulatory
17 (+)-Catechin Rhizome Flavonoids C
15
H
14
O
6
Antitumor
Antidiabetic
Anti-inflammatory
18 Eriodictyol Roots Flavonoids C
15
H
12
O
6
Anti-inflammatory
Antioxidant
Antidiabetic
19 Quercetin Seeds, Stems,
Roots, Leaves
Flavonoids C
15
H
10
O
7
Anti-inflammatory
Antioxidant
Antimicrobial
Immunomodulatory
20 Rutin Flowers, Seeds,
Leaves
Flavonoids C
27
H
30
O
16
Anti-inflammatory
Antioxidant
Anti-viral
21 Genkwanin Rhizome Flavonoids C
16
H
12
O
5
Antitumor
Anti-viral
22 Chrysoeriol Rhizome Flavonoids C
16
H
12
O
6
Anti-inflammatory
23 Pratol Rhizome Flavonoids C
16
H
12
O
4
Anti-inflammatory
24 Luteolin-7,4′-dime-thylether Rhizome Flavonoids C
17
H
14
O
6
Anti-inflammatory
(Continued on following page)
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TABLE 1 (Continued) Phytochemical constituents of FDR.
No. Chemical component Plant Part Chemistry Chemical
Formula
Chemical Structures Biological activity
25 Rhamnetin Rhizome Flavonoids C
16
H
12
O
7
Antitumor
Anti-inflammatory
26 3,6,3′,4′-Tetrahydroxy-7-
methoxyflavon
Rhizome Flavonoids C
16
H
12
O
7
Anti-inflammatory
27 Procyanidin B2 Rhizome Tannins C
30
H
26
O
12
Anti-inflammatory
Antimicrobial
28 Procyanidin C1 Rhizome Tannins C
45
H
38
O
18
Antitumor
Anti-diabetic
29 Procyanidin B4 Rhizome Tannins C
30
H
26
O
12
Antitumor
Antioxidant
30 3,3’-Digalloyl procyanidin B2 Rhizome Tannins C
44
H
34
O
20
Antitumor
Antioxidant
31 β-Sitosterol Rhizome Steroids C
30
H
52
OAntitumor
32 β-Daucosterol Rhizome Steroids C
35
H
60
O
6
Antitumor
(Continued on following page)
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TABLE 1 (Continued) Phytochemical constituents of FDR.
No. Chemical component Plant Part Chemistry Chemical
Formula
Chemical Structures Biological activity
33 Hecogenin Rhizome Steroids C
27
H
42
O
4
Anti-inflammatory
34 Glutinone Rhizome Terpenoids C
19
H
18
O
3
Antimicrobial
35 Glutinol Rhizome Terpenoids C
30
H
50
O
1
Antimicrobial
36 N-Butyl-β-D-fructopy-ronoside Rhizome Others C
10
H
20
O
6
Antitumor
37 Methyl-3,4-dihydroxybenzoatem Rhizome Others C
8
H
8
O
4
Anti-inflammatory
Antioxidant
38 Gglycerol monop-almitate Rhizome Others C
19
H
38
O
4
Anti-inflammatory
39 p-Hydroxyl-benzaidehyde Roots Others C
7
H
6
O
2
Anti-inflammatory
Antimicrobial
40 N-Trans-coumaroyl tyramine Rhizome Others C
17
H
17
NO
3
Anti-inflammatory
41 Emodin Rhizome Others C
15
H
10
O
5
Antimicrobial
42 Diboside A Rhizome Others C
49
H
48
O
20
Anti-inflammatory
43 3-Methyl-gossypetin 8-O-
d-glucopyranoside
Rhizome Others C
22
H
22
O
13
Anti-inflammatory
(Continued on following page)
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triterpenoids (Lin et al., 2016), which support its potential use as a
medicinal and food plant. These compounds likely explain the
differentiated pharmacological effects based on the characteristics
of these chemical components. A list of phytochemical constituents
is presented in Table 1.
3.1 Organic acids
Organic acids are compounds that contain -COOH, -SO
3
H,
RSOOH, and RCOSH in their molecular structure, and leaves, roots,
and Chinese herbs are abundant in these molecular structures. Twelve
organic acids have been identified in FDR, including gallic acid,
protocatechuic acid, (-)-epicatechin (Li et al., 2020;Huang et al.,
2022), (-)-epicatechin-3-O-gallate acid ester, tans-p-hy-droxy
cinnamic methyl ester, 3,4-dihydroxy benzamide, monopalmitin,
protocatechuic acid methyl ester (Shao et al., 2004), 3,5-dimethoxy
benzene carbonic acid-4-O-glucoside, syringic acid, ferulic acid,
p-hydroxyl-benzaldehyde, and succinic acid (Zhao et al., 2011).
3.2 Flavonoids
Flavonoids are widely present in naturally growing plants and refer
to a class of compounds with two benzene rings connected by three
carbon atoms that create the C6-C3-C6 structure (Cook and Samman,
1996). Quercetin, rutin (Tang et al., 2014), luteolin (Shao et al., 2005),
genkwanin, chrysoeriol (Yan, 2006), pratol, luteolin-7,4′-dime-
thylether, rhamnetin, iorhamnetin, 3,6,3′,4′-tetrahydroxy-7-
methoxyflavon (Zhang et al., 2016), eriodictyol (Zhao et al., 2011),
dimeric procyanidin (Liu et al., 1983), 3-galloyl (+) catechin, 3-galloyl
(-) epicatechin (Liu et al., 1998), (+)-catechin, (-) epicatechin (Zhang
et al., 1994)andotherflavonoids were isolated from FDR using column
chromatography and high-performance liquid chromatography
(HPLC).
3.3 Tannins
Tannins are phenolic compounds with complex structures that
are widely distributed in plants. Procyanidin b2, procyanidin c1
(Huang et al., 2022), procyanidin b4 (Peng et al., 1996), and 3,3′-
digalloyl procyanidin b2 were isolated from FDR.
3.4 Steroids
Steroids are a class of natural chemical components that exist
widely in nature and have the steroid parent nucleus of
cyclopentane-polyhydrophenanthrene in their structure.
Chromatography on silica and Sephadex LH-20 columns isolated
β-sitosterol and β-daucosterol from FDR (Wu et al., 2008). Liu et al.
obtained hecogenin from FDR (Liu et al., 1983).
3.5 Terpenoids
Terpenoid is a general term that summarizes all polymers of
isoprene and their derivatives, which are commonly found in plants.
Terpenoids have important physiological activities and are an
important resource for the study of natural products and the
development of new drugs. Silica gel column chromatography,
Sephadex LH-20 column chromatography and recrystallization
were used to separate the ethyl acetate extract as glutinone and
glutinol (Shao et al., 2005).
3.6 Other components
Emodin (Wu et al., 2008), glycerol monop-almitate, n-butyl-β-
D-fructopy-ronoside, methyl-3,4-dihydroxybenzoate (Shao et al.,
2005), diboside A, 3-methyl-gossypetin 8-O-d-glucopyranoside
(Wang et al., 2005), 5,5-di-α-furaldehyde dimethylether (Tian
et al., 1997), n-trans-coumaroyl tyramine, and p-hydroxy-
benzaidehyde (Zhao et al., 2011) were also isolated from FDR.
4 Pharmacological activities
FDR is widely used in Chinese herbal medicine for its antitumor,
anti-inflammatory, antimicrobial, antioxidant, and
immunomodulatory properties in recent years (Figure 1). A
variety of extracts and their chemical constituents showed
various and significant biological and pharmacological activities
in previous studies (Yang et al., 2019). Extracts and constituents
of FDR were tested, and the results support their renowned
applications in the treatment of a variety of ailments. Detailed
pharmacological studies are discussed in the following sections.
4.1 Antitumor activity
The antitumor activity of FDR has drawn increasing attention
over the past decades. FDR components had beneficial effects in the
treatment of a variety of cancers in several studies. As shown in
Figure 2, Wang et al. (Wang and Bao, 2020) found that gallic acid
prevented non-small cell lung cancer progression via inhibition of
epidermal growth factor receptor activation and impairment of the
TABLE 1 (Continued) Phytochemical constituents of FDR.
No. Chemical component Plant Part Chemistry Chemical
Formula
Chemical Structures Biological activity
44 5,5-Di-α-furaldehyde
dimethylether
Rhizome Others C
7
H
10
O
3
Immunomodulatory
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Geng et al. 10.3389/fphar.2023.1095554
binding of coactivator-associated arginine methyltransferase 1 to
proline, glutamic acid, and leucine-rich protein 1. Vergara et al.
(Pereyra-Vergara et al., 2020) showed that reactive oxygen species
(ROS) mediated (-)-epicatechin-induced apoptosis in human breast
cancer cells. Apoptosis and autophagy were induced by procyanidin
b2 in colorectal cancer cells (CRC) in a dose-dependent manner via
downregulation of the expression of phosphorylated-
phosphatidylinositol 3-kinase (p-PI3K), phosphorylated-protein
kinase B (p-Akt) and phosphorylated-mammalian target of
rapamycin (p-mTOR) of the PI3K/Akt pathway (Zhang et al.,
2019). Procyanidin b2 prevented the binding of nuclear factor
kappa B (NF-κB) to DNA in the H-RS cell line and inhibited
NF-κB-driven genes, including anti-apoptotic proteins
(Mackenzie et al., 2008). Another study revealed that β-sitosterol
regulated the treatment response in CRC by mediating the p53/NF-
κB/BCRP signal transduction axis (Wang et al., 2020). Melanoma
cell growth inhibition by procyanidin c1 was attributed to activation
of the 67LR/PKA/PP2A/CPI17/MRLC pathways (Bae et al., 2020).
Genkwanin increased host immunity and decreased the levels of
inflammatory cytokines, which may make it an effective
chemotherapeutic agent for the treatment of CRC (Wang X
et al., 2015). Rhamnetin inhibited the expression of the pregnant
x receptor (PXR) by increasing miR-148a levels, which decreased the
expression of its downstream genes. Therefore, sorafenib was more
effective against hepatocellular carcinoma (Li Y et al., 2021).
The treatment of cancer cells with FDR extract inhibited their
growth. FDR extract showed significant proliferation inhibitory
activity on HeLa cells, which was primarily associated with
modulation of the expression of the apoptotic inducible factor
Bcl2-associated X (Bax) and inhibition of the anti-apoptotic
factor B-cell lymphoma-2 (Bcl2). The extract of FDR can also
activated caspase-8, caspase-9, and caspase-3 and released
mitochondrial cytochrome C (Pan et al., 2018). Some extracts
from FDR possessed potential antitumor activity. For example,
an extract from the FDR rhizome had antiproliferative and
proapoptotic effects on the human esophageal cancer cell line
CaEs-17 (Zhang et al., 2010). Chen et al. (Chen et al., 2012)
revealed that FDR prevented Bowes melanoma cell
WM239 proliferation and migration, which was accomplished via
reduced activation of Src protein, decreased levels of N-cadherin
intracellular segment phosphorylation and dissociation of
N-cadherin from β-catenin. Fr4 is a polyphenolic substance
extracted from FDR. Fr4 reduced tumor weight, increased tumor
suppression, and showed good antitumor activity in a mouse Lewis
lung cancer model (Chen et al., 2005). Fr4 promoted a dose-
dependent increase in the inhibition of HL-60 proliferation in
leukemic cells and induced apoptosis (Chen et al., 2006). The
FDR extract Fr4 also had an antitumor effect on kidney cancer.
Fr4 inhibited the proliferation and induced apoptosis of kidney
cancer cells via a mechanism related to the upregulation of
DNA damage-induced transcript 4 protein expression (Song
et al., 2020).
Wei Mai Ning capsules are the main raw material extracts from
FDR, which inhibit tumor growth, invasion, and blood flow
metastasis, and it has been approved for clinical cancer therapy
(Lou et al., 2004a). Wei Mai Ning had effects on the lung cancer cell
lines PG, PAa and A549 and inhibited the liver cancer cell line BEL-
7402, gastric cancer cell line MGC-803 and melanoma cell line
B16 to varying degrees (Lou et al., 2004b). Wei Mai Ning inhibited
the adhesion between PG and HUVECs in vitro via the dual action
of PG cells and HUVECs, which inhibited tumor cell metastasis in
the blood channel (Lou et al., 2007).
FIGURE 1
Molecular pharmacological activity mechanisms of FDR.
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Geng et al. 10.3389/fphar.2023.1095554
4.2 Anti-inflammatory activity
Various in vitro and in vivo experiments investigated the anti-
inflammatory effects of FDR extracts (Figure 3). The effects of
(-)-epicatechin on lipopolysaccharide (LPS)-induced
inflammation in RAW264.7 cells were demonstrated, and its
anti-inflammatory effect may be related to a reduction in
inflammatory cytokines, such as nitric oxide (NO), tumor
necrosis factor-alpha (TNF-α), interleukin-1 and interleukin-6
(IL-6) and inhibition of the expression of nitric oxide synthase,
phosphorylation of p38 mitogen-activated protein kinase
(p-p38MAPK), extracellular signal regulated kinases 1/2 (ERK1/
2) and c-Jun N-terminal kinase (JNK) (Ruan and Mu, 2017).
Different (-)-epicatechin metabolites have anti-inflammatory
properties that boost vascular health partially by reprogramming
epigenetic signaling in endothelial-immune cells and reversing low-
grade systemic inflammation (Milenkovic et al., 2020).
Protocatechuic acid inhibited BV2 microglia and keratinocytes by
reducing the activation of toll-like receptor 4 (TLR4)-dependent
Akt, mTOR, and NF-κB transcription factors and activating JNK
and p38 MAPK (Wang H. Y et al., 2015;Amini et al., 2018;Nam and
Lee, 2018). Rhamnetin treatment inhibited the inflammatory and
proatherosclerosis pathways in ApoE−/−mice, and aortic tissue
from ApoE−/−mice exhibited amelioration of TLR4 mRNA and
components of the TLR4 pathway after treatment with rhamnetin
(Wang et al., 2021).
By inhibiting the TLR4-mediated activation of NF-κB and
activator protein 1 and suppressing the phosphorylation of PI3K/
Akt and MAPK, chrysoeriol inhibited the inflammatory response of
LPS-stimulated RAW 264.7 cells (Yoon and Park, 2021). Gallic acid
is a promising treatment for gouty arthritis. These effects are
induced by suppression of ROS generation, which limits NOD-
like receptor protein 3 (NLRP3) inflammasome activation and
pyroptosis dependent on nuclear factor erythroid 2-related factor
2 (Nrf2) signaling (Lin et al., 2020). The anti-inflammatory
properties of procyanidin b2 are attributed to suppression of
NLRP3 inflammasome activation (Jiang et al., 2018). Byun et al.
(Byun et al., 2013) indicated that procyanidin c1 inhibited LPS-
induced activation of MAPK and NF-κB signaling via TLR4 in
macrophages. Zhang et al. (Zhang et al., 2020) demonstrated that β-
sitosterol suppressed NF-κB and activated heme oxygenase-1 (HO-
1)/Nrf-2 pathways to inhibit arthritis.
FDR extract inhibits the transcription factor NF-κBandthe
induced production of TNF-α, interleukin-8, IL-6, transforming
growth factor-β1 and precollagen peptide III activity in chronic
obstructive pulmonary disease rats, which improves lung tissue
inflammation (Tang et al., 2014;Tang et al., 2016). The FDR
extract prevented lung tissue injury in rats with pneumonia by
downregulating TLR2/4, myeloid differentiation primary
response 88 mRNA and NF-κB inhibitor alpha protein
expression (Dong et al., 2011). FDR tablets attenuated
inflammatory symptoms and inflammatory damage in
colorectal tissues of mice with a dextran sulfate sodium-
induced inflammatory bowel disease model by downregulating
TNF-α, IL-6 and interleukin-1βfactor expression (Shen et al.,
2019;Tan et al., 2020).
Clinical studies proposed combination therapy with Chinese
medicines as an effective treatment strategy. FDR tablets combined
with salazosulfapyridine (SASP) were more effective than SASP
alone in ulcerative colitis (UC), and the mechanism may be the anti-
inflammatory and immunomodulatory effects of intervening in UC
via the TLR4/NLRP3 signaling pathway (Ge et al., 2021). FDR
tablets were combined with compound kangfuxin solution and
showed good efficacy in the treatment of UC (Hua and Yin,
2016). The effectiveness of FDR in controlling lung disease has
been demonstrated in several clinical studies, including the
treatment of adult and childhood bronchial asthma, and FDR
capsules combined with salmeterol xinafoate and fluticasone
propionate powder were effective (Li and Wu, 2018;Feng et al.,
2021). Some studies also revealed that FDR tablets combined with
FIGURE 2
Schematic diagram of the antitumor mechanisms of FDR and its constituents.
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Geng et al. 10.3389/fphar.2023.1095554
cefoperazone and gubenkechuan tablets had a significant effect in
chronic bronchial patients (Li, 2010;Han, 2020).
4.3 Immunomodulatory activity
Pharmacological studies confirmed that the extract from FDR
showed an anti-rheumatoid arthritis effect, which may be due to its
anti-inflammatory and immune activities (Shen, 2013). The
polysaccharide content of FDR repairs the immune function of
the thymus and spleen, enhances nonspecific immune function,
improves specific humoral immunity and cellular immune function,
and ultimately enhances the body’s immune function via multiple
pathways, links, and targets (Gu et al., 2015). An extract of FDR
reduced the expression of caspase-1, caspase-3, caspase-9, and
matrix metallopeptidase-1 (MMP-1) in articular cartilage of a
rabbit knee osteoarthritis model, which reduced cartilage damage
and had an osteoprotective effect (Pan et al., 2019). FDR enhanced
the phagocytosis of ventral and reticuloendothelial macrophages,
which showed that it enhanced the immune function of mice (Yang
et al., 1992;Zhang and Lin, 1999). Ethanol extract from FDR roots
had an immunomodulatory role by promoting the proliferation of
chicken spleen lymphocytes and the secretion of interleukin-2 and
interferon-γby peripheral blood T lymphocytes (Qiao et al., 2010).
4.4 Antioxidant activity
Organic acids, flavonoids, and tannins found in FDR demonstrate
scavenging properties against free radicals and superoxide anions.
Figure 4 shows the antioxidant effect of FDR via some pathways.
Flavonoids remarkably reduced superoxide anion radicals and hydroxyl
radicals in a concentration-dependent manner (Wang et al., 2017).
Protoconuic acid is a naturally occurring organic acid that is widely
distributed. Han et al. (Han et al., 2018;Han et al., 2019)foundthatthe
antioxidant properties of protocatechuic acid were beneficial for
reducing the oxidative damage caused by palmitic acid in induced
human umbilical vein endothelial cells (HUVECs) or high fat-induced
oxidative damage in mice via downregulation of the CD36/AMPK-
dependent pathway. PA had a beneficial effect on oxidative damage to
the gastrointestinal mucosa by upregulating the DJ-1/PI3K pathways,
increasing Nrf2 and mTOR expression, reducing ROS levels and lipid
peroxidation, downregulating proapoptotic and inflammatory factors,
and enhancing antioxidant enzyme activity and cell viability (Farombi
et al., 2016;Cheng et al., 2019). (-)-Epicatechin in FDR extract exhibited
stronger antioxidant activity and reduced superoxide anion radicals and
hydroxyl radicals (Huang R et al., 2014). Procyanidin b2 prevented
oxidative injury in aged mice via citrate cycle regulation, fatty acid
regulation, and bile acid regulation, and procyanidin b2 suppressed
intracellular ROS generation by activating Nrf2 expression to prevent
oxidative damage (Xiao et al., 2018;Li B et al., 2021). Procyanidin
c1 plays an important role in antioxidant activity by mediating the
nuclear translocation of Nrf2 and increasing the expression levels of
HO-1. Procyanidin c1 also blocks glutamate-induced phosphorylation
of MAPKs, including ERK1/2 and p38, but not JNK (Song et al., 2019).
Kim et al. (Kim et al., 2021)confirmed that chrysoeriol treatment
prevented HO-induced oxidative stress in RPE cells, which significantly
decreased the mitochondrial dysfunction caused by HO-induced
oxidative stress. A reduction in MMP and an increase in
mitochondrial-associated genes and proteins were also observed.
Chrysoeriol also markedly induced the transcription factors
Nrf2 and NAD(P)H:quinone oxidoreductase 1, which are related to
antioxidants.
FDR leaf tea has significant antioxidant scavenging ability
against DPPH radicals, ABTS radicals and hydroxyl radicals
(Huang et al., 2016). FDR extract reduces cartilage damage by
reducing malondialdehyde (MDA) and lipid peroxide content
and enhancing superoxide dismutase (SOD) activity, which
reduce oxygen free radicals and provide osteoprotective effects
(Pan et al., 2020).
FIGURE 3
Schematic diagram of the anti-inflammatory mechanisms of FDR and its constituents.
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Geng et al. 10.3389/fphar.2023.1095554
4.5 Antimicrobial activity
Ethanol extracts of FDR showed antimicrobial effects (Ai et al.,
2002;Zhou et al., 2009). The ethanol extract of FDR showed
inhibition of βHemolyticus Streptococcus and Streptococcus
pneumoniae in vitro and inhibited infections caused by strains of
Streptococcus pneumoniae in mice in vivo (Yan et al., 2006). Fang
et al. (Feng et al., 2006) evaluated the inhibitory activities of FDR
against bacteria and fungi, and their results indicated that FDR
exhibited obvious antibacterial effects on Staphylococcus aureus,
Escherichia coli and Diplococcus carriae It also exhibited
antifungal activities against Giardia and Candida albicans. FDR
also demonstrated antibacterial activity by scavenging
Staphylococcus aureus, Bacillus subtilis and Saccharomyces
cerevisiae (Huang and Yi, 2015). KQH-01, KQH-02 and JQY-1
isolated from FDR showed strong antibiotic activity against some
indicator microorganisms, such as Staphylococcus aureus,
Escherichia coli,Bacillus subtilis and Pythium aphanidermatum
(Zhang et al., 2011). FDR powder protected mice from
Salmonella infection and suggested a dose-activity relationship
(Wang et al., 2013).
FDR tablets combined with ceftriaxone had important
antimicrobial activities in acute bacillary dysentery, and one of
the mechanisms of action was the promotion of inflammatory
absorption (Li, 2012). When FDR tablets combined with
levofloxacin showed significant antimicrobial activity and may be
used for the treatment of acute bacillary dysentery (Bi et al., 2012;
Yu, 2014).
4.6 Antidiabetic activity
FDR flavonoids improved objective indices in streptozotocin-
induced diabetes mellitus type 2 (T2DM) mice and regulated lipid
metabolism and oxidative stress levels in model animals (Ruan et al.,
2017). FDR leaf tea reduced blood glucose, blood lipids and MDA
activity, increased SOD activity and improved pancreatic and liver
lesions in mice with T2DM (Huang X et al., 2014). The FDR mixture
significantly improved the clinical symptoms of diabetic nephropathy
and significantly reduced the patient’s blood glucose, glycosylated
hemoglobin and blood lipids (Huang et al., 2009).
4.7 Others
FDR also performs other functions in the above-described
pharmacological activities. For example, FDR extract has an
obvious antiviral effect in vitro, and its active ingredient is the
flavonoid of FDR, which is concentration dependent (Zhao et al.,
2019). Lianhua Qingwen associated with FDR tablets was more
effective, faster and safer than oseltamivir alone in the treatment of
patients with influenza A (Guo, 2015). Procyanidin b1 may be an
effective treatment for hepatitis C virus, which may be an HCV RNA
polymerase inhibitor (Li et al., 2010).
The tannic compound procyanidin b2 has analgesic effects,
primarily via anti-inflammatory antioxidant free radicals to
protect nerve cell membranes and prevent the production and
release of the neurotransmitter 5-HT. It also antagonizes the
ligand-type receptor 5-HT3A expression or promotes the
expression of the G protein-coupled superfamily 5-HT1A
receptor via the upstream signaling pathway to improve irritable
bowel syndrome (IBS). Downregulation of transient receptor
potential vanilloid 1 (TRPV1) expression also had a therapeutic
effect on hyperalgesia in IBS rats (Liu et al., 2012a;Liu et al., 2012b;
Liu et al., 2016). The hot plate test and the acetic acid twist test
showed that FDR medicinal liquid had analgesic effects, and it
increased the pain threshold and reduced the number of twists in
mice (Pan and Wan, 2015). Jia et al.used dysmenorrhea models in
mice to evaluate the analgesic effect of FDR extract and found that it
showed potential analgesic activity (Jia et al., 2010).
FIGURE 4
Schematic diagram of the antioxidant mechanisms of FDR and its constituents.
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Geng et al. 10.3389/fphar.2023.1095554
Othman et al. suggested that the vasorelaxant effect of ethyl
cinnamate was mediated via multiple pathways, and the inhibition
of Ca
2+
influx into vascular cells and release of NO and prostacyclin
from endothelial cells were involved (Othman et al., 2002).
5 Conclusions and perspectives
The current review systematically discussed the ethnobotany,
phytochemistry, and pharmacology of FDR. Various ailments have
traditionally been treated with FDR, including chronic bronchitis,
tumor, sore throat, rheumatic disease, dysentery, and enteritis. The
predominant natural compounds in FDR are organic acids, tannins,
and flavonoids, but over 100 compounds have been identified. FDR
exerts antitumor, anti-inflammatory, immunomodulatory,
antioxidant, antimicrobial, antidiabetic, and other
pharmacological activities. In addition to the phytochemical and
pharmacological studies mentioned above, FDR has also received
considerable attention because it contains a variety of essential
nutrients, and the chemical composition of human health has
received widespread attention. Therefore, a better understanding
of the phytochemistry and pharmacology of FDR will undoubtedly
promote a more rational development and utilization of FDR.
FDR has rich nutritional value and healthcare functions. It is a
medicinal resource plant with high developmental value. It contains
organic acids, tannins, flavonoids, and other antitumor active
ingredients, and gallic acid, procyanidin B2, (-)-epicatechin and
genkwanin show significant antitumor activity. However, whether
the antitumor effects of FDR are the result of the joint action of
various components and the specific antitumor mechanism are not
clear. Therefore, there is a need for in-depth research on the
following aspects. According to pharmacodynamic studies, the
effective site of the antitumor effect of FDR must be clarified via
separation and purification to improve its antitumor potency. From
the molecular or genetic level, more in-depth research is needed to
reveal the antitumor effect of FDR. Because FDR has certain anti-
invasive and metastatic effects, it is necessary to perform further
research to understand the value and significance of its intervention
in tumor cell invasion and metastasis. FDR tablets have also been
clinically proven to increase the efficacy of pneumonia treatment,
pulmonary abscess treatment, and rheumatic disease treatment.
However, as a “Chinese Pharmacopoeia”collection, its
mechanism of action of “removing heat and toxins and removing
pus and stasis”must be further clarified. This pharmacological effect
of FDR may be due to the extract or active ingredients as clearing
and detoxifying lung agents in drinks and beverages to promote the
full use of FDR resources. The antitumor and anti-inflammatory
effects and mechanisms of FDR have been widely studied. However,
the mechanism of antimicrobial, antidiabetic and
immunomodulatory activity of FDR still needs to be further
explored. The research on the mechanism of action of FDR
should be continuously strengthened, and the potential medicinal
function of it should be expanded to promote the development and
utilization of its medicinal resources.
Author contributions
QG Designing the review, Writing original draft,
Writing—review and editing. BL Designing the review, Revising
the pharmacology part, Writing—review and editing. ZC designed
the review and revised the botanical characterization and
phytochemistry section. LiL designed the review and revised the
pharmacological part. PL designed the review and revised the
manuscript. LinL preparation table and schematic diagram. LY
Preparation schematic diagram and polishing the language and
grammar. CL was involved in conception, supervision,
manuscript reviewing and editing. Submission of the final version
was approved by all authors.
Funding
This study was supported by the Scientific and Technological
Innovation Project of the China Academy of Chinese Medical
Sciences (CI2021B003), the National Key R&D Program of China
(2020YFE0205100) and the Innovation Team and Talents
Cultivation Program of the National Administration of
Traditional Chinese Medicine (ZYYCXTD-D-202005).
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed or
endorsed by the publisher.
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