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molecules
Review
Tabebuia impetiginosa: A Comprehensive
Review on Traditional Uses, Phytochemistry,
and Immunopharmacological Properties
Jianmei Zhang 1, †, Stephanie Triseptya Hunto 1, †, Yoonyong Yang 2, Jongsung Lee 1 ,* and
Jae Youl Cho 1,*
1Department of Integrative Biotechnology, and Biomedical Institute for Convergence at SKKU (BICS),
Sungkyunkwan University, Suwon 16419, Korea; zhangjianmei1028@163.com (J.Z.);
stephunto@gmail.com (S.T.H.)
2Biological and Genetic Resources Assessment Division, National Institute of Biological Resources,
Incheon 22689, Korea; tazemenia@korea.kr
*Correspondence: bioneer@skku.edu (J.L.); jaecho@skku.edu (J.Y.C.);
Tel.: +82-31-290-7861 (J.L.); +82-31-290-7868 (J.Y.C.)
†These authors contributed equally to this work.
Academic Editors: Raffaele Pezzani and Sara Vitalini
Received: 29 August 2020; Accepted: 16 September 2020; Published: 18 September 2020
Abstract:
Tabebuia impetiginosa, a plant native to the Amazon rainforest and other parts of Latin
America, is traditionally used for treating fever, malaria, bacterial and fungal infections, and skin
diseases. Additionally, several categories of phytochemicals and extracts isolated from T. impetiginosa
have been studied via various models and displayed pharmacological activities. This review aims
to uncover and summarize the research concerning T. impetiginosa, particularly its traditional uses,
phytochemistry, and immunopharmacological activity, as well as to provide guidance for future
research. A comprehensive search of the published literature was conducted to locate original
publications pertaining to T. impetiginosa up to June 2020. The main inquiry used the following
keywords in various combinations in titles and abstracts: T. impetiginosa, Taheebo, traditional uses,
phytochemistry, immunopharmacological, anti-inflammatory activity. Immunopharmacological
activity described in this paper includes its anti-inflammatory, anti-allergic, anti-autoimmune,
and anti-cancer properties. Particularly, T. impetiginosa has a strong effect on anti-inflammatory
activity. This paper also describes the target pathway underlying how T. impetiginosa inhibits the
inflammatory response. The need for further investigation to identify other pharmacological activities
as well as the exact target proteins of T. impetiginosa was also highlighted. T. impetiginosa may provide
a new strategy for prevention and treatment of many immunological disorders that foster extensive
research to identify potential anti-inflammatory and immunomodulatory compounds and fractions
as well as to explore the underlying mechanisms of this herb. Further scientific evidence is required
for clinical trials on its immunopharmacological effects and safety.
Keywords:
Tabebuia impetiginosa; Taheebo; traditional uses; immunopharmacology; immunological
disorders
1. Introduction
Historically, people have used natural products such as plants, animals, microorganisms, and other
biological resources to assuage and cure diseases [
1
]. Many of the commercial drugs (such as atropine,
teniposide, aescin, digoxin, silymarin, and so on) available today were initially developed from
plants and other biological resources used in traditional medicines [
2
,
3
]. Therefore, knowledge of the
traditional use of natural products plays a large role in drug discovery and development.
Molecules 2020,25, 4294; doi:10.3390/molecules25184294 www.mdpi.com/journal/molecules
Molecules 2020,25, 4294 2 of 16
Tabebuia impetiginosa (Mart. Ex DC. Mattos) is a plant belonging to the family Bignoniaceae,
which is mainly distributed in the Amazon rainforest and other tropical regions of Central and Latin
America [
4
]. It is not only a decorative plant but also has high pharmaceutical value. T. impetiginosa has
been used as a traditional medicine to treat various diseases and has antinociceptive, anti-edematogenic,
antibiotic, and antidepressant effects [
5
–
7
]. Moreover, the inner bark of this tree can be made into
poultice or concentrated tea to treat various skin inflammatory diseases [
8
]. Several categories of
compounds have been isolated and identified from T. impetiginosa, principally quinones, flavonoids,
naphthoquinones, and benzoic acids [
9
–
12
]. In recent years, many investigations have demonstrated
that extracts or compounds isolated from T. impetiginosa reveal an extensive range of pharmacological
activities such as anti-obesity, antifungal, anti-psoriatic, antioxidant, anti-inflammatory, and anti-cancer
activities [
4
,
7
,
13
–
18
]. It is particularly prominent in immunopharmacology. Typically, the mechanism
of anti-inflammatory activity of extract from the inner bark of Tabebuia was studied through a molecular
biological approach. Nevertheless, the clinical applications of T. impetiginosa have been poorly
researched, and there is a void of information on its mechanisms of action.
As far as we know, no review in the literature provides a comprehensive summary of T. impetiginosa.
Thus, in an attempt to provide a basis for the in-depth exploration and clinical application of this
plant, we reviewed the traditional medicinal uses, botany, immunopharmacology, phytochemistry,
and ethnopharmacology of T. impetiginosa, in addition to perspectives and possible directions of future
research. Furthermore, this review will be conducive to identifying the information gaps important for
future research into T. impetiginosa.
2. Methodology
A scientific literature review regarding the traditional uses, phytochemistry, anti-inflammatory,
anti-cancer, antioxidant, and anti-autoimmune disease activities of T. impetiginosa was performed using
bibliographic databases. Keywords used for this study were ‘anti-inflammatory,’ ‘T. impetiginosa,’
‘Taheebo,’ and other names synonymous with Taheebo. Research articles were chosen if they tested a
compound isolated from T. impetiginosa and investigated the related pharmacological activity. Studies
using
in vitro
assays included inhibition of nitric oxide, oxidative enzymes, or cytokines.
In vivo
trials
were included if they used antigens to induce ear edema, arthritis, or colitis in inflammatory animal
models. Websites, articles, and scientific papers were used as sources of information on historical uses,
components, taxonomy, and morphology of T. impetiginosa. Other sites, including mapchart.net, were
used to create a distribution map of T. impetiginosa.
3. Taxonomy and Botanical Traits
3.1. Taxonomy
T. impetiginosa is also known as Handroanthus impetiginosus (Mart. ex Dc.) Mattos as accepted
on the website www.theplantlist.org [
19
]. There are 17 valid synonymous names for Handroanthus
impetiginosus (Mart. ex Dc.) Mattos and one invalid synonymous name (Tecoma impetiginosa Mart.).
Synonymous names for Handroanthus impetiginosus (Mart. ex DC.) Mattos within one confidence
level are T. ipe var. integra (Sprague) Sandwith, Tecoma avellanedae var. alba Lillo, Tecoma ipe var.
integra Sprague, Tecoma ipe var. integrifolia Hassl., and Tecoma ipe f. leucotricha Hassl. Synonymous
names for Handroanthus impetiginosus (Mart. ex DC.) Mattos within three confidence levels are
Gelseminum avellanedae (Lorentz ex Griseb.) Kuntze, Handroanthus avellanedae (Lorentz ex Griseb.)
Mattos, T. avellanedae (Lorentz ex Griseb.), T. dugandii Standl., T. impetiginosa (Mart. ex DC.) Standl.,
T. nicaraguensis S.F. Blake, T. palmeri Rose, T. schunkevigoi D.R. Simpson, Tecoma adenophylla Bureau
and K. Schum, Tecoma avellanedae (Lorentz ex Griseb.) Speg., Tecoma impetiginosa Mart. ex DC.,
and Tecoma integra (Sprague) Hassl (The Plant List, 2013) (Table 1). This paper will use the name
T. impetiginosa (Mart. ex DC.) Standl and present it as T. impetiginosa.T. impetiginosa is a member of
family Bignoniaceae, genus Tabebuia, and species impetiginosa as written in NCBI: txid429701. Its genus
Molecules 2020,25, 4294 3 of 16
name is derived from a native language of Brazil, while the species name is derived from the Latin
word impetigo, a common and highly contagious skin infection. It was so named because people
believed that this plant could be used to treat impetigo [20].
Table 1. Synonymous names for Tabebuia impetiginosa from The Plant List, 2013.
Synonym Name Remarks
Handroanthus impetiginosus (Mart. ex Dc.) Mattos Accepted name
Tabebuia ipe var. integra (Sprague) Sandwith One confidence level
Tecoma avellanedae var. alba Lillo One confidence level
Tecoma ipe var. integra Sprague One confidence level
Tecoma ipe var. integrifolia Hassl. One confidence level
Tecoma ipe f. leucotricha Hassl. One confidence level
Gelseminum avellanedae (Lorentz ex Griseb.) Kuntze Three confidence levels
Handroanthus avellanedae (Lorentz ex Griseb.) Mattos Three confidence levels
Tabebuia avellanedae Lorentz ex Griseb. Three confidence levels
Tabebuia dugandii Standl. Three confidence levels
Tabebuia impetiginosa (Mart. ex DC.) Standl. Three confidence levels
Tabebuia nicaraguensis S.F. Blake Three confidence levels
Tabebuia palmeri Rose Three confidence levels
Tabebuia schunkevigoi D.R. Simpson Three confidence levels
Tecoma adenophylla Bureau and K. Schum Three confidence levels
Tecoma avellanedae (Lorentz ex Griseb.) Speg. Three confidence levels
Tecoma impetiginosa Mart. ex DC. Three confidence levels
Tecoma integra (Sprague) Hassl Three confidence levels
Tecoma impetiginosa Mart Invalid name
3.2. Botanical Traits
T. impetiginosa is also known as pink trumpet tree or purple trumpet tree due to its flower color [
21
].
In English, it is called Ipe, Taheebo (ant wood), and purple tabebuia. In French, it is known as Poui,
while its Spanish names include Lapacho negro, lapacho, and quebracho. In German, the common
name is Lapachobaum, Trompetenbaum, and Feenkraut. In Portuguese, this plant is recognized as
Pau d’arco (bow tree), Ipe-roxo (red thick bark), and Ipe [
19
,
20
]. T. impetiginosa is well known due
to its conspicuous appearance. This deciduous species can grow to a height of 30 m and sheds its
leaves during the dry season. The palmately compound and serrated leaves are green and arranged in
opposite or subopposite pairs. The leaf shape is elliptic or oblong with pinnate or banchidodrome
venation. Showy purple, dark pink, or pink flowers appear in spring. The calyx is campanulate to
tubular with five lobes and is trumpet shaped. Its fruit is contained in a pod and is comprised of an
elongated cylindrical capsule with thin seeds [21,22].
3.3. Distribution
T. impetiginosa is a tree found in South and Central America and in some parts of North America.
Information on the distribution of this species was obtained from www.tropicos.org [
23
] and a review
paper on red lapacho [
20
]. Although it is best known for its presence in the Amazon rainforest, it is
also found in Argentina, Bolivia, Brazil, Colombia, Costa Rica, Ecuador, El Salvador, French Guiana,
Guatemala, Honduras, Mexico, Nicaragua, Panama, Paraguay, Peru, Suriname, Trinidad and Tobago,
and Venezuela, as shown in Figure 1and Table 2.
Molecules 2020,25, 4294 4 of 16
Molecules 2020, 25, x 4 of 18
4
.
Figure 1. Distribution map of Tabebuia impetiginosa.
Table 2. Geographical distribution of Tabebuia impetiginosa.
Species Distribution
Tabebuia avellanedae
Lorentz ex Griseb. Argentina
Handroanthus avellanedae
(Lorentz ex Griseb.) Mattos Bolivia
Bignonia heptaphylla
Vell. Brazil
Handroanthus impetiginosus
(Mart. ex DC.) Mattos Bolivia, Brazil, Mexico
Gelseminum avellanedae
(Lorentz ex Griseb.) Kuntze Bolivia
Tabebuia avellanedae
var.
paulensi
s Toledo Brazil
Tabebuia dugandii
Standl. Colombia
Tabebuia eximia
(Miq.) Sandwith Bolivia, Panama
Tabebuia
heptaphylla
(Vell.) Toledo Argentina, Bolivia, Brazil, Paraguay
Tabebuia hypodictyon
(A. DC.) Standl. Bolivia, Panama
*
Tabebuia ipe
(Mart.) Standl. Panama
Tabebuia ipe var. integra
(Sprague) Sandwith Bolivia, Paraguay
Tabebuia nicaraguensis
S.F. Blake Nicaragua
Tabebuia palmeri Rose Costa Rica, El Salvador, Guatemala, Honduras,
Mexico, Nicaragua, Panama
Tabebuia schunkevigoi
D.R. Simpson Peru
Tecoma adenophylla
Bureau ex K. Schum. Brazil
Tecoma avellanedae
(Lorentz ex Griseb.) Speg. Honduras
Tecoma avellanedae
var
.
alba
Lillo Argentina
Tecoma eximia
Miq.
Brazil
Tecoma hassleri
Sprague
Paraguay
!
Tecoma heptaphylla
(Vell.) Mart.
Panama
Tecoma hypodictyon
A. DC.
Brazil
**
Tecoma impetiginosa
Mart.
Panama
!
Tecoma impetiginosa
Mart. ex DC
.
Brazil
Tecoma impetiginosa
var.
lepidota
Bureau
Brazil
Tecoma integra (Sprague)
Chodat
Bolivia, Panama
Tecoma ipe fo.
leucotricha Hassl.
Paraguay
Figure 1. Distribution map of Tabebuia impetiginosa.
Table 2. Geographical distribution of Tabebuia impetiginosa.
Species Distribution
Tabebuia avellanedae Lorentz ex Griseb. Argentina
Handroanthus avellanedae (Lorentz ex Griseb.) Mattos Bolivia
Bignonia heptaphylla Vell. Brazil
Handroanthus impetiginosus (Mart. ex DC.) Mattos Bolivia, Brazil, Mexico
Gelseminum avellanedae (Lorentz ex Griseb.) Kuntze Bolivia
Tabebuia avellanedae var. paulensis Toledo Brazil
Tabebuia dugandii Standl. Colombia
Tabebuia eximia (Miq.) Sandwith Bolivia, Panama
Tabebuia heptaphylla (Vell.) Toledo Argentina, Bolivia, Brazil, Paraguay
Tabebuia hypodictyon (A. DC.) Standl. Bolivia, Panama
* Tabebuia ipe (Mart.) Standl. Panama
Tabebuia ipe var. integra (Sprague) Sandwith Bolivia, Paraguay
Tabebuia nicaraguensis S.F. Blake Nicaragua
Tabebuia palmeri Rose Costa Rica, El Salvador, Guatemala, Honduras,
Mexico, Nicaragua, Panama
Tabebuia schunkevigoi D.R. Simpson Peru
Tecoma adenophylla Bureau ex K. Schum. Brazil
Tecoma avellanedae (Lorentz ex Griseb.) Speg. Honduras
Tecoma avellanedae var. alba Lillo Argentina
Tecoma eximia Miq. Brazil
Tecoma hassleri Sprague Paraguay
!Tecoma heptaphylla (Vell.) Mart. Panama
Tecoma hypodictyon A. DC. Brazil
** Tecoma impetiginosa Mart. Panama
!Tecoma impetiginosa Mart. ex DC. Brazil
Tecoma impetiginosa var. lepidota Bureau Brazil
Tecoma integra (Sprague) Chodat Bolivia, Panama
Tecoma ipe fo. leucotricha Hassl. Paraguay
** Tecoma ipe Mart. Bolivia, Panama
Tecoma ipe var. integra Sprague Paraguay
Tecoma ipe var. integrifolia Hassl. Bolivia
Tecoma ochracea Cham. Brazil
!=legitimate, * =illegitimate, ** =invalid.
Molecules 2020,25, 4294 5 of 16
4. Traditional Uses
T. impetiginosa has been used traditionally to treat cancer [
24
], obesity [
25
], depression [
26
], viral,
fungal, and bacterial infections [
27
], and inflammatory symptoms such as pain [
28
], arthritis [
15
],
colitis [
29
], and prostatitis since the Inca civilization. The Callawaya Tribe makes a concentrated tea
out of the tree’s inner bark for treating skin inflammatory diseases [
8
]. Moreover, it can be used as an
astringent and diuretic [
30
]. Caribbean folk healers utilize the bark and leaves of T. impetiginosa to
cure toothaches, backaches, and sexually transmitted diseases [
31
]. Latino and Haitian populations
were also reported to use this plant for the treatment of infectious disease [
32
]. Brazilian people have
traditionally used this plant for anti-inflammatory, analgesic, and antiophidic purposes against snake
venom [
33
]. Traditional healers in Brazil prescribed T. impetiginosa for cancer and tumor prevention or
treatment; 69.05% for the treatment of tumors and cancer in general and 30.95% for specific tumors
or cancers [
34
]. Such ethnomedicinal uses of T. impetiginosa led us to pay attention to it for a full
understanding of its immunopharmacological properties for the future development of an effective
drug against ethnopharmacologically targeted diseases with this plant.
5. Phytochemistry
Several categories of phytochemicals have been identified in the leaves, bark, and wood of
T. impetiginosa. From T. impetiginosa bark, 19 glycosides comprised of four iridoid glycosides, two lignan
glycosides, two isocoumarin glycosides, three phenylethanoid glycosides, and eight phenolic glycosides
were methanol-extracted [
35
]. Major constituents of T. impetiginosa are furanonaphthoquinones,
naphthoquinones, anthraquinones (e.g., anthraquinone-2-carboxylic acid (Compound 1in Figure 2)),
quinones, benzoic acid, flavonoids, cyclopentene dialdehydes, coumarins, iridoids, and phenolic
glycosides [
4
,
8
,
36
]. The presence of naphthoquinones attracted scientific attention, with lapachol
(2) and β-lapachone (3) especially piquing the interest of professionals in the medical field. Lapachol
inhibits proliferation of tumor cells, while
β
-lapachone exhibits strong toxicity in murine and human
cells. Lapachol has been shown to reduce the number of tumors caused by doxorubicin in Drosophila
melanogaster heterozygous for the tumor suppressor gene. Lapachol can also decrease the invasion of
HeLa cells, which could represent an interesting scaffold for the development of novel antimetastatic
compounds [4].
Fatty acids, especially oleic acid (
4
), palmitic acid (
5
), and linoleic acid (
6
), are found in the
bark of T. impetiginosa. Free sugars also were identified in the bark, with glucose being the most
abundant, followed by fructose and sucrose. Organic acids, especially oxalic acid (
7
), are present,
as well as the fat-soluble alcohols
α
-tocopherol (
8
) and
γ
-tocopherol (
9
).
α
-Tocopherol can reduce
cardiovascular disease risk and neurodegenerative disorders [
4
]. In addition, T. impetiginosa has some
volatile constituents that exhibit antioxidant activity. The major volatile constituents in T. impetiginosa
include 4-methoxybenzaldehyde (
10
), 4-methoxyphenol (
11
), 5-allyl-1,2,3-trimethoxybenzene (
12
),
1-methoxy-4-(1E)-1-propenylbenzene (13), and 4-methoxybenzyl alcohol (14) [37].
Cyclopentene derivatives are secondary metabolites of plants, and this constituent from
T. impetiginosa contained six known cyclopentenyl esters (avallaneine A–F (
15–20
)), two new
cyclopentyl esters (avallaneine G (
21
) and H (
22
)), and two known cyclopentenyl esters. These
cyclopentene derivatives may provide a significant anti-inflammatory effect on the lipopolysaccharide
(LPS)-mediated inflammatory response by blocking the production of NO and PGE
2
; therefore, it is
important to determine the molecular mechanism whereby cyclopentenyl esters from T. impetiginosa
inhibit inflammatory responses [
16
]. Moreover, Koyama et al. [
38
] isolated two cyclopentene
dialdehydes, 2-formyl-5-(4
0
-methoxybenzoyloxy)-3-methyl-2-cyclopentene-1-acetaldehyde (
23
) and
2-formyl-5-(3
0
,4
0
-dimethoxybenzoyloxy)-3-methyl-2-cyclopentene-1-acetaldehyde (
24
), that exert
anti-inflammatory activity in human leukocytes. Thus, it is necessary to further investigate
their activities.
Molecules 2020,25, 4294 6 of 16
Molecules 2020, 25, x 6 of 18
6
acetaldehyde (23) and 2-formyl-5-(3′,4′-dimethoxybenzoyloxy)-3-methyl-2-cyclopentene-1-
acetaldehyde (24), that exert anti-inflammatory activity in human leukocytes. Thus, it is necessary to
further investigate their activities.
Figure 2. Chemical structures of Tabebuia impetiginosa-derived components.
6. Pharmacological Activities
Previous research has indicated various pharmacological effects of T. impetiginosa and its crude
extracts and chemical compounds in a series of in vitro and animal models. It exhibits antibacterial,
antioxidant, antifungal, antinociceptive, antidiabetic, anti-edema, anti-inflammatory, and anti-cancer
Figure 2. Chemical structures of Tabebuia impetiginosa-derived components.
6. Pharmacological Activities
Previous research has indicated various pharmacological effects of T. impetiginosa and its crude
extracts and chemical compounds in a series of
in vitro
and animal models. It exhibits antibacterial,
antioxidant, antifungal, antinociceptive, antidiabetic, anti-edema, anti-inflammatory, and anti-cancer
activities at different concentrations or doses. The main pharmacological activities of extracts or
compounds isolated from T. impetiginosa reported in
in vitro
and
in vivo
studies are briefly summarized
in Table 3and described in detail in the following subsections.
Molecules 2020,25, 4294 7 of 16
Table 3. Immunopharmacological effects of Tabebuia impetiginosa.
Pharmacological
Activity
Extract/Isolated
Compounds Model Concentration/Dose Results Ref.
Immunomodulatory Water extract RAW264.7 (murine macrophage cell),
U937 (human promonocytic cell) 50, 100, 200, and 400 µg/mL
Maintained cluster formation of RAW264.7 cells even after lipopolysaccharide
(LPS) treatment.
Downregulated the phagocytic uptake of FITC-labeled dextran.
Upregulated cell-cell interactions by decreasing migration of cells and
enhancing CD-29-mediated cell-cell adhesion and the surface levels of
adhesion molecules and costimulatory molecules linked to macrophage
stimulation, as seen in upregulation of reaction oxygen species (ROS) release.
Suppressed an alteration in the membrane level of macrophages (phagocytic
uptake and morphological changes).
[39]
Ethanol extract IL-2-independent T-lymphocyte 0.25, 0.5, 0.75, 0.9, and 1.0, mg/mL Inhibited activation and proliferation of IL-2-independent T-lymphocyte [40]
Anti-inflammatory Water extract
LPS-stimulated macrophages,
arachidonic acid, or croton oil-induced
mouse ear edema models
0–400 µg/mL,
100–400 mg/kg
Inhibited the production of NO and PGE
2
and suppressed the mRNA levels of
COX-2 and iNOS.
Curative effect in an in vivo PGE2-based inflammatory symptoms model
induced by arachidonic acid.
[8]
Ethanol extract
TPA- or arachidonic acid-induced ear
edema, hot plate, acetic acid-induced
vascular permeability in rats
100, 200, or 400 mg/kg
Inhibited inflammation of paw edema, ear inflammation, and dye leakage in
the vasculature using various animal models including acetic acid-induced
vascular permeability, 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced
ear edema, arachidonic acid-induced mouse ear edema, and
carrageenan-induced paw.
[28]
Five novel compounds Human myeloma THP-1 cells 25 µM
Showed inhibitory activity on production of the inflammatory cytokines, such
as TNF-αand IL-1β.[41]
Cyclopentene
derivatives RAW264.7 cells 12.5, 25, 50 µg/mL Suppressed the production of NO and PGE2. [16]
Anti-cancer Naphthoquinones MDA-BB-231, MCF7, and A549 cells 0–30 µM Inhibited growth of cancer cell lines and STAT3 phosphorylation activity. [14]
Water extract Estrogen receptor (ER)+human
mammary carcinoma MCF-7 cell line 0.05, 0.125, 0.25, 0.5, 0.75, 1.5 mg/mL Exhibited dose-dependent growth inhibition of MCF-7 cells. [24]
β-lapachone A549 human lung carcinoma cells
Inhibited growth of A549 cells and telomerase activity; induced apoptosis by
reducing the expression of Bcl-2, increasing the expression of Bax, and
activating caspase-3 and caspase-9.
[13]
Molecules 2020,25, 4294 8 of 16
Table 3. Cont.
Pharmacological
Activity
Extract/Isolated
Compounds Model Concentration/Dose Results Ref.
β-lapachone HepG2 hepatoma cell line
Inhibited the activity of HepG2 by inducing apoptosis; downregulation of Bcl-2 and
Bcl-XL, upregulation of Bax expression; induced apoptosis by activating caspase-3 and
caspase-9 and degrading poly (ADP-ribose) polymerase protein.
[42]
Methanol extract
Human tumor cell lines MCF-7,
NCI-H460, HeLa, and HepG2; porcine
liver primary cells (PLP2).
GI50 values: 110.76 ±5.33 µg/mL
(MCF-7), 76.67 ±7.09 µg/mL
(NCI-H460), 93.18 ±1.46 µg/mL
(HeLa), 83.61 ±6.61 µg/mL (HepG2),
and >400 µg/mL (PLP2).
Showed cytotoxic effects on MCF-7, NCI-H460, HeLa, and HepG2 cells. [4]
Antinociceptive Ethanol extract
Acetic acid-induced writhing response in
rats 100, 200, or 400 mg/kg
Increased the pain threshold in a mouse model when assessed through the hot plate test
and inhibited the number of writhes compared to controls in the acetic acid-induced
writhing responses mouse model.
[28]
Osteoarthritis Ethanol extract
RAW264.7 cells and chondrosarcoma cell
line (SW1353); monoiodoacetate
(MIA)-induced osteoarthritis in rats
75, 150, and 300 µg/mL
Showed a chondroprotective effect by preventing cartilage degradation through targeting
of NF-κB and AP-1 signaling pathways in macrophage and chondrocyte cells.
Downregulated MMP2, MMP9, and MMP13 in a PMA-induced, dose-dependent manner;
no effect on the gene expression of COL2A1 and CHSY1.
[15]
Colitis Water extract
RAW264.7 cells
Dextran sulfate sodium (DSS)-induced
colitis in mice
100, 300, 900, and 2700 µg/mL
2 mg/day, a total of 5 days
Activated DC to produce immunosuppressive IL10; upregulated anti-inflammatory Th2
and Foxp3+Treg cells in mesenteric lymph node (MLN) and downregulated
pro-inflammatory Th1 and Th17 cells.
By upregulating type II T-assisted immune response, weight loss and inflammation of
colon tissue were downregulated in DSS-induced colitis mice.
[29]
Antioxidant Methanol extract
EC50 values: 0.68 ±0.03 (DPPH
scavenging activity), 0.27 ±0.01
(Reducing power), 0.23 ±0.04
(β-carotene bleaching inhibition),
0.14 ±0.01 (thiobarbituric acid
Thiobarbituric acid reactive
substances (TBARS) inhibition).
Showed the highest antioxidant activity, which may be related to its total phenol content.
[4]
Methanol, butanol, and
water extracts H2O2-induced NIH3T3 cells 0–2 mg/mL
Regenerated superoxide dismutase (SOD), catalase, and glucose 6-phosphate
dehydrogenase activities; enhanced the concentration of glutathione in the cell; protected
proteins from oxidative attack of H2O2, reduced formation of malondialdehyde in the
cell, and protected NIH3T3 cells from H2O2-induced oxidative stress.
[43]
Volatile constituents 5, 10, 50, 100, and 500 µg/mL Displayed dose-dependent activity in antioxidant assays [37]
Phenylpropanoid
glycosides
Compound 5 had the highest
antioxidant activity, with an IC50 of
0.12 µM
Had inhibitory effects on cytochrome CYP3A4 enzyme [18]
Anti-obesity n-butanol extract Ovariectomized (OVX) mice. 3T3-L1
cells A total of 16 weeks Preventing the accumulation of adipocyte in mice, weight loss and fat mass ↓in
ovariectomized mice. [17]
Ethanol extract Triton WR-1339-treated Wistar rats A total of 24,700 kJ/kg energy Decreased postprandial triglycerides in rats given a fatty meal. [25]
Anti-allergic Five novel compounds RBL-2H3 cells 100 µM Inhibited release of β-hexosaminidase of the allergy marker. [41]
Antidepressant Ethanol extract Forced swimming test (FST) and tail
suspension test (TST) in mice.
100 mg/kg, p.o. (in the FST) and
10–300 mg/kg, p.o. (in the TST) Produced antidepressant effects in the tail suspension test and forced swimming test. [26]
Antiplatelet Methanol extract Rabbit platelets and cultured rat aortic
vascular smooth muscle cells (VSMCs) 10, 50, 100, and 200 µg/mL Reduced platelet aggregation by inhibiting arachidonic acid release and ERK1/2 MAPK
activation. [30]
Molecules 2020,25, 4294 9 of 16
6.1. Anti-inflammatory Activity
6.1.1. Regulation of Inflammatory Mediators.
T. impetiginosa can alter the expression of signaling molecules involved in the inflammation
process, including nitric oxide (NO), prostaglandin (PGE
2
), and leukotriene B
4
(LTB
4
) [
8
,
15
,
28
]. NO is
essential for maintaining homeostasis and protecting human hosts and provides immunosuppressive
effects as well as immunopathological and immunoprotective activities [
44
]. PGE
2
is a mediator
of inflammation, especially in diseases such as rheumatoid arthritis and osteoarthritis, playing
an important role in stimulating the inflammatory response, facilitating tissue regeneration,
and maintaining homeostasis [
45
]. LTB
4
, a pro-inflammatory lipid mediator, is synthesized from
arachidonic acid, expressed on many inflammatory and immune cells, and is a powerful chemokine
that promotes migration of macrophages and neutrophils to tissues [
46
]. T. impetiginosa can also
inhibit the proinflammatory cytokines interleukin (IL)-1
β
and IL-6 [
15
,
47
]. IL-1
β
has an important
homeostatic function; however, overproduction of IL-1
β
can result in pathophysiological changes
related to pain and inflammation [
48
]. Likewise, IL-6 is a pro-inflammatory mediator with pleiotropic
effects on immune response, inflammation, and hematopoiesis, but excessive production of IL-6 can
cause various diseases [
49
]. In addition, the mRNA expressions of IL-1
β
and inflammatory genes
inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 were markedly decreased when treated
with T. impetiginosa [
8
,
15
,
28
,
47
]. Information gained from
in vitro
and
in vivo
models provided insights
to other researchers for further investigation. Some focused on macrophages, the main cells involved
in inflammation, while others focused on neutrophils, the most abundant blood leukocytes, and their
role in defense against pathogens [
50
,
51
]. Previously, Byeon et al. [
8
] discovered that suppression of
PGE
2
production negatively regulated the macrophage-mediated inflammatory response. Similarly,
Suzuki et al. [52]
found that T. impetiginosa repressed neutrophil activation. Interestingly, T. impetiginosa
did not inhibit the migration of neutrophils but instead inhibited the reactive oxygen species (ROS)
produced by migrating neutrophils. The ROS produced from normal cellular metabolism play an
important role in the signaling pathways of plant and animal cells in response to environmental
changes [
53
], and future studies should investigate their mechanisms and active substances in the
context of neutrophil functional modulation.
Our body has two protective effects against infections in the form of innate and adaptive immune
cells. Adaptive immune cells include T and B cells, while innate immune cells include macrophages,
dendritic cells, and other cell types. Dendritic cells are the most effective antigen presenting cells due to
their ability to express high levels of major histocompatibility complex II (MHC II), cluster differentiation
80 (CD80), and CD86 that are required for antigen presentation. This expression allows dendritic cells
to effectively trigger an immune response [
54
]. Dendritic cells are predominantly found in two forms,
mature and immature. Mature dendritic cells are important for stimulating the T cell immune response,
while immature dendritic cells support T cell tolerance [
55
]. Previous research has discovered that the
water extract of T. impetiginosa impacted dendritic cells by upregulating the expression of MHC II and
CD86, the markers of dendritic cell maturation, but had no effect on production of pro-inflammatory
cytokines. On the other hand, dendritic cells can affect the differentiation of CD4
+
T cells, which are
important for adaptive immunity, while treatment with
T. impetiginosa
can induce differentiation of
CD4
+
T cells, resulting in induction of Th2 and differentiation of regulatory T cells. The expansion of
regulatory T and Th2 cells may suppress the Th1 response, thereby preventing dextran sulfate sodium
(DSS)-induced colitis in mice [29].
6.1.2. Effects on Inflammatory Signaling
When pattern recognition receptors (PRRs) interact with pathogen-associated molecular patterns
(PAMPs) or damage-associated molecular patterns (DAMPs), intracellular signal transduction pathways
are induced to activate and translocate transcription factors such as nuclear factor (NF)-
κ
B, activator
protein (AP)-1, signal transducer and activator of transcription 3 (STAT3), and interferon regulatory
Molecules 2020,25, 4294 10 of 16
factor 3 (IRF3) into the nucleus to stimulate the expression of pro-inflammatory genes, thereby
producing an inflammatory response [
56
]. NF-
κ
B is one of the transcription factors that expresses
pro-inflammatory genes and is involved in both innate and adaptive immune responses. NF-
κ
B can be
activated through canonical and non-canonical signaling pathways. The canonical NF-
κ
B pathway is
mostly involved in immune response, while the non-canonical NF-
κ
B pathway is only involved in
parts of the adaptive immune system [57].
Park et al. [
15
] used an immunoblotting technique to show that the ethanol extract of T. impetiginosa
suppressed the activation of Src and spleen tyrosine kinase (Syk). Furthermore, to determine the direct
molecular targets, they conducted kinase assays and found that both Syk and Src were suppressed
by T. impetiginosa [
46
]. However, Byeon et al. [
8
] discovered that the water extract of T. impetiginosa
did not function in the NF-
κ
B pathway due to non-inhibition of phospho-I
κ
B and the upstream
molecules that activate phosphorylation of I
κ
B and AKT. Results from Park et al. [
15
] showed inhibition
of phospho-I
κ
B, even though they did not assess AKT expression. However, phospho-Syk and
phospho-Src upstream of AKT were inhibited by ethanol extracts of T. impetiginosa. These results
could vary depending on the proportion of active components contained in extracts using different
solvents [58].
Park et al. [
59
] investigated the effect of anthraquinone, a main component of T. impetiginosa. They
specifically focused on anthraquinone-2-carboxlic acid (9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic
acid) (AQCA:
1
) and discovered through immunoblotting that an inhibitor of I
κ
B (IKK) and I
κ
B
α
decreased when treated with 100
µ
M of AQCA in LPS-induced RAW264.7 cells. They repeated the
kinase assay and found that Syk and Src were inhibited by treatment with AQCA [59].
Another pathway, the mitogen-activated protein kinase (MAPK) pathway, activates the activator
protein (AP)-1 transcription factor that can lead to expression of pro-inflammatory genes. The MAPK
pathway consists of three families: extracellular-signal-regulated kinases (ERKs), c-Jun N-terminal
kinases (JNKs)/stress-activated protein kinases (SAPKs), and p38s. ERKs can be divided into two
subgroups: classic ERKs that include ERK1 and ERK2 and larger ERKs such as ERK5. Classic ERKs are
mainly responsible for cell growth, survival, differentiation, and development. JNK family members,
which include JNK1, JNK2, and JNK3, are stress-activated [60].
Anthraquinone-2-carboxlic acid (AQCA) was identified as one of the major anthraquinones
in T. impetiginosa. Administration of AQCA to mice treated with HCl/EtOH and aspirin resulted
in reduced expression of phospo-p38 and interleukin 1 receptor associated kinase 1 (IRAK1) [
61
].
Treatment with AQCA reduced the expression of phospo-p38, c-JNK, mitogen-activated protein kinase
3/6 (MKK3/6), and transforming growth factor
β
-activated kinase (TAK1) in RAW264.7 cells. However,
the expression of ERK was not inhibited. The upstream level of TAK1 was inhibited, as evidenced by
degradation of IRAK1. These findings were confirmed using a conventional kinase assay with purified
enzyme, and results showed potent suppression of IRAK1 by AQCA. Transfection was performed
using HEK293 cells with the IRAK1 gene to validate the results, and treatment with AQCA suppressed
phosphorylation of p38 protein without altering FLAG and IRAK1 protein levels. Taken together,
these findings suggest that downregulation of IRAK1 by AQCA contributes to an anti-inflammatory
effect [59]. Results are summarized in a pathway chart (Figure 3).
Molecules 2020,25, 4294 11 of 16
Molecules 2020, 25, x 3 of 18
.
Figure 3. Inhibitory targets of Tabebuia impetiginosa in the NF-κB and AP-1 pathways.
6.2. Anti-Cancer Activity
T. impetiginosa exhibits inhibitory effects on the growth of several human tumor cell lines, such
as breast carcinoma (MCF-7), lung carcinoma (NCI-H460), cervical carcinoma (HeLa), and
hepatocellular carcinoma (HepG2), and the GI50 values (corresponding to a sample concentration
achieving 50% growth inhibition in human tumor cell lines) were 1.21, 1.03, 0.91, and 1.10 μg/mL,
respectively [4]. Woo et al. [42] reported that β-lapachone isolated from T. avellanedae significantly
inhibited the proliferation of human hepatoma cell line HepG2 by inducing apoptosis, which is
associated with upregulation of pro-apoptotic Bax and downregulation of anti-apoptotic Bcl-2 and
Bcl-XL expression, proteolytic activation of caspase-3 and -9, as well as degradation of poly (ADP-
ribose) polymerase protein.
In a human breast carcinoma derived estrogen receptor (ER+) MCF-7 cells model, Taheebo
showed antiproliferative effects by upregulating xenobiotic metabolism-specific genes (dual specific
phosphatase genes) and apoptosis-specific genes and by downregulating estrogen response and cell
cycle regulatory genes [24]. Particularly, Taheebo treatment upregulated the dual specific
phosphatase (DUSP) gene family and downregulated cyclin A and cdk2, indicating that Taheebo also
inhibited the MAPK signaling pathway and phosphorylation of the ER N-terminal AF-1 domain [24].
Junior et al. [62] found that the anti-cancer activity of T. impetiginosa was correlated with the presence
of lapachol and β-lapachone in its constitution. It is noteworthy that T. impetiginosa not only displayed
growth inhibition against various tumor cell lines in vitro but also prolonged the duration of survival
in a number of mouse models in vivo. For example, Queiroz et al. [63] examined the effects of T.
avellanedae (30–500 mg/kg) and the naphtoquinone β-lapachone (1–5 mg/kg) in Ehrlich’s ascites
tumor-bearing mice. They observed that T. avellanedae administration prolonged the lifespan of
tumor-bearing mice by increasing the number of bone marrow granulocyte-macrophage colony-
forming units and reducing colony-stimulating activity levels; the optimal biologically active dose
was 120 mg/kg. In addition, Tahara et al. [14] found that naphthoquinones isolated from T. avellanedae
markedly blocked the STAT3 pathway while reducing hyperactivation of these signals as well as
inhibited growth of cancer cell lines.
6.3. Anti-Autoimmune Diseases
Figure 3. Inhibitory targets of Tabebuia impetiginosa in the NF-κB and AP-1 pathways.
6.2. Anti-Cancer Activity
T. impetiginosa exhibits inhibitory effects on the growth of several human tumor cell lines,
such as breast carcinoma (MCF-7), lung carcinoma (NCI-H460), cervical carcinoma (HeLa), and
hepatocellular carcinoma (HepG2), and the GI
50
values (corresponding to a sample concentration
achieving 50% growth inhibition in human tumor cell lines) were 1.21, 1.03, 0.91, and 1.10
µ
g/mL,
respectively [
4
].
Woo et al. [42]
reported that
β
-lapachone isolated from T. avellanedae significantly
inhibited the proliferation of human hepatoma cell line HepG2 by inducing apoptosis, which is
associated with upregulation of pro-apoptotic Bax and downregulation of anti-apoptotic Bcl-2 and
Bcl-X
L
expression, proteolytic activation of caspase-3 and -9, as well as degradation of poly (ADP-ribose)
polymerase protein.
In a human breast carcinoma derived estrogen receptor (ER
+
) MCF-7 cells model, Taheebo
showed antiproliferative effects by upregulating xenobiotic metabolism-specific genes (dual specific
phosphatase genes) and apoptosis-specific genes and by downregulating estrogen response and cell
cycle regulatory genes [
24
]. Particularly, Taheebo treatment upregulated the dual specific phosphatase
(DUSP) gene family and downregulated cyclin A and cdk2, indicating that Taheebo also inhibited the
MAPK signaling pathway and phosphorylation of the ER N-terminal AF-1 domain [
24
].
Junior et al. [62]
found that the anti-cancer activity of T. impetiginosa was correlated with the presence of lapachol
and
β
-lapachone in its constitution. It is noteworthy that T. impetiginosa not only displayed growth
inhibition against various tumor cell lines
in vitro
but also prolonged the duration of survival in a
number of mouse models
in vivo
. For example, Queiroz et al. [
63
] examined the effects of T. avellanedae
(30–500 mg/kg) and the naphtoquinone
β
-lapachone (1–5 mg/kg) in Ehrlich’s ascites tumor-bearing
mice. They observed that T. avellanedae administration prolonged the lifespan of tumor-bearing mice by
increasing the number of bone marrow granulocyte-macrophage colony-forming units and reducing
colony-stimulating activity levels; the optimal biologically active dose was 120 mg/kg. In addition,
Tahara et al. [
14
] found that naphthoquinones isolated from T. avellanedae markedly blocked the STAT3
pathway while reducing hyperactivation of these signals as well as inhibited growth of cancer cell lines.
Molecules 2020,25, 4294 12 of 16
6.3. Anti-Autoimmune Diseases
Recent research has shown that T. impetiginosa has effects on various autoimmune diseases such
as psoriasis, osteoarthritis, allergy, and inflammatory bowel disease. Suo et al. [
41
] found that five
novel compounds isolated from the water extract of Taheebo had strong anti-inflammatory activity but
displayed weak or no effect on anti-allergic and antioxidant activities. Muller et al. [64] reported that
Lapacho, a common constituent in the inner bark of T. impetiginosa, suppressed growth of the human
keratinocyte cell line (HaCaT) and could be promising as an effective anti-psoriatic agent. In addition, it
has been reported that T. impetiginosa bark extracts significantly inhibited the growth of some bacterial
species associated with gastrointestinal disease and diarrhea, implying their suitability for prophylactic
therapeutic usage [
7
]. Park et al. [
15
] examined the effect of T. avellanedae on monoiodoacetate-induced
osteoarthritis in a Sprague-Dawley rat model. They observed that T. avellanedae administration
ameliorated osteoarthritis symptoms by decreasing the serum levels of proinflammatory cytokines
and inflammatory mediators, such as PGE
2
, LTB4, and IL-1
β
[
15
]. De Miranda et al. [
5
] further
investigated its effects using animal models and described anti-edematogenic and antinociceptive
effects of T. impetiginosa in rat paw edema induced by carrageenan. In this study, an aqueous extract
containing a 200 mg/kg dose ameliorated rat paw edema in a way similar to indomethacin, the control
drug. However, at a dose of 400 mg/kg, the edema was not reduced, suggesting that the edema-reducing
compounds were competing with other constituents and nullifying any edema-reducing effect.
Lee et al. [
28
] investigated the analgesic and anti-inflammatory effects of T. impetiginosa, especially
with regard to osteoarthritis. In this study, the analgesic effects were tested using pain threshold
methods assessed by a hot plate test. A T. impetiginosa ethanol extract-treated group showed a significant
analgesic effect at 200 mg/kg compared with a control group treated with diclofenac. Using an acetic
acid-induced writhing response, they confirmed results from previous experiments that 100–400 mg/kg
of T. impetiginosa ethanol extract significantly inhibited the number of writhes compared to the control
group. This analgesic model used acetic acid because it causes inflammatory pain by increasing capillary
permeability, and the hot plate-induced pain indicated narcotic involvement. Anti-inflammatory activity
was assessed using acetic acid-induced vascular permeability, 12-O-tetradecanoylphorbol-13-acetate
(TPA)-induced ear edema, arachidonic acid-induced mouse ear edema, and carrageenan-induced paw
edema. Most of the group treated with T. impetiginosa exhibited reduced inflammation at a dose of
100–400 mg/kg, including suppression of ear weight and thickness, inhibition of ear inflammation,
and reduction
of edema in a TPA-induced ear edema test volume [
28
]. Byeon et al. [
8
] performed a
similar study using a hot water extract and tested the edema model with different inducers. They
found that prostaglandin E
2
(PGE
2
) production was blocked and edema symptoms were reduced
when treated with T. impetiginosa. However, in this study, T. impetiginosa only affected arachidonic
acid-induced ear edema.
Park et al. [
29
] investigated the effect of T. impetiginosa on a DSS-induced colitis mouse model.
They discovered that T. impetiginosa protected the colon from inflammation by reducing mucosal
edema loss, epithelial crypts, and inflammatory cell infiltration. In addition, the use of T. impetiginosa
in traditional arthritis medicines led researchers to perform experiments in an osteoarthritis model.
Park et al. [
46
] used an ethanol extract of T. impetiginosa in the form of Tabetri
™
(Ta-EE) in a
monoiodoacetate-induced osteoarthritic mouse model. They compared the pain indicator of a
mechanical paw withdrawal threshold to Von Frey stimuli and found that pain was significantly
increased in osteoarthritic rats,
which was
suppressed by Ta-EE. Moreover, they also compared the
results to those of methylsulfonylmethane (MSM) and Pc-LE and found that Ta-EE produced results
comparable to those of these anti-inflammatory agents. Interestingly, results with Ta-EE were not
dose-dependent, indicating that Ta-EE can be used in small doses. The osteoarthritic rats showed
no weight loss, indicating no toxicity or side effects regarding weight loss or appetite caused by
Ta-EE treatments. To investigate further, they measured the degradation of articular cartilage in rats
administered Ta-EE and found it to be dramatically inhibited. Strangely, the chondroprotective effect
of Ta-EE was better than that of MSM at 60 and 120 mg/kg doses in a dose-dependent manner.
Molecules 2020,25, 4294 13 of 16
7. Clinical Trials
In recent years, along with thorough research, some of the principal active components of
T. impetiginosa
have been used in clinical research. For example,
β
-lapachone, mainly distributed in
heartwood of T. impetiginosa, has entered into phase 2 clinical trials for treatment of squamous cell
carcinoma, and 2-acetylnaphtho (2,3-
β
) furan-4,9-dione, also referred to as STAT3 inhibitor BBI608
(Napabucacin), was developed by Boston Biomedical Inc [14].
8. Conclusions
In this paper, we summarized the traditional uses, botanical traits, phytochemistry,
and pharmacological
activities of T. impetiginosa with collation and analysis of relevant studies.
T. impetiginosa has been used as a traditional medicine in Central and South America to treat edema,
arthritis, diuretic, and infections. Based on its traditional use,
in vivo
and
in vitro
experiments
examining its pharmacological potential have been conducted.
In vivo
experiments were conducted
using edema, osteoarthritis, animal paw edema, and writhing (and other) models to screen effects
of T. impetiginosa. Moreover, there are numerous studies confirming that extracts or compounds
isolated from T. impetiginosa have various pharmacological activities such as anti-obesity, antibacterial,
antifungal, antiviral, anti-psoriatic, antioxidant, anti-inflammatory, and anti-cancer activities.
Currently, substantial progress has been made in exploration of the phytochemistry and
pharmacological activity of T. impetiginosa. Nonetheless, there are still challenges and gaps in
published research papers that should be further explored to establish its clinical application value.
Firstly, the extracts and compounds isolated from T. impetiginosa possess multiple pharmacological
activities, though most functional mechanisms remain unclear and need to be further explored through
in vivo
and
in vitro
experiments. Furthermore, most studies on T. impetiginosa are still in the
in vitro
and
in vivo
mouse model stages. Toxicological research can be conducted on other animals such as
rabbits in the future to evaluate its safety, which will pave the way for further clinical trials. In addition,
further comprehensive experiments are needed to enrich the data and discover other pharmacological
uses of T. impetiginosa and to find the exact mechanisms by which its extracts bind to target proteins.
Author Contributions:
Original draft preparation, J.Z. and S.T.H.; conceptualization, Y.Y. and J.Y.C.;
writing—review and editing, J.L. and J.Y.C.; funding acquisition, J.Y.C. All authors have read and agreed
to the published version of the manuscript.
Funding:
This research was supported by the Basic Science Research Program (2017R1A6A1A03015642) through
the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Korea.
Conflicts of Interest: The authors declare that they have no conflict of interest.
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