Apocynum venetum, a medicinal, economical and ecological plant: a review update

Keywords analysis of CiteSpace

Keywords represent the core content of an article and provide information on the topic or the important category to which an article belongs. The keywords with high frequency and highly mediated centrality were analyzed and presented in the form of a visual mapping through the Citespace software (Fig. 2). The most frequent keywords from 1987–2022 were Apocynum venetum L. (111), Apocynum venetum leaves (52), Apocynum venetum leaf extract (31). The keywords with the highest centrality before 2018 include Apocynum venetum L. (0.49), component (0.28), hepatoprotective activity (0.27), identification (0.25) and antioxidant (0.23) (Fig. 2A, Table 1). However, after 2018, among the top ten keywords showing the highest centrality, two words that are poorly correlated with Apocynum venetum leaves appeared: Apocynum venetum fiber (0.28) and Apocynum pictum schrenk (0.27). These results implied that the studies before 2018 mainly focused on the components and the pharmacological effects of Apocynum venetum leaves while Apocynum venetum fiber and Apocynum pictum Schrenk have also attracted the attention of researchers in recent years.

Based on the keyword co-linear graph (Fig. 2A), the parameter of “burstiness” was set to γ = 0.5, minimum duration = 1. Sixteen burst entries were generated. Among them, the words that have kept the outbreak status were oxidative stress (3.93), Apocynum venetum fiber (3.26), identification (2.68) and tolerance (2.0) (Fig. 2B). These data confirmed that apart from the further in-depth pharmacological investigations, the fiber of this plant has recieved attention in recent years. In addition, the ecological value of Apocynum venetum L and Apocynum pictum Schrenk L has attracted increasing attentions.

The bioactive components of A.venetum

Flavonoids

With the deepening of research and the technological improvement in high performance liquid chromatography, mass spectrometry etc., many phytochemicals of A.venetum have been identified and isolated. Some of these phytochemicals were flavonoids such as hyperoside and isoquercetin, which bioactivities have been comprehensively reviewed previously (Xie et al., 2016a; Xie et al., 2016b; Xie et al., 2012). Since then, more studies have reported on the isolation and bioactivities of known and novel flavonoids from A.venetum. The flavonoids isolated from A. venetum since 2012 are listed in Table 2 and their structures shown in Fig. 3. Kaempferol, quercetin, isoquercitrin (quercetin-3-O-β-D-glucose) and astragalin (kaempferol-3-O-β-D-glucose) isolated from A. venetum leaves have significant anti-depressant activities in mice (Yan et al., 2016). Hyperoside isolated from the leaves of A. venetum showed antidepressant-like effect in P12 cell lines which could improve neuronal viability by protecting neurons from corticosterone damage (Zheng et al., 2012). Hyperoside had protective effect on H₂O₂-induced apoptosis of human umbilical vein endothelial cells (Hao et al., 2016). For acetaminophen-induced liver injury, both hyperoside and isoquercetin exerted hepatoprotective effect by upregulating the expression and activity of detoxifying enzymes such as sulfotransferases (hyperoside could also increase activities of UDP-glucuronosyltransferase) in liver microsomes and inhibited the activity of cytochrome P450 2E1, accelerating the harmless metabolism of acetaminophen. Additionally, isoquercetin could significantly inhibit acetaminophen induced oxidative stress and nitrosative stress (Xie et al., 2016a; Xie et al., 2016b). Isoquercitrin, isolated from the A. venetum leaf aqueous extract exerted anti-obesity effect in high fat diet induced obese mice by inhibiting adenosine 5′-monophosphate-activated protein kinase (AMPK)/sterol regulatory-element binding protein (SREBP-1c) signaling pathway, glucose uptake, and glycolysis flux. C-1-tetrahydrofolate synthase, carbonyl reductase, and glutathione S-transferase P are potential target proteins of isoquercitrin (Manzoor et al., 2022). 8-O-methylretusin (Fig. 3) isolated from A venetum leaves showed antifouling activity (Kong et al., 2014). On the other hand, 4′,7-dihydroxy-8-formyl-6-methoxyflavone isolated from A venetum leaves showed high anti-inflammatory activity via significant inhibitory effect on the production of nitric oxide (NO) and tumor necrosis factor-α (TNF-α) (IC₅₀ values were 9.0 ± 0.7 and 42.1 ± 0.8 µM, respectively) in lipopolysaccharide-induced mouse peritoneal macrophages (RAW 264.7) (Fu et al., 2022).

Table 2:

Flavonoids isolated from A. venetum between 2012 to 2022.

Class	Compound identified	Bioactivity	Plant part isolated from	Reference
Flavonols	Tamarixetin		70% methanol extract in A. venetum leaves	Gao et al. (2019), Yan et al. (2016)
	Isorhamnetin		95% ethanol extract in A. venetum leaves	Huang et al. (2017)
	4′-hydroxy-7-O-(4-hydroxybenzyl)-3-methoxy-6-prenylflavone	anti-inflammatory	The ethyl acetate -soluble extract of the leaves of A. venetum	Fu et al. (2022)
	Myricetin		75% ethanol extract in A. venetum leaves	Zhang et al. (2022)
Flavones	Luteolin	antidepressant	70% methanol extract in A. venetum leaves	Gao et al. (2019)
	Isoorientin			Gao et al. (2019)
	Apigenin			Gao et al. (2019)
	Acacetin			Gao et al. (2019)
	Acacetin-7-O-rutinoside			Gao et al. (2019)
	Chrysoeriol-7-O-glucoside			Gao et al. (2019)
	Chrysoeriol	anti-inflammatory	The ethyl acetate -soluble extract of the leaves of A. venetum.	Fu et al. (2022)
	6,7-dimethoxy-4′-hydroxy-8-formylflavone	anti-inflammatory		Fu et al. (2022)
	4′,7-dihydroxy-8-formyl-6-methoxyflavone	anti-inflammatory		Fu et al. (2022)
Flavonones	Hesperidin		70% methanol extract in A. venetum leaves	Gao et al. (2019)
	Neocarthamin			Gao et al. (2019)
	Bavachin	anti-inflammatory	The ethyl acetate -soluble extract of the leaves of A. venetum.	Fu et al. (2022)
Flavonol glycosides	Kaempferol-3-O-(6″-O-malonyl)- galactoside		70% ethanol extract in A. venetum leaves	An et al. (2013)
	Kaempferol-3-O-(6″-O-malonyl)- glucoside			An et al. (2013)
	Eriodictyol-7-O-glucoside		70% ethanol extract in A. venetum leaves	Zhao et al. (2014)
	Quercetin-3-O-sophoroside		83% methanol extract in A. venetum leaves	Wang et al. (2020)
Flavan-3-ols	Plumbocatechin A	radical-scavenging activity	The ethyl acetate fraction of the methanol extract	Kong et al. (2014)
Isoflavones	8-O-methylretusin	antifouling activities		Kong et al. (2014)
Anthocyanidins	Delphinidin		70% methanol extract in A. venetum leaves	Gao et al. (2019)
	Pelargonidin			Gao et al. (2019)
	Malvidin			Gao et al. (2019)
	Peonidin			Gao et al. (2019)
	Cyanidin			Gao et al. (2019)
Proanthocyanidins	Procyanidin c1			Gao et al. (2019)
	Procyanidin			Gao et al. (2019)
Chalcones	Carthamin			Gao et al. (2019)

DOI: 10.7717/peerj.14966/table-2

Wang et al. (2020) investigated the absorption and metabolism of quercetin-3-O-sophoroside, isolated from the leaves of A. venetum, in rats. The results indicated that quercetin-3-O-sophoroside was completely absorbed in the small intestine and metabolized in the jejunum to sulfated quercetin-3-O-sophoroside, methylated quercetin-3-O-sophoroside, and methylated quercetin-3-O-sophoroside sulfate. Quercetin-3-O-sophoroside was deglycosylated to aglycones by the cecal microbiota to form derivatives of benzoic, phenylacetic and phenylpropionic acids (Wang et al., 2020).

To obtain larger amounts of flavonoids, A. venetum hairy roots were induced with Agrobacterium rhizogenes strain Ar.1193, and 117 kinds of flavonoids were detected in the roots. The flavonoid content and antioxidant activity of the roots were significantly increased as compared to field-planted roots, therefore, this technique could be used for large-scale production of flavonoids from A. venetum (Zhang et al., 2021).

Other phytochemical components of A. venetum

Many studies have reported other phytochemicals from A. venetum leaf extracts and their pharmacological effects. The ethanol extract of A. venetum leaf possesses anti-cancer activity. A fraction separated from the extract could inhibit the proliferation of Human PCa cells tumor cells. Lupeol accounted for approximately one-fifth (19.3% w/w) of the components of the fraction and was implicated for the induced cytotoxicity against PCa cells. The fraction and lupeol elicited similar anti-proliferative mechanisms, involving: regulating apoptosis signal molecules (P53, cytochrome c, Bcl-2, and caspase 3 and 8), promoting G2/M arrest through impairing the DNA repair system via downregulating the expression of uracil-DNA glycosylase, as well as downregulating the expression of β-catenin (Huang et al., 2017). In preventing D-galactose-induced oxidative damage in mice, the polyphenol extract of A. venetum was superior to the antioxidant vitamin C (Guo et al., 2020). Within its safe concentration range (0–100 µg/ml), the polyphenol extract of A. venetum inhibited U87 glioma cell proliferation and caused cell apoptosis by affecting NF- κB and genes of other relevant pathways (Zeng et al., 2019). Additionally, A. venetum leaf extract inhibited doxorubicin induced cardiotoxicity through (protein kinase B) Akt/(B-cell lymphoma-2) Bcl-2 signaling pathway (Zhang et al., 2022). The efficacy and mechanism of action of individual chemical components, as well as their possible synergistic effects, of A. venetum leaf extract need to be further investigated.

In addition to flavonoids, polysaccharides and polyphenols, sterols (β-sitosterol, sitgmasterol), triterpenoids (lupeol, uvaol), glycolipids (apocynoside I), natural lignan glycoside (alloside of benzyl alcohol) and amino acids have been isolated from A. venetum (Huang et al., 2017; Sun et al., 2022). A. venetum flowers are rich in free amino acids, accounting for about 3% of the total dried weight, including leucine (13.71 µg/mg), isoleucine (7.86 µg/mg), lysine (2.22 µg/mg), tryptophan (1.67 µg/mg) and valine (1.20 µg/mg) (Jin et al., 2019). Uvaol from A. venetum leaves had potent anti-inflammatory effects on dextran sulfate sodium-induced experimental colitis and lipopolysaccharide-stimulated RAW264 cells (Du et al., 2020). Validation of the activities of other components in A. venetum should be the focus of future studies.

A. venetum fiber

The fiber of A. venetum has been used in textile and paper industries with superior properties compared to other commonly used fibers. Fiber from Apocynum species has a higher average length to diameter ratio (up to 1219) compared to kenaf (209), another natural plant fiber (Liu et al., 2020; Wang, Han & Zhang, 2007; Xie et al., 2012). Another reason for the popularity of A. venetum fabric is the antibacterial effect that A. venetum fiber naturally possesses (Li et al., 2012; Song et al., 2019). Such antibacterial activity might be because: (i) A. venetum fiber has small openings between microstructures, which improve the breathability of the A. venetum fabric, which subsequently destroy the environment for bacterial growth (Han et al., 2008); (ii) the A. venetum stem cells contain tanning agents, which is resistant to microbial decomposition (Thevs et al., 2012); (iii) the presence of water-insoluble polyphenol derivatives confers antimicrobial properties to the fabric (Xu et al., 2020a).

A. venetum is rich in cellulose, but impurities such as pectin, lignin, and waxes must be removed to produce clean fibers (Lou et al., 2019). In the direction of environmental safety and high efficiency, various degumming methods have been proposed, including chemical degumming, biological degumming and microwave-assisted ultrasonic degumming. A study revealed that microwave-assisted ultrasonic degumming showed the advantages of requiring less chemical reagents during degumming (1 kg raw A. venetum bast needed 0.6 kg of reagents while the chemical degumming treatment required 1.34 kg) and shorter time, as well as higher quality (low residual gum content of 5.15%; lignin content less than 3%; whiteness more than 80% in the refined A. venetum fibers) (Li et al., 2020). Degumming methods and the fiber quality of A. venetum reported from 2012 to 2022 are listed in Table 4.

In addition to the textile industry, A. venetum fiber also has many potential applications in medicine as well as in the construction industry. Microcrystalline cellulose (MCC-N) from A. venetum fibers was shown to have a rougher structure and less macrostructure than commercially available microcrystalline cellulose (MCC-C). MCC-N had a crystallinity of up to 78.63% and a thermal stability comparable to that of MCC-C, which made it suitable as a load-bearing material for composite structures, and could be used in polymer composites with high temperature resistance (Halim, 2021). Furthermore, cellulose nanofibers (CNFs) from A. venetum straw were added into poly lactic acid (PLA), and the prepared PLA/CNFs film did not only improve the wettability and permeability of PLA, but also had superior antibacterial properties (the antibacterial growth inhibition rate on Escherichia coli and Staphylococcus aureus were 96.31% and 92.83% at PLA/6% (w/w) CNFs film, respectively). Then, polyvinyl pyrrolidone was added to this film to form a sustained-release nanofiber membrane (PLA/drug-loaded PVP nanofiber membranes), and a purified sea buckthorn was embedded in the drug-loaded film to evaluate its performance. The nanofiber membrane extended and sustained the release of purified sea buckthorn, and the cumulative release reached a maximum of 75.41%. It showed the advantage of a profile with a high initial release followed by a slow diffusion phase (Wang et al., 2021b; Wang et al., 2019a). In addition, when the hydrogel was prepared with chitosan as the matrix, the addition of CNFs improved the mechanical properties and swelling rate of the chitosan-based hydrogel. As the CNFs was 1.5%, the compressive strength of the hydrogel increased by nearly 20%, the swelling capacity reached 140%. In this form, the antibacterial efficacy against Escherichia coli and Staphylococcus aureus were 98.54% and 96.15%, respectively (Wang et al., 2021a). See Abubakar, Gao & Zhu (2021) for further details on the composition, properties and degumming methods of A. venetum fiber.

Other Apocynum species similar to A. venetum: Apocynum pictum Schrenk

Due to excessive exploitation, wild A. venetum has declined in recent years. A similar species, Apocynum pictum Schrenk (Apocynum hendersonii Hook) is often used in the market as a substitute for A. venetum due to their similarity in morphological characteristics and geographical distribution. The incorporation of A. pictum may affect the safety and effectiveness of A. venetum (An et al., 2013; Chan et al., 2015; Zheng et al., 2022). Although A. pictum has not been included in the Chinese Pharmacopoeia (Chinese Pharmacopoeia, 2020), some studies have reported that it is an important medicinal plant (Gao et al., 2021; Jiang et al., 2021a). For the quality control of A. venetum and to explore the potential application of A. pictum, some studies compared the similarities and differences between the two species in terms of genome size, flavonoid content, chemical composition and biological activity. The whole genomes of the two species were both small and similar, with 232.80 megabase (A. venetum) and 233.74 megabase (A.pictum). The contents of quercetin, hyperoside and total anthocyanin in A. venetum were much higher than those of A. pictum, which was considered to be the reason for the difference in color between the two species (Gao et al., 2019). Hyperoside could be a suitable chemical marker to distinguish between the two species (Gao et al., 2019). In addition, A. venetum has a better antioxidant activity than A. pictum (Chan et al., 2015). However, recent studies have shown that the flavonoids from A. pictum (quercetin-3-sophoroside, isoquercetin, quercetin-3-O-(6-O-malonyl)-galactoside) and A. venetum (hyperoside, isoquercetin, quercetin-3-O-(6-O-malonyl)-galactoside, quercetin-3-O-(6-O-malonyl)-glucoside, and quercetin-3-O-(6-O-acetyl)-galactoside) both exhibited significant antimicrobial activity against methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa and the fungus, Aspergillus flavus, but A. pictum was superior to A. venetum in terms of antimicrobial capacity (Gao et al., 2021). Apart from the pharmacological value, in recent years, A. pictum is often studied together with A. venetum because of its high ecological value.

The ecological value of A. venetum and A. pictum

Phytoremediation is one of the appropriate ways to deal with land problems such as drought, salinity and metal pollution (Pilon-Smits, 2005). Apocynum spp. were selected to stabilize sands and restore the degraded saline lands due to their advantages of easy propagation, resistance to harsh environment, and high economic value (Jiang et al., 2021a; Jiang et al., 2021b). The matured seeds of A. venetum appeared to possess higher drought tolerance than seeds of A. pictum. The simulation of the critical values of Apocynum spp. seeds under PEG-6000 simulated drought conditions are summarized in Table 5. Different PEG-6000 concentrations (0%–35%) was used to simulate natural drought conditions to study the effect of drought stress on the germination of Apocynum spp. seeds. The results showed that low concentrations PEG (0–20%) had no significant impact on the germination rate of Apocynum spp. seeds. However, when the concentration was more than 20%, the germination rates of the seeds were reduced, and the negative impact on A. pictum seeds was higher than that on A.venetum. In addition, after the drought stress was alleviated, the seeds were able to germinate under appropriate conditions (Han et al., 2021; Jiang et al., 2021a). Moreover, the membership function (A mathematical tool for representing fuzzy sets) was used to comprehensively evaluate the drought resistance of A. venetum and another desert economic plant, Lycium ruthenicum, by analyzing the physiological and biochemical indices (the content of chlorophyll a, chlorophyll b, proline and soluble sugar, antioxidant enzyme activity, etc.). The results showed that when the soil moisture content was 9.70%, 6.89% and 5.54%, the drought resistance of A. venetum was stronger than that of Lycium ruthenicum (Wang, 2017).

Low concentration of salt solution (0–200 mM NaCl) had no significant effect on the germination rate of current season mature seeds the two species (Jiang et al., 2021a; Shi et al., 2014). However, another study showed that under 200 mM NaCl stress, the growth and development of A. venetum seedlings were inhibited, the phenotypic characteristics (plant height, root length, leaf length, leaf width) were damaged, and the total flavonoid content decreased. However, salt stress increased the content of quercetin and kaempferol in seedlings (Xu et al., 2020b). In addition, the seeds of Apocynum spp. both exhibited high tolerance to lithium salts during germination, particularly LiCl (Table 5) (Gao et al., 2020; Jiang, Wang & Tian, 2018a; Jiang et al., 2018b). The simulated critical value of A. venetum was as high as 196 mM (Jiang, Wang & Tian, 2018a). To put the salt tolerance of A. venetum into perspective, Brassica carinata, another heavy metal tolerant plant with phytoremediation potential, has a germination rate of less than 50% at LiCl concentration above 120 mM (Li et al., 2009). Notably, the addition of lithium in soil did not reduce the concentrations and antioxidant capacity of total flavonoids, rutin and hyperoside in A. venetum leaves (Jiang et al., 2019). Therefore, Apocynum spp. are suitable for the restoration of degraded saline soil in arid areas, and are promising species in the remediation of lithium pollution in the environment (Jiang et al., 2021a; Jiang et al., 2021b; Rouzi et al., 2018).