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Pharmacology & Pharmacy
Prunella vulgaris L. (PV) is a well-known renewable drug resource full of different groups of biologically active substances with a wide range of pharmacological actions and applications in medicine.
- Prunella vulgaris L.
- phytochemicals
- extracting
1. Introduction
Nowadays, the reduction of pharmaceutical production costs along with increasing the efficacy, quality and safety of medicines is of great interest. The use of domestic types of medicinal plant raw materials seems to be economically viable for many researchers. The Prunella Vulgaris L. (PV) has a great scientific interest and practical use as well.
Prunella vulgaris L. (Figure 1) is a perennial herbaceous plant of the Lamiaceae/Labiatae family, originally in Europe and Asia as a widespread plant of temperate climate. Currently, it has an extensive range and grows in all temperate regions of the world, including Eurasia, Africa, America, and Australia [1].
Figure 1. Appearance of Prunella vulgaris at the flowering stage.
It usually grows in low mountains and foothills, forest fringe, sparse birch forests and aspen copses, shrubs, wet and sometimes saline meadows and glades, lake shores and oxbow lakes, riverbed gravel stones, and forest roads [2].
Prunella vulgaris L. has been successfully used as a drug in European and Chinese traditional medicine since ancient times. Prunella vulgaris L. was called a “self-healing” or “all-healing” plant. Prunella vulgaris L. fruits are included in the Chinese Pharmacopoeia [3] and the European Pharmacopoeia [4] in 2017. However, the rest of the PV aerial parts are not included in any country’s pharmacopeia, which makes the plant attractive to scientists.
2. Botany
Prunella vulgaris is a perennial plant 10–50 cm high. It is green and almost glabrous, and its rhizome is creeping and oblique. The stem is erect, simple, and almost glabrous.
The дeaves oblong or ovate, glabrous or sparsely pubescent, entire, sometimes obscurely serrated, 2–6 cm long. The lower leaves on the petioles are longer than the blades, the upper ones are sessile under the inflorescence. The flowers are located in false whorls, in dense capitate, ovoid or oblong terminal, sometimes lateral inflorescences. Bracts broadly ovate or almost round, about 1 cm long, sessile with a heart-shaped base, long pointed, membranous-reticulate, almost glabrous, rarely pubescent, with cilia along the edge, from red to black-violet.
Its calyx is two-lipped, humpbacked above, usually hairy at the base, sessile, or on a short stalk. The upper lip is almost square and flat with three very short sharp teeth.
The corolla purple is 8–12 mm long, 1.5–2 times as long as the calyx. The corolla tube is straight; the upper lip is broadly obovate, concave, and slightly notched at the apex. The lower lip is shorter than the upper ones with an almost round, sharply dentate middle lobe and small rounded ovoid lateral. The filaments of long stamens are located under anther with a subulate, straight or slightly curved process. The nuts are ovoid and elliptical, 1.5–2 mm long, nearly 1 mm wide, trihedral, flat outside, and shiny. The flowering stage occurs between June–September.
It grows on the meadows, forest edges, and glades in shrubs, river valleys and springs, along ditches along the banks of lakes and reservoirs, near housing, and in gardens and orchards. Prunella vulgaris is totally spread in Caucasus, Central Asia, Western and Eastern Siberia, the Far East, Western Europe, North Africa, the Balkans, Asia Minor, Iran, India, Tibet, Mongolia, China, and Japan. In Kazakhstan, it is found in the Tobolsk-Ishim, Irtysh, Semipalatinsk, and Kokshetau regions, as well as in Ulutau, Altai, Dzungarian Alatau, and Western Tien Shan [18].
3. Extracting Methods of PV
Various extraction methods have been used for PV extraction. Aqueous [19,20,21], methanol [22,23,24,25], ethanol [26,27,28], hexane, and ethyl acetate [29] PV extracts are obtained by traditional methods such as heating, boiling, or refluxing (Table 1). However, the disadvantage of these methods is the loss of flavonoids due to hydrolysis, oxidation, and ionization during extraction, as well as a long extraction time. Currently, there are many alternative modern methods for obtaining extracts from medicinal plants that can solve these problems. Such preparation methods include supercritical [30], accelerated solvent [31], pulsed-electric field [32], enzyme-assisted [33], pressurized liquid extraction [34], ultrasonic [35], and microwave [36] extraction.
Table 1. Methods of extraction of Prunella vulgaris.
| Method | Plant Part | Solvent | Liquid/Solid Ratio | Temperature, °C | Time | References |
|---|---|---|---|---|---|---|
| Reflux | Aerial part | DI water | - | 100 | 2 h | [19] |
| Reflux | Herb | DI water | - | 70 | 5 h | [24] |
| Reflux | Herb | 70% ethanol | 2:19 | - | 1 h | [27] |
| Reflux | Herb | 95% ethanol | - | 60 | 4 h | [28] |
| Stirring | Seed | Methanol | 3 × 10 mL methanol g−1 | - | 30 min | [22] |
| Stirring | Herb | Methanol Hexane Ethyl acetate |
9:1 | Room temperature | 48 h | [29] |
| Maceration | Leaves, stems, flowers | Methanol DI water |
2:1 | Room temperature | 16 h 24 h |
[21] |
| Maceration | Aerial part | 80% methanol | - | Room tempersture | - | [25] |
| Maceration | Whole plant | Hexane Cloroform Butanol |
- | - | - | [26] |
| Infusing | Leaves of herbal tea | DI water | 1:1 | 80 | 15 min | [23] |
| Supercritical fluid extraction | Flowers and dried fruit spikes | - | 30 | 2 h | [30] | |
| Ultrasonic | Leaf, spike inflorescence | DI water 70% methanol |
10:1 | 60 | 1 h | [20] |
| Ultrasonic | Herb | from 20 to 60% | from 10:1 to 50:1 | From 40 to 80 | From 10 to 50 | [35] |
| Deep eutectic solvent extraction | Water-deep eutectic solvent | 15 mL·g−1 | 83 | 42 min | [38] |
4. Chemical Composition of PV Plant Parts
The chemical composition of PV is quite diverse and rich in various classes of compounds: mono- and sesquiterpenoids, phenolic acids, flavonoids, polysaccharides, pentacyclic triterpenes, higher fatty acids, vitamins, nitrogen-containing compounds, tannins, etc.
Fazal et al. [50] found that abiotic stresses such as drought, different concentrations of nutrients in the soil, and different light spectra affect the increase in the content of active ingredients, in particular phenolic compounds and flavonoids in PV plants. It has also been defined that the maximum accumulation of the major biologically active substances (BAS) occurs in early flowering. However, high concentrations of BAS are observed from the period of budding through the mass flowering phase. The maximum content of BAS in the aerial part of PV is observed in leaves and inflorescences [51].
The authors Isolated two new compounds from the PV seeds extraction, i.e., amolsamic acid A and B, using methanol and found that the main components are rosmarinic and caffeic acids [29]. Another paper [40] published conflicting data on the presence of rosmarinic acid in the methanolic extract of PV seeds.
In the analysis of 50% ethanol extract obtained from the aerial part, five components were identified: chlorogenic, caffeic, and rosmarinic acids, rutin, and quercetin-3-O-glucoside [54]. It was established that the dominant component is rosmarinic acid and the total content of phenolic compounds PV is 65.53 mg/g, whereas the amount of hydroxycinnamic acids is 45.83 mg/g.
Lin et al. identified 16 components in the PV spike using GC-MS. The basic constituents were squalene (28.03%), linoleic acid (9.96%), and oleic acid (5.51%) [30].
Golembiovska et al. [55] studied the chemical composition of volatile substances of each part of PV (leaves, stems, and roots) grown in Ukraine. They identified 26 hydrocarbons, 13 aldehydes, 10 aromatics, 9 sesquiterpenes, 8 ketones, 7 monoterpenes, 6 acids and esters, and 18 different compounds, where various components predominated in each plant part. According to their study, the main component was squalene, in flowers 164.3 mg/kg, and 156.5 mg/kg in roots.
5. Biological Activities of PV Extracts
5.1. Antiviral Activity
There are literature data on the activity of PV against SARS-coronavirus 2 (SCoV-2) virus infection [65]. The authors demonstrated [66] that an aqueous extract of PV and the compound suramin exhibit a potent inhibitory effect on both wild and mutant (G614) pseudotyped SCoV-2-SP-mediated infections. The IC50 for PV and suramin on this type of infection are 30 and 40 µg/mL, respectively. The results of the study showed that the combination of suramin with PV with a neutralizing antibody against SARS-CoV-2 mediated a more powerful blocking effect against SCoV2-SP-PV and therefore can be used as a new antiviral agent against SCoV-2 infection.
5.2. Antibacterial Activity
Komal et al. showed [19] the growth inhibition of 38 resistant isolates of Escherichia coli strains of the PV ethanolic and aqueous extracts in comparison with ciprofloxacin, ofloxacin, cefixime, and tobramycin by the well diffusion method. It has been established that water and alcohol extracts have a positive effect on the multiresistant strain of Escherichia coli, separately and in combination with each other. In this regard, there is likelihood of using PVs as a maintenance therapy in parallel with standard antibiotics used to treat urinary tract infections.
Patel et al. [69], in their study, tested the in vitro methanol and petroleum ether extracts of PV for activity against Bacillus subtilis, Escherichia coli, Staphylococcus aureus, and Salmonella typhi. Similarly, the in vivo studies were conducted by using peritonitis caused by Escherichia coli on laboratory rats where they were given ofloxacin allopathic antibiotics. The results were compared with those rats which were given herbal extracts under controlled conditions. The study has defined that the petroleum ether extracts exhibit the lowest antibacterial activity compared to the methanol extracts. The PV methanolic extracts effectively restrict the growth of Escherichia coli at 100 µg/mL, Bacillus subtilis at 50 µg/mL, and Staphylococcus aureus at 100 µg/mL, while Salmonella typhi showed complete resistance.
5.3. Antitumor Activity
The cell count kit-8 (CCK-8) on cancer cells from the SCC154 oral squamous cell carcinoma cell line was used in order to assess the antitumor effect of PV distillate. The PV distillate was found to be cytotoxic for SSC154 cancer cells depending on the dosage [41].
According to the study [70], the main components that determine the antitumor properties of PV are caffeic and rosmarinic acids. In this study, chemotherapy was performed in combination with a taxane for treating patients with breast cancer. The mean follow-up time was 41 months. The PV treatment improved a complete response rate and an overall survival time compared to those in the control group (p < 0.05). The three-year overall survival rates were 86.5 and 77.2% among patients in the experimental and control groups, respectively (p < 0.05). In addition, the PV treatment prevents side effects, namely neutrophil fever and chemotherapy-induced anemia. Therefore, PV may be a potential adjuvant in treating breast cancer.
5.4. Antioxidant Activity
Total flavonoid (TFC) content including rosmarinic acid, caffeic acid, and hyperoside directly affects the antioxidant capacity (DPPH• and ABTS•+). Chen et al. [72] revealed a pattern that during the growth of spika, TFC significantly decreased, while the content of salviaflazid increased. Spika had the highest TFC and rosmarinic and caffeic acids, as well as the highest antioxidant activity at the flowering stage, and the highest hyperoside content in a bud-formation period.
An experiment described by Seo et al. [73] with a methanolic extract of PV flowering stems showed a DPPH inhibitory activity of 35.4% and an ABTS inhibitory activity of 61.7% at a concentration of 100 µg/mL. Hwang et al. [26] found that the methanol extract of PV seeds is much more active than the extract obtained from the PV flowering stems.
5.5. Treatment of Thyroiditis-Associated Diseases
Traditional Chinese medicine has been treating thyroid diseases with PV for thousands of years. There are many studies on a potential therapeutic effect of the PV extracts on autoimmune thyroiditis and other types of thyroiditis-dependent diseases [75]. Serum thyroglobulin antibodies (TgAb) and thyroid volume in rats in an experimental model of autoimmune thyroiditis (EAT) dropped sharply after administrating an aqueous extract of PV spikes. In addition, PV induced indoleamine-2,3 dioxygenase (IDO1) mRNA and protein expression in the spleen and intestines of rat EAT treated with PV [52].
Han et al. conducted 13 randomized clinical trials involving 1468 patients. A meta-analysis has shown that PV in combination with levothyroxine sodium tablets or thyroxine tablets has more benefits in thyroid nodules, further increasing clinical efficacy, reducing the diameter of nodules, and reducing the frequency of adverse reactions [76].
5.6. Other Activities
Grosan et al. have identified that the hydroalcoholic extracts of PV in an in vivo experiment have a dose-dependent antiulcer effect due to a rich content of polyphenols which have a protective effect for stomach ulcers when taking the non-steroidal anti-inflammatory drugs (NSAIDs) [40].
The aqueous and methanolic extracts of PV were evaluated for anthelmintic efficacy against ovine gastrointestinal nematodes both in vitro and in vivo using the worm motility inhibition assay, egg hatch assay, and faecal egg reduction percentage assay, respectively. The methanol extract (LC50 = 2.48 mg/mL) has a stronger inhibitory effect compared to an egg hatching aqueous extract (LC50 = 3.36 mg/mL) showing a higher ovicidal activity. In vivo the largest reduction of fecal eggs (92.86%) was recorded for a crude methanol extract, followed by a crude aqueous extract (80.34%) at 2 g/kg body weight on the 15th post-treatment day [21].
The methanolic PV seed extract showed a strong anti-inflammatory activity on neutrophils, myeloperoxidase, and horseradish peroxidase models. The anti-inflammatory effect of PV seed extract was also characterized by its ability to modulate the myeloperoxidase enzyme activity [22]. The results of the study showed that treatment with PV tea (water extract of leaves) significantly increased inducible nitric oxide synthase and demonstrated anti-inflammatory effects through the 5-lipoxygenase, myeloperoxidase, and nitric oxide synthase pathways [23].
Anti-IHNV (infectious hematopoietic necrosis virus) activity was studied on 32 medicinal plants using cyprini papulosum epithelioma (EPC) cells. Among these plants, PV showed the strongest inhibition of IHNV replication, with a 99.3% inhibition rate at 100 mg/L. In addition, it was found that the IC50 of ursolic acid after 72 h on IHNV is 8.0 μM. In addition, UA can significantly reduce a cytopathic effect and virus titer induced by IHNV in EPC cells [80].
An aqueous methanolic extract of the PV aerial part increased wound strength by 33.9% in a linear wound model and caused a 75.2% contraction on the 12th day in a circular wound model. In a postoperative wound model, the ethyl acetate extract increased wound tensile strength by 39.3%, whereas the 86.3% reduction was found in the excisional wound model on the 12th day [25].
All PV parts have antihypertensive effects in the clinical management of hypertension. An aqueous extract and a water-ethanol (30%) extract of PV reduce animals’ blood pressure [81].
6. Dosage Forms and Clinical Applications
In recent years, the PV-based drugs have been of great interest in clinical practice, used both as a separate substance and in combination with other drugs and non-drugs. Currently, PV is used to produce various drugs such as injections, oral liquid, and ointment.
According to the Order of the Ministry of Health of the Republic of Belarus, dated February 25, 1998, No. 56, PV is included in the Nomenclature of Homeopathic Medicines. PV is an active ointment substance for treating burns [82]. It is included in the Liren Bio-lipopolis anti-cellulite firming gel (Lab. Dr Irena Eris Production), a mixture of plant raw materials used to produce the mammoleptin capsules for treating fibrocystic mammopathy, as well as the Frudia face mask (WelcosCo. LTD Production, South Korea). PV is actively used by manufacturers to produce dietary supplements called Selfheal in the form of tablets, and liquid extracts based on PV (manufacturers: Nature’s Health, Secrets of the Tribe, HawaiiPharm).
In order to be used in the form of tablets, the PV extract is dried and compressed. The drug in this form has a broad spectrum of activity, including good results in the treatment of benign prostatic hyperplasia [83]. The authors conducted taxane chemotherapy together with the oral form of PV, which found high efficacy and safety in treating breast cancer patients [70].
This entry is adapted from the peer-reviewed paper 10.3390/ph16081106
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