Introduction
Diverse concepts and strategies have driven the search for novel treatment options
based on medicinal plants. Natural product isolation, building libraries, and their
subsequent screening have been one “classical” approach [1], [2], as have been ethnopharmacological ones generally focusing on small collections
of often lesser-known species [3] and subsequent screening. There have been continuous efforts to develop strategies
for a more stringent and evidence-based preselection, based, for example, on specific
chemical parameters and rules (in the case of natural product screening or the frequency
of use in ethnopharmacology). Individual species, especially those already available
as herbal medicinal products, continue to be developed, often with a vision for a
more evidence-based practice [4]. However, little attention has been paid to the existing generally
published information on the use of medicinal plants, based on the pre-existing
evidence in larger datasets and its systematic exploration. Here we explore such a
strategy focusing on potential new methods for treating infected wounds based on the
information available in the Pharmacopoeia of the Peopleʼs Republic of China [5].
Wound treatment
The effective treatment of chronic wounds is one of the major unmet medical needs
in healthcare. There is a considerable body of literature available on applying Chinese
medicinal plants for the treatment of wounds. With over 2000 years of documented use,
TCM has formed a unique system of medicine for the diagnosis and treatment of disease
[6]. It heavily relies on plant-based medicines, with nearly 1000 medicinal plants recorded
in ancient books and documents as main therapeutic agents. TCM has vast and untapped
potential for evidence-based therapy [7] and modern therapeutic agents, with the CP [5] being a resource well worth exploring in more detail.
Wound healing is the physiological process of restoring the integrity of the skin
and/or mucosae after trauma [8] Both ancient documents and modern TCM literature report medicinal plants recommended
for their wound treatment properties. Medicinal plants and their active metabolites
may positively stimulate or support the wound-healing process using different mechanisms.
They can strengthen the interaction between various cells and growth factors on the
wound surface, enhance the oxidative metabolism of the activated immune cells at the
wound site, improve local microcirculation, affect the pH of the wound, help keep
the wound moist, influence trace elements on the wound surface, and improve the expression
ratio of type III and type I collagen to promote wound healing [9]. In addition, antibacterial, antiviral and antifungal effects will provide support
in wound treatment. Clearly, there are potential risks
associated with such uses, an aspect that also calls for a detailed assessment
of the potential and limitations of such interventions.
The CP, which is based on the theoretical concepts of TCM, distinguishes between 2
major types of wounds: wounds caused by physical trauma (like traumatic bleeding,
insect and snake bites, burns, bruises, gouges, and frostbites) and inflammation-related
wounds (including ulcerations, hemorrhoids, dermatitis, eczema, psoriasis, ringworm,
and skin infections). Much of the previous research in this area has focused on the
plantsʼ anti-inflammatory, antimicrobial, and circulatory properties, as reported
in the CP. A recently proposed strategy for identifying lead extracts and metabolites
for novel topical treatments is the search for light-absorbing metabolites in species
used traditionally in wound treatment, as we had detailed recently [10]. Medicinal plants combining antimicrobial and photoactivity could be reasonable
candidates for photo-enhanced wound treatment, further developing photodynamic therapy
(PDT) [11], [12]. The screening of the CP [5] for plants used in TCM for wound treatment and displaying both antimicrobial and
photodynamic activity seems a suitable novel strategy to identify species for potential
clinical application of PDT.
Photoactivity
It is well known that certain medicinal species contain photosensitizers (PSs), light-sensitive
molecules that may have evolutionary evolved as part of the plantʼs defense system
against pathogens and herbivores [13], [14]. A very well-investigated example of a herbal PS is hypericin, a perylenequinone
found in the flowers and leaves of Hypericaceae (the St. Johnʼs Wort family), which
may cause pronounced skin photosensitivity (e.g., in grazing animals) [15]. Other plant-derived PSs may belong to chemical classes of furanocoumarins, polyacetylenes,
xanthenoids, anthraquinones, porphyrins, thiophenes, curcuminoids, or phenalenones
[16]. However, not all of these are likely to be suitable candidates due to well-known
photototoxic effects and the potential absence of photosensitizing effects.
Generally, the effects of PSs after light-activation may be clinically exploited for
PDT, which has shown very promising outcomes in the treatment of wounds in animals
and humans, including chronic conditions such as ulcers as well as for keratosis [11], [12].
PDT has been developed in Europe from the beginning of the twentieth century and is
now clinically approved worldwide as a modality against different types of cancer
[17]. By attacking vital cellular components like nucleic acids, proteins, and lipids,
photosensitizers may damage cells to the extent that eventually induces cell death
mechanisms and locally destroy the illuminated PS-bearing tissue [16].
The role of PDT in wound treatment
It has been observed that with certain “mild” PDT conditions (e.g., low photosensitizer
and/or low light doses), photodynamic actions may not cause cytotoxicity but rather
result in repair processes. The exact mechanisms of action responsible for PDT-promoted
wound healing are not completely clear yet. However, they have been reported to relate
to the proliferation and activation of wound-associated fibroblasts and the induction
of acute inflammation with subsequent recruitment of immune cells and secretion of
growth factors that remove damaged cells and promote the healing process, respectively
[11], [12].
However, in cases of wounds infected with microbes, such as chronic wounds that are
prone to difficult-to-treat infections, PDT may additionally exert beneficial activities
since, with different natural and synthetic PSs, it had been shown to successfully
kill microorganisms, including bacteria, viruses, fungi, and protozoa [18]. Especially given emerging clinical problems with multidrug-resistant bacteria,
approaches such as PDT that work on drug-resistant strains and do not seem to generate
resistance themselves are urgently needed. While the underlying mechanisms of antimicrobial
PDT are not fully resolved for all pathogenic species, it had been proposed that it
may target bacterial cell walls and/or nucleic acids and may even be effective on
bacterial biofilms that are often inaccessible for common drugs [19], [20], [21]. Many in vivo wound
treatment studies have focused on Staphylococcus aureus, one of the major culprits of wound infections, as well as Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii
[11], [12].
Results and Discussion
Among the 618 medicinal materials/entries/ingredients recorded in the CP, 535 are
botanical drugs from 624 medicinal plant species, 376 genera, and 132 plant families
[5]. Of these, 183 medicinal plant species are indicated for wound treatment. Included
are species used to treat open “traumatic wounds”. These may result from injuries
where an external force has caused a trauma that led to a break in the skin tissue–from
lacerations to bruises, burns, and abrasions. Also included are species indicated
to treat inflammation-related wounds (including dermatitis, skin rash) and other related
changes in physiological and biochemical conditions in the body.
In the CP, among the 183 medicinal plant species used in wound treatment, there are
112 species that, based on the presence of some metabolites (see step 2 in Methods
for the list of classes considered of interest), could show potential photoactivity
(see supplementary Table 1S for the complete list). Among these species, those with the lowest number of literature
hits (see step 3 in Methods) were further evaluated on a case-by-case basis. This
led to the exclusion of endangered species (e.g., Psammosilene tunicoides W. C.Wu & C. Y.Wu), do not contain known chromophore-bearing structures, or showed
problems relating to the evidence base available, including poorly conducted studies.
After applying the exclusions, there was a list of 10 species of interest (see [Fig. 1] and [Table 1]). The selected herbal candidates were then critically evaluated concerning their
potential for wound treatment, based
on the chemical, pharmacological, and toxicological evidence available in published
literature, and short monographs were produced for each of them.
Fig. 1 Flow chart–the overarching strategy for the data mining approach.
Table 1 Species selected for this analysis for their applicability in the treatment of traumatic
wounds and inflammatory skin conditions.
|
Drug
|
Botanical source
|
Family
|
Plant part used
|
Use
|
Preparation
|
|
Bistortae Rhizoma
|
Bistorta officinalis Delarbre
|
Polygonaceae
|
Dried rhizome
|
Insect or snake bites
|
Decoction, poultice
|
|
Conyzae Herba
|
Eschenbachia blinii (H.Lév.) Brouillet
|
Asteraceae
|
Dried aerial part
|
Traumatic bleeding
|
Decoction, poultice
|
|
Echinopsis Radix
|
Echinops humilis M.Bieb. Echinops grijisii Hance
|
Asteraceae
|
Dried root
|
Dermatitis, skin rashes
|
Decoction
|
|
Knoxiae Radix
|
Knoxia roxburghii subsp. brunonis (Wall. ex G.Don) R.Bhattachariee & Deb
|
Rubiaceae
|
Dried tuberous root
|
Dermatitis
|
External application, internally in pills and powder
|
|
Polygalae japonicae Herba
|
Polygala japonica Houtt.
|
Polygalaceae
|
Aerial parts
|
Insect or snake bites, bruises and gouges
|
Decoction, powder, poultice
|
|
Polygoni perfoliati Herba
|
Persicaria perfoliata (L.) H.Gross
|
Polygonaceae
|
Aerial parts
|
Insect or snake bites
|
Decoction, lotion poultice
|
|
Saururi Herba
|
Saururus chinensis (Lour.) Bail.
|
Saururaceae
|
Dried aerial parts
|
Dermatitis, eczema
|
Poultice
|
|
Semiaquilegiae Radix
|
Semiaquilegia adoxoides (DC.) Makino
|
Ranunculaceae
|
Dried root
|
Insect or snake bites
|
Decoction
|
|
Siphonostegiae Herba
|
Siphonostegia chinensis Benth
|
Orobanchaceae
|
Dried aerial parts
|
Traumatic bleeding
|
Decoction, powder
|
|
Trachelospermi Caulis et Folium
|
Trachelospermum jasminoides (Lindl.) Lem.
|
Apocynaceae
|
Dried stem with leaves
|
Bruises and gouges
|
Decoction
|
Bistortae Rhizoma
Bistortae rhizoma consists of the roots of Persicaria bistorta (L.) Samp. (syn: Polygonum bistorta L., Polygonaceae). In the CP, B. rhizoma is designated for clearing heat and detoxifying, reducing swelling, and stopping
bleeding. It is indicated for diarrhea, fever, cough, scrofula, mouth and tongue sores,
hemorrhoids, and snake and insect bites. B. rhizoma shows a prominent cardiovascular protective [22], antimicrobial [23], [24], [25], anti-inflammatory [26], antitumor [27], and analgesic effects [28].
According to Wang et al., a total of 158 metabolites have been identified from B. rhizoma, including 78 from its essential oil [29]. Other metabolites include organic acids, flavonoids, phenolic acids, and alkaloids.
In the CP, gallic acid is used as a quality marker in TLC. The most typical metabolites
are 5-glutine-3-one and catechin with anti-oxidation and anti-inflammatory activities,
respectively [29].
Liu et al. (2006) tested the antibacterial effects of ethanol extracts of B. rhizoma and bistortaside A (absorbance maxima at 214, 253, and 279 nm); gallic acid (absorbance
maximum at 269 nm in an acidic environment); and 1 ([Fig. 2]), mururin A, a flavonolignan with absorbance maxima between 220 and 393 nm [23], [30]. Both total ethanolic extract and the individual compounds showed different degrees
of inhibition on S. aureus, E. coli, Bacillus subtilis, Bacillus proteus, Enterobacter aerogenes, P. aeruginosa, and S. pneumoniae, with gallic acid having the strongest bacteriostatic effect [23], [24], [25].
Fig. 2 Sample metabolites, with potential relevance.
The plant has also shown anti-inflammatory activity that has been linked to the presence
of 5-glutinen-3-one and friedelanol. In the carrageenan-induced rat paw edema model,
2 fractions obtained from the 70% ethanol extract showed a significant inhibitory
effect on the rat paw edema. The effect was similar to that of positive control indomethacin
[26]. After structural analysis, the 2 fractions consisted respectively of 5-glutinen-3-on
and friedelanol [26].
Anthraquinones, a well-known class of photoactive compounds, have been isolated from
different Polygonum species, including Persicaria (formerly Polygonum) bistorta. Included among them are the widely known emodin, chrysophanol, and aloe-emodin [31], [32]. The latter has a photo yield [ΦΔ] of 0.54 (MeCN, 355 nm) with an absorbance maximum
of 430 nm [33].
No data on toxicity and clinical data on wound treatment activity is available for
B. rhizoma.
Conyzae Herba
Conyzae herba is the dried aerial part of Conyza blinii H.Lév (syn: Conyza dunniana H.Lév., Asteraceae). C. Herba is recorded in the CP to treat lung inflammation, cough, excessive phlegm, throat
pain, dental ulcer, jaundice, and traumatic bleeding. C. Herba has anti-inflammatory effects on chronic bronchitis [34], anti-ulcer effects on gastric ulcers [35], and antitumor and bacteriostatic effects [36], [37].
The main metabolites are diterpenoids and triterpenoids, including saponins, the latter
accounting for 1.6% to 3% of the metabolites in C. Herba
[36]. The diterpene blinin, isolated by Yang et al. in 1989, is a marker substance for
C. Herba in the CP, with the content of blinin not being less than 0.3% [38]. Other metabolites include alkenynes, flavonoids, sterols, phenylpropanoyl esters,
lactones, tannins, coumarins, essential oil, and organic acids [36].
The aqueous extract of C. Herba had a significant inhibitory effect on Gram-positive bacteria, including S. aureus and B. subtilis, with a minimum inhibitory concentration (MIC) of 12.5 mg/mL and 50 mg/mL, respectively
[37]. However, no relevant effects on Gram-negative bacteria were recorded [37].
Some potentially relevant pharmacological effects of the drug if used internally have
also been reported. Su et al. applied pyloric ligation-induced acute gastric ulcer
in rats to test the anti-ulcer effect [39]. The results suggested that the ethanol extract of C. Herba, at the dose of 50 mg/kg, significantly reduced the size of the ulcer and the content
of malondialdehyde (MDA) in the gastric mucosal tissue. Further studies by Ma and
Liu indicated a protective effect against gastric ulceration [39], [40]. C. Herba can be used to treat chronic bronchitis [34].
Qi et al. tested acute toxicity on mice, guinea pigs, and cats for C. Herba. For intragastric administration in mice, the value of LD50 measured was 508 mg/kg, and the maximum tolerance was 315 mg/kg [41]. The LD50 was 140 mg/kg for guinea pigs, and the maximum tolerance was 82 mg/kg.
The drug was given to guinea pigs by intraperitoneal injection [41]. The maximum tolerance for cats was 25 mg/kg [41]. The LD50 of the total saponins from C. Herba was 1.29 g/kg [42].
Echinopsis Radix
Echinopsis radix is the dried root of Echinops davuricus Fisch. ex Hornem. (syn: E. latifolius Tausch., Asteraceae) or Echinops grijsii Hance, and both species are accepted as sources of the botanical drug. Importantly,
before 1995, the CP did not distinguish between E. radix and Rhapontici radix (from Leuzea uniflora [L.] Holub., syn.: Rhaponticum uniflorum [L.] DC.), which were collectively recorded
as Rhapontici radix.
According to the CP, E. radix can be used to clear heat, detoxify the body, promote lactation, reduce breast swelling
and pain, and treat carbuncles, skin rash and treat tuberculosis. The photoactive
tiophene α-terthienyl is used as a chemical quality marker in the CP [43]. Thiophenes have absorption maxima in the 314 – 350 nm range [16].
E. radix contains thiophenes, flavonoids, terpenes (triterpenes and sesquiterpenes), alkaloids,
steroids, and fatty acids, as well as lignans, lactones, amides, and coumarins [44], [45], who have been reported for a variety of activities, including antiviral, antitumor,
antifungal, anti-inflammatory hepatoprotective [46], and antibacterial [44].
The antiviral activity of α-terthienyl (2; [Fig. 2]) specifically required 320 – 400 nm wavelength for activation [47], which is lower than the preferred wavelengths (around 600 nm) for therapeutic applications.
A variety of thiophenes has been isolated from E. radix, including 5-(but-3-en-1-ynyl)-2,2′-bithiophene, α-terthienyl, cardopatine (3; [Fig. 2]), and 5-acetyl-2,2′-bithiophene [48], which when photoactivated have antiviral and cytotoxic effects [43]. Irradiation of α-terthienyl and its 15 analogs with near-UV light showed antiviral and cytotoxic effects
on murine mastocytoma cells and murine cytomegalovirus while in the dark, only 5 analogs
were cytotoxic and 1 was antiviral [43]. A study reported that under irradiation at 320 – 400 nm,
α-terthienyl had antiviral activity against the human immunodeficiency virus, while
in the dark or visible light, this activity was nonexistent or not apparent [47]. Under UVA radiation, α-terthienyl inhibited the growth rate of Microsporum cookei
[49], which can cause dermatophytosis such as tinea capitis. In addition, recently, 3
bithiophenes with interesting dimeric structures–echinbithiophene dimers A, B, and
C, isolated from E. davuricum–showed significant activity against different phytopathogenic fungi and 1 nematode,
especially echinbithiophene dimer A, which is comparable to the positive control,
carbendazim [50].
Hong et al. studied the influence of the extraction method on the antibacterial effect
of a total polysaccharide fraction isolated from the ethanol extract of E. radix. The fraction showed the strongest antibacterial effects on P. aeruginosa
[51]. The decoction of E. radix inhibited B. subtilis with a MIC of 0.25 g/mL and S. aureus and P. aeruginosa, both with MIC of 0.5 g/mL [44]. In addition, Li et al. compared the antibacterial effect of different fractions
of the ethanolic extract. The ethyl acetate fraction and n-butanol fraction had a bacteriostatic effect on S. aureus, E. coli, S. enterica, B. subtilis, and P. aeruginosa
[52].
Li et al. assessed the anti-inflammatory effect of an ethanol extract of E. Radix. The total ethanol extract at the dose of 2.5 g/kg significantly affected xylene-induced
ear swelling in mice, reducing the swelling by one-third [52]. The chloroform fraction had the strongest effect, with an inhibition of 64% at
the dose of 0.023 g/kg, while the inhibition rate by aspirin was 40.8% [52]. The decoction of E. radix also has an anti-inflammatory effect, as shown by Shuo et al. using xylene-induced
ear swelling in mice and formaldehyde-induced paw edema in mice [44]. Lin et al. suggested that the main anti-inflammatory fraction of the ethanolic
extract of E. radix was the chloroform-soluble fraction, which had a significant effect on carrageenan-induced
paw edema in mice [53]. The decoction (2.50 g/kg, 5.00 g/kg) inhibited xylene-induced ear
swelling in mice and reduced the number of writhing times caused by acetic acid
in mice (p < 0.05). The decoction (2.50 g/kg) exerted an anti-inflammatory effect
on mice foot swelling caused by formaldehyde (p < 0.05) [54]. This suggests that E. radix has good anti-inflammatory and analgesic effects.
E. radix is a promising candidate in the context of PDT, considering the photoactive thiophenes
as potential PSs. However, there is no clinical evidence regarding its topical application
on wounds nor any studies assessing adverse events.
Knoxiae Radix
Knoxiae radix is the dried root of Knoxia roxburghii subsp. brunonis (Wall. ex G.Don) R. Bhattacharjee & Deb (Rubiaceae). In the CP, it is listed under
its synonym Knoxia valerianoides Thorel ex Pitard. with uses to treat carbuncles and sores, as a purgative and anti-ulcer
agent, as well as to dislodge phlegm.
The main bioactive metabolites of K. radix include anthraquinones, triterpenoids, lignans, coumarins and sitosterones [55], [56]. Several anthraquinones, well-known photoactive compounds, have been isolated. Among
them are rubiadin (4; [Fig. 2]) and damnacanthol (5; [Fig. 2]) [57], with [ΦΔ] = 0.34 (CHCl3, 377 nm), absorbance maximum = 410 nm, and [ΦΔ] = 0.31 (CHCl3, 377 nm), absorbance maximum = 350 nm, respectively [58]. In the CP, 3-hydroxymorindone and lucidin are TLC-based quality markers. Two fractions
of the ethanolic extract of K. radix showed antiviral activity on Coxsackievirus B3, an enterovirus, with IC50 values of 19.24 µM and 11.11 µM, and one of them also inhibited influenza virus A/Hanfang/359/95
with an
IC50 value of 11.11 µM [57]. It was reported that the 50% ethanol extract of K. radix has significant inhibitory effects on E. coli K88 and hemoclastic E. coli at a concentration of 0.5 g/mL, while water extracts did not exert any significant
effect [59].
In assessing the acute toxicity of both the water and alcohol extract of K. radix, no mice died at any of the administered dosages (24.6 to 60.0 g/kg) [60]. Eyes and skin irritation tests were carried out in the same study. The water and
alcohol extracts were applied into rabbitsʼ eyes respectively and rinsed after 2 min.
No sign of edema and hyperemia was observed in the eye areas [60]. A wound was cut in the shape of ‘#’ on one side of the rabbitʼs spine, then 0.1 mL
of the extract was applied to the wound for 4 hours. The wound did not worsen, and
no edema occurred, which indicated that both extracts were nonirritating to rabbit
eyes and skin [60]. It needs to be highlighted that such assessments are of ethical concern and, most
likely, also of limited scientific value.
In the Chinese Compendium of Materia Medica (a monograph written by Li Shizhen in
the Ming dynasty), it is reported that the combination of Knoxia valerianoides and Glycyrrhiza radix should be avoided, as it can be toxic. While some preliminary data point to potential
toxicity [61], the CP suggests that K. radix has low toxicity, and no obvious acute and subacute toxicity have so far been reported
[62].
Polygalae japonicae Herba
Polygalae japonicae herba is the dried aerial part of Polygala sibirica L. (syn: Polygala japonica Houtt., Polygalaceae). Based on the CP, P. japonica is used to treat cough, excessive phlegm, throat pain and swelling, snake and insects
bite, traumatic wounds, and sebaceous glands suppurate.
Saponins are the main metabolites of P. japonica, including hederagenin, tenuifolin and polygalasaponin F [63]. In the CP, polygalasaponin F is used as a quality marker, and its content should
not be less than 0.6%. At present, about 54 saponins have been isolated from P. japonica
[63]. Other metabolites include flavonoids [64], polysaccharides [65], anthraquinones (including emodin, aloe-emodin emodin-8-O-β-D-glucopyranoside and trihydroxyanthraquinone), and xanthones [66]. The plant has shown anti-inflammatory [67], analgesic [68], antitumor, cell-protective, anti-depressant [63], and anti-bacterial effects [69].
Li et al. tested the bacteriostatic effect of an oral decoction with P. japonica as its main ingredient. The experiment utilized 20 mice infected with S. aureus. Ten Mice were given the preparation by intragastric administration, and 10 were
administered water as a control. After 24 h, all the mice in the control group died,
while the 6 mice in the drug treatment group survived (17.5 g/kg) [70]. This result suggests that the oral decoction may improve the ability of mice to
resist S. aureus infection [70].
The anti-inflammatory effect of P. japonica has been widely reported. In one study, the total saponin fraction isolated from
fermented Polygalae japonicae herba, which was administered intragastrically (6 g/kg)
for 5 consecutive days, significantly inhibited xylene-induced ear swelling in mice
with an inhibition rate of 42.5%, while that of the positive control indomethacin
was 64.6% [68]. The total saponin (6 g/kg) also significantly inhibited the acetic acid-induced
vascular permeability in mice with an inhibition rate of 44.7% [68]. In addition, Liu et al. investigated its analgesic effect. The total saponin fraction
significantly reduced acetic acid-induced writhing numbers in mice at the dose of
6 g/kg [68]. Two sucrose esters, tenuifolioside B and (β-D-[3-O-(3,4,5-trimethoxycinnamoyl)]-fructofuranosyl-α-D-[6-O-(4-methoxybenzoyl)]-glucopyranoside from the root
of P. japonica, inhibited the nitrite and PGE2 production in LPS-stimulated BV2 microglia cells
with IC50 ranging from 11.7 to 22.5 µM [67]. This result suggests that these 2 metabolites may be of interest for further research
on neuroinflammatory diseases.
Mashed fresh Polygalae japonicae herba was applied topically to the wounds of 6 patients
with a snake bite, without including a control group. The woundsʼ redness and swelling
disappeared after 4 days, and the patients recovered after 7 days [71].
Yuan et al. performed an acute toxicity test by intraperitoneal injection on mice
with an LD50 of 32 g/kg [69]. Zhu et al. determined the acute oral toxicity of total saponins in Polygalae japonicae
herba at the highest dose of 13.3 g/kg by intragastric administration in mice. The
authors did not observe death in the mice after 7 days [72].
Polygoni perfoliati Herba
Polygoni perfoliati herba is the aerial part of Persicaria perfoliata (L.) H. Gross. (Polygonaceae), and it is listed under its synonym Polygonum perfoliatum L. in the CP. Polygoni perfoliati herba is used as pectoral, and it is used in TCM,
as described in the Wanbing Huichun (1615 A. D.), as a compress to treat snake and insect bites, as an aqueous decoction
applied topically as a wash in cases of eczema, and as a water or wine decoction taken
orally to alleviate the symptoms of other skin diseases.
More than 80 metabolites with anti-inflammatory, antibacterial, anti-hemorrhage and
other activities have been isolated, including flavonoids, anthraquinones (including
emodin, emodin methyl ether and aloe-emodin [73]) [74], [75] (for their photoactivity, see B. rhizoma), terpenoids, phenolic acid, and alkaloids [76], [77]. In the CP, quercetin is used as the quality marker using TLC. Some metabolites
isolated from Polygoni perfoliati herba are useful to differentiate P. perfoliata from other plants in the Polygonaceae family. Homoisoflavanones have only been isolated
from P. perfoliata and other 2 Polygonum species [78]. Two different sesquilignans have been isolated from P. perfoliata and P. orientale L., respectively, one with a 2,6-di-(substituted
aryl)-cis-3,7-dioxabicyclo[3.3.0] octane skeleton and one with a tetrahydrofuran-9,9′-monoepoxy
lignan structure [78]. 8-Oxo-pinoresinol (6, [Fig. 2]; another 2,6-diaryl-cis-3,7-dioxabicyclo[3.3.0] octane lignan) was isolated from
P. perfoliata, and it has not been reported from other species of Polygonum yet [78].
As early as 1978, in China, some scholars recorded the therapeutic effect of P. perfoliatum on Herpes zoster
[79]. The ethanolic extract of P. perfoliatum exhibited antiviral activity on Herpes simplex virus-1 (HSV-1), with a viral inhibition rate of 78% [76]. This rate was close to that of the positive control, acyclovir, which was 82% [76].
The 75% ethanol extract of Polygoni perfoliati herba was shown to have a strong inhibitory
effect on S. aureus (MIC = 5 × 10−2 mg/mL), P. aeruginosa (MIC = 10 × 10−2 mg/mL), B. subtilis (MIC = 10 × 10−2 mg/mL), and Proteus (MIC=5 × 10−2 mg/mL) [80]. The ethyl acetate extract and n-butanol extract also had a strong inhibitory effect on B. subtilis and P. aeruginosa
[80]. In addition, the ethyl acetate extract also inhibits the growth of fungi, such
as Candida albicans with MBC = 0.49 g/mL [77].
In a recent study, a mouse skin wound model demonstrated the therapeutic effect of
the water decoction of P. perfoliatum on wounds [81]. The mice were given the decoction by intragastric administration before cutting
a wound on the soles of their paws. Both the decoction and the positive control dexamethasone
had anti-inflammatory effects, but the former accelerated wound healing while the
latter slowed it down. In this study, the percentage of wound area at different times
was used as the standard to measure the degree of wound healing.
Several studies have shown the anti-inflammatory properties of Polygoni perfoliati
herba. In a single cohort clinical study with no control group, by Ling, Fang, and
Yang (2010), the decoction of Polygoni perfoliati herba was used topically to treat
hemorrhoids with a healing rate of 92.5% [82]. The ethanol extract reduced the xylene-induced auricle swelling in mice by 82%
compared to 62% for aspirin as the positive control [77]. The ethanol extract of P. perfoliatum could reduce the contents of prostaglandin E2 and interleukin 24 in the inflammatory
tissue in the mice toe swelling model induced by carrageenan with a dose of 5 g/kg
[83]. Additionally, quercetin-3-O-β-D-glucuronide isolated from P. perfoliatum had a stronger anti-inflammatory effect on dimethyl benzene-induced mice ear edema
than aspirin [84].
In an acute toxicity test in mice, Polygoni perfoliati herba, formulated as capsules,
did not show any obvious acute toxicity (p > 0.05), as no deaths were recorded and
major physiological functions were not altered, except for a decrease of activity
within 1 h from administration [85].
Polygoni perfoliati herba has shown antiviral, bacteriostatic, anti-inflammatory,
and hepatoprotective effects [76]. It is often applied clinically in TCM to treat skin diseases of viral origin and
inflammatory gynecological conditions [76]. The bacteriostatic, antiviral, and anti-inflammatory effects might support its
use in wound treatment, as suggested by the recent results of Du et al. [81]. A preliminary clinical study points to a reduction of the wound area and a shortening
of the wound treatment time in traumatic infected wounds [86], but more detailed pharmacodynamic and clinical research is needed.
Saururi Herba
Saururi herba is the dried aerial part of Saururus chinensis (Lour.) Baill. (syn: Saururopsis chinensis [Baill.] Turca., Saururaceae). In the CP, Saururi herba is recorded to treat edema
in the body and dysuria; as a topical application, it is recommended for infected
suppurative skin and eczema.
An essential oil and many metabolites have been isolated from Saururi herba, including
lignans, flavonoids, polysaccharides, polyphenols, terpenes [87], anthraquinones (including emodin and physcion, 7, [Fig. 2]), and aristolactam alkaloids (8, 9, and 10 where the latter, cephalenone B, has an absorbance maximum in methanol at 384 nm;
[Fig. 2]) [88]. The lignans, including saucernetin and sauchinone, were the main bioactive metabolite
[89]. Sauchinone is used as a quality marker in the CP, with a minimum content of 0.1%.
Flavonoids are another abundant class consisting mainly of flavonols and their glycosides,
including lutein, quercetin and hyperoside [90].
Saururi herba has hepatoprotective [91], central nervous inhibiting [92], anti-inflammatory [93], blood sugar-regulating [94], antitumor [95], antiviral [96], and antibacterial [97] effects. A 70% ethanol extract and a water extract of Saururi herba are bacteriostatic
on S. aureus
[97]. The water extract (8 g/kg) of Saururi herba significantly inhibited the xylene-induced
ear swelling and cotton ball implantation-induced granuloma in mice by 36% and 22%,
respectively [93]. The water extract (8 g/kg) also significantly inhibited acetic acid-induced writhing
numbers in mice and raised the pain threshold of hot plated-induced pain in mice [93].
A formula with Saururi herba as the main ingredient had an inhibitory effect on skin
itching caused by phosphoric histamine [98]. Wang and Zhou applied the formula lotion to the trimmed back of guinea pigs, and
then 0.2% phosphoric histamine was injected subcutaneously. The inhibition rate of
the lotion was 26%, compared to 34% for the positive control fluocinolone acetonide
[98].
The water extract, essential oil, and 95% ethanol extracts of the aerial parts and
roots were tested for acute toxicity in mice, with only the ethanol extracts showing
toxicity [99]. The LD50 of 95% ethanol aerial part extract and root extract were 3.15 g/kg and 17.15 g/kg,
respectively [99].
Semiaquilegiae radix
Semiaquilegiae radix is the dried root of Semiaquilegia adoxoides (DC.) Makino (Ranunculaceae), as listed in the CP.
In the clinical application of TCM, a decoction of Semiaquilegiae radix is used to
treat carbuncles, scrofula, mastitis, snake bite, tumor, and nephropathy [100]. Semiaquilegiae radix can be combined with Lonicerae Japonicae flos, Violae herba,
Chrysanthemi indici flos, and Taraxaci herba in a formula named Wu Wei Xiao Du Yin
(toxin dispersing beverage) to treat acne [101], [102]. Lithospermoside and griffonilide are used, by the CP, as quality markers for the
herbal material. Semiaquilegiae radix contains alkaloids, lactones, cyanogenic glycosides,
phenolic acids, and at least one nitro compound [103].
Photoactive alkaloids are considered the main antibacterial active ingredients. Liu
and Ji isolated berberine (11) and berberrubine (12) from Semiaquilegiae radix [104]. The 2 metabolites had bacteriostatic effects on some bacteria affecting plants,
such as Ralstonia solanacearum, Erwinia carotovora pv. Carotovora, and Pseudomonas syringae pv. actinidiae. The 2 alkaloids inhibit various bacteria and fungi; berberine has antifungal effects
on C. albicans, Cryptococcus, and dermatophytes [105]. Berberrubine has a good inhibitory effect on E. aerogenes, E. coli, Shigella castellani, and methicillin-resistant S. aureus
[106]. Wang et al. (2003) tested the bacteriostatic effects of water decoction of the
“toxin dispersing beverage” formula and each plant in this formula. Semiaquilegiae
radix showed the best effects on P.
aeruginosa among the 5 herbal ingredients of the formula and was also active against S. aureus
[102].
Lithospermoside and griffonilide serve as quality markers and have also shown anti-inflammatory
activity. They inhibit xylene-induced ear swelling in mice with the dosage of 50 mg/kg,
and griffonilide, in particular, can inhibit inflammation by up to 64% [107].
Berberine and berberrubine are known photoactive alkaloids. Berberine has previously
been experimentally applied in PDT for cancer treatment [14], showing an absorbance maximum of 420 nm [108], and berberrubine has shown an absorbance between 300 and 516 nm depending on the
choice of solvent and pH [109].
No toxicity data is available, but there is a single major adverse event report from
2002 (trance and trembling potentially ascribable to idiosyncrasy), using the previously
mentioned quintaherbal formula “toxin dispersing beverage” [110].
Siphonostegiae Herba
Siphonostegiae herba consists of the dried aerial part of Siphonostegia chinensis Benth. (Orobanchaceae). According to the CP, Siphonostegiae herba is mainly used
to treat hemorrhage, bruise, abnormal menstruation, edema, and other diseases related
to blood circulation. It is mostly used externally on wounds (including the juice
obtained by crushing fresh plants), prepared as a decoction or soaked in yellow wine
and taken orally to treat trauma.
It contains essential oil, flavonoids, alkaloids, and lignans [111]. In the CP, luteolin and acteoside are quality markers with minimal contents of
0.05% and 0.06%, respectively.
The pharmacological activities of Siphonostegiae herba include hepatoprotective effects,
antiplatelet aggregation, cholagogue, removing blood stasis, and antimicrobial action
[111].
A decoction of Siphonostegiae herba showed bacteriostatic effects on S. aureus, Bacillus anthracis, group B Streptococcus, Corynebacterium diphtheriae, Salmonella typhi, P. aeruginosa, and Shigella dysenteriae
[111].
Mice were given a drug decoction (10 mL/kg) by intragastric administration to assess
whether it promotes blood circulation using the clotting time via the angular vein
method [112]. It prolonged the clotting time (250.3 ± 94.4 s) compared with the normal saline
group (133.40 ± 16.6 s). In addition, its effect on thrombosis in rats was determined.
Measurements of the length of the clot showed that the water decoction made it shorter
than the normal saline group [112].
In the acute toxicity test, mice were given a single liquid injection at a dosage
of 130 g/kg. The intervention resulted in mild diarrhea in a small number of mice,
but none died; this compares to using 30 g in humans in clinical settings. Assuming
50 kg for an adult patient,
this suggests that Siphonostegiae herba is safe in the clinical application as the
maximum tolerable dose is over 200 times higher than that used in humans [113].
Trachelospermi Caulis et Folium
Trachelospermi caulis et folium are the dried leafy stems of Trachelospermum jasminoides (Lindl.) Lem. (Apocynaceae). In TCM, Trachelospermi caulis et folium is used to clear
heat, remove edema, treat swelling and painful throat, and relieve muscle spasms and
injuries [114]. In other TCM documents, like Jiangxi Herbal Medicine (Revolutionary Committee of Health Bureau of Jiangxi Province, 1970), Trachelospermi
caulis et folium is used as a powder for external use and soaked in wine for oral
use to treat skeletomuscular pain, open wounds, and bleeding. It is classed as having
compatibility with myrrh and licorice, among others, for treating sores.
Metabolites isolated from Trachelospermum caulis et folium mainly include flavonoids,
lignans, triterpenes, alkaloids, anthraquinones (including emodin) [115], [116], and steroids [117]. One triterpene, tracheloside, is used as a quality marker in the CP, with a minimum
amount of 0.45% [114]. Five indole alkaloids bearing chromophores with potential photoactivity were isolated
from the leaves and stems, including coronaridine, voacangine, apparicine, conoflorine,
and 19-epi-voacangarine [118].
Anti-fatigue, antioxidative, antitumor, anti-inflammatory, analgesic, sedative, and
hypnotic effects have been reported [114], [119], [120], [121]. The hot plate method and acetic acid writhing method were used [122], [123] to determine the analgesic effect of Trachelospermi caulis et folium after intraperitoneal
injection or intragastric administration in mice [122], [123]. The total flavonoids extracted from Trachelospermi caulis et folium water extract
raised the pain threshold of hot plate reaction in mice and reduced writhing. The
total flavonoids inhibited ear swelling and toe swelling in mice [123].
Apparicine has demonstrated potential in treating gout by inhibiting xanthine oxidase
in vitro with an IC50 of 0.65 µM, while the positive control allopurinol had an IC50 of 0.60 µM [124]. It is worth noting that voacangine has shown antiangiogenetic activity both in vitro and in vivo, which could be detrimental while treating wounds [125].
The existing literature focuses on its antifatigue, sedative, antitumor, antioxidative,
and hypolipidemic effects. Studies on antibacterial activity are lacking. Overall
research on Trachelospermi caulis et folium is very limited and lacks clinical data.
