Isodon rubescens (Hemls.) Hara.: A Comprehensive Review on Traditional Uses, Phytochemistry, and Pharmacological Activities

Isodon rubescens is a medicinal and food plant, often eaten as a wild vegetable in ancient China, and has been widely used for decades to treat sore throats, tonsillitis, colds and headaches, bronchitis, chronic hepatitis, joint rheumatism, snake and insect bites, and various cancers. This comprehensive and systematic review of the ethnomedicinal uses, phytochemical composition, pharmacological activity, quality control and toxicology of I. rubescens provides updated information for the further development and application in the fields of functional foods and new drugs research. To date, a total of 324 substances have been isolated and identified from the plant, including terpenoids, flavonoids, polyphenols, alkaloids, amino acids, and volatile oils. Among these substances, diterpenoids are the most important and abundant bioactive components. In the past decades pharmacological studies have shown that I. rubescens has significant biological activities, especially in the modulation of antitumor and multidrug resistance. However, most of these studies have been conducted in vitro. In-depth in vivo studies on the quality control of its crude extracts and active ingredients, as well as on metabolite identification are still very limited. Therefore, more well-designed preclinical and clinical studies are needed to confirm the reported therapeutic potential of I. rubescens.

Introduction

The genus Isodon (Lamiaceae family) consists of more than 150 species of perennial herbs that are widely distributed in tropical Africa, tropical and subtropical Asia, and East Central Siberia, with a few species in Malaysia, Australia, and the Pacific Islands. There are 90 species and 21 varieties in China, among which the largest number of species is found in the Southwest provinces. I. rubescens (Hemsl.) H. Hara is a perennial herb of the genus Isodon in the Labiaceae family. I. rubescens (Figure 1) is also known as Rabdosia rubescens var. lushiensis, I. rubescens var. eglandulosus, Rabdosia rubescens var. taihangensis, Rabdosia dichromophylla (The Plant List, 2013) as well as under local names such as “Donglingcao,” “Binglingcao,” “Xuehuacao,” “Poxuedan,” “Shanxiangcao,” “Yehuoxiang,” and “Liuyueling” in China (Wei, 2012).

FIGURE 1

FIGURE 1. The aerial part (A), Plant flower (B), Plant leaves (C) (http://ppbc.iplant.cn/), and I. rubescens tea (D).

I. rubescens is sweet and bitter in a prescription and slightly cold after the drug acting on the body, clears away heat, and has detoxifying, anti-inflammatory, analgesic, and antitumor effects. It has been used in the treatment of esophageal cancer in He’nan province in China for more than 50 years (Xiong, 2014). The aboveground parts of I. rubescens are commonly used in traditional Chinese medicine (TCM) for sore throats, tonsillitis, laryngothralgia, colds, headaches, fever, heating, choking, nausea, tracheitis, chronic hepatitis, joint rheumatism, and snake and insect bites. It is also used alone or in combination with other herbs to treat cardiac cancer, liver cancer, lung cancer, prostate cancer, and bladder cancer in TCM (Feng et al., 2008). I. rubescens was first recorded in the “Jiuhuang Bencao” (simplified Chinese: 救荒本草) compiled by Zhu Xun in the Ming Dynasty (A.D. 1368–1644), it was often used as a wild vegetable in ancient China. In addition, many kinds of products related to I. rubescens such as I. rubescens tea, have been developed in the past decades.

In recent years, I. rubescens has received increasing attention due to the diverse chemical constituents and extensive biological activities, as well as its excellent clinical antitumor efficacy (Xue et al., 2007; Xiong, 2014). Previous phytochemical studies of I. rubescens have led to the identification of numerous diterpenoids, triterpenoids, phenols, alkaloids, volatile oils and other compounds. Its crude extract and some of its compounds have antitumor, anti-inflammatory, antibacterial, antioxidant, immunomodulatory, hypoglycemic, diarrheal and other biological activities (Han et al., 2003a). In particular, hundreds of enantio-kaurane and spirofo-kaurane diterpenes discovered in recent years are attracting increasing attention because of their novel structures and diverse biological activities. They have significant anti-proliferative, multidrug resistance (MDR) reversal properties as well as anti-inflammatory and anti-cardiovascular activities (Han, 2018).

To date, 324 compounds have been isolated and identified from I. rubescens. The main compound type are diterpenes of which the most representative one is oronidin (1). The results showed that oronidin has multiple biological activities and especially antitumor activity (Bae et al., 2014). However, the existing literature lacks a systematic review of traditional uses, toxicity, quality assessment, human studies, and newly discovered compounds of I. rubescens. In this review, in light of the widely recognized curative effect of I. rubescens, and hundreds of terpenoids with significant pharmacological activity have been isolated from I. rubescens in the past decades, we attempted to systematically and critically summarize the traditional uses, phytochemical constituents, pharmacological activity, quality evaluation, and toxicity of I. rubescens based on a database of scientific reports on human studies of I. rubescens. We believe that this review will provide important guidance for the further research and development of I. rubescens and its active components.

Materials and Methods

Information for this review (until August 2021) was collected through several popular search engines and databases such as Web of Science, Scifinder Scholar, Google Scholar, ScienceDirect, ACS, PubMed, and classic texts of Chinese herbal medicines (e.g., Jiuhuang Bencao), and other web sources, such as the Flora of China, the Plant List, YaoZh website (https://db.yaozh.com/). The selection criteria of this article were: 1) Research involves the traditional application and modern pharmacological activity of I. rubescens; 2) research involves the preparation of crude extract and the separation and identification of monomer compounds; 3) research involves the determination of the activity of the crude extract and isolated compounds; 4) research involves the mechanism of action; 5) research involves the botany, toxicity, quality control, etc. Exclusion criteria of this review were: 1) Research did not properly address the topic of this review 2) research with obvious defects or unethical problems. Keywords used in the literature search were: “I. rubescens,” “冬凌草,” “phytochemistry,” “pharmacology,” “biological activity,” “traditional uses,” “clinical trial,” “safety,” “quality control,” “medicinal uses,” “toxicology,” and other related search terms. The chemical structures of these compounds isolated from I. rubescens were drawn using the software ChemBioDraw Ultra 14.0 (The world’s leading chemical structure drawing tool can draw various complex structural equations).

Botanical Description and Traditional Usages

Botanical Description

According to the Flora of China, I. rubescens is a shrub of up to 1.2 m in height; Rootstock woody, stem erect, glabrous, branched with inflorescences, young branches very densely tomentose, purplish red. Cauline leaves opposite, base-wide cuneate, lateral veins on both sides very obvious, often purplish red; Petiole gradually shortening toward the top of stem and branch. Cymes, peduncles and peduncles, and rachis densely puberulent, but often purplish red; Bracts tapering upward, much beyond cyme in lower panicle, calyx campanulate, calyx teeth slightly two-lipped, fruity calyx enlarged, tubular campanulate, outer corolla sparsely puberulent and glandular, inner surface glabrous, shallow saccate above corolla tube, corolla eaves two-lipped, filaments flattened, styles filiform, disk annular. Obovate-trigonal nutlets flower from July to October, and bear fruits from August to November. I. rubescens is widely distributed in the Yellow River and Yangtze River basins in the provinces of Hu’bei, Si’chuan, Gui’zhou, Guang’xi, Shan’xi, Gan’su, Shaan’xi, He’nan, He’bei, Zhe’jiang, An’hui, Jiang’xi, and Hu’nan in China (Figure 2) (http://ppbc.iplant.cn/sp/222546). Its main production area is located in the southern part of the Taihang Mountain in Jiyuan, He’nan, with 1,400 hectares cultivation in 2015, and has been recognised as “National Geographical Indication Protected Product” since 2006. I. rubescens has been more used in the local owning to its high quality and clear efficacy. It may be related to the higher content of oridonin (1) and ponicidin (2) in the local I. rubescens.

FIGURE 2

FIGURE 2. The red spots in the map depicted the main region of I. rubescens distribution in China.

Traditional Usages

The first known record of I. rubescens is found in “Jiuhuang Bencao” (simplified Chinese: 救荒本草) (Ming Dynasty, A.D. 1,406), which is an encyclopedia that specializes in endemic plants and combines edible aspects with famine relief. Moreover, I. rubescens is recorded in various versions of the Chinese Pharmacopoeia. In the Chinese pharmacopoeia 2020 edition, I. rubescens is sweet and bitter in a prescription and slightly cold after the drug acting on the body. To the lung, stomach, and liver meridian, it has the effects of clearing away heat, detoxification, activating blood and relieving pain, which are employed for the treatment of sore throats, scratches, snake bites and other diseases. In the Chinese Pharmacopoeia, the recommended dosage of I. rubescens is 30–60 g per day (China Pharmacopoeia, 2020). I. rubescens has also been included in many local herbal standards. For instance, according to the records of He’nan folks materia medica, I. rubescens is often used to treat sore throat, cold and headache, bronchitis, chronic hepatitis, rheumatism and joint pain, snake bites, as well as esophageal cancer, cardia cancer, liver cancer, lung cancer, prostate cancer, bladder cancer, colon cancer, cervical cancer and many other cancers.

According to the folk medicine from the Taihang Mountains area of China, “a bowl of I. rubescens can be consumed daily to prevent wrinkles, remove spots and nourish the appearance, brighten and clear the voice, and drive away the disease of the body and mind”. Relatively few ancient prescriptions of I. rubescens are reported, but since the 1980s, the number of studies on I. rubescens has been increasing. I. rubescens related drugs and compatible formulations have emerged one after the other. The relevant ingredients and contents of the treatment of diseases are shown in Table 1. In clinical practice, I. rubescens is usually used alone or in combination with other TCM herbs. Many TCM herbs or classical prescriptions containing I. rubescens have been used in the form of decoction, powders, granules, tablets, pills and drop pills. For example, Fufang Donglingcao Lozenge, a representative classic formula containing I. rubescens, Mentha canadensis, Platycodon grandiflorus, and Glycyrrhiza uralensis, improves throat dryness, burning and pain, chronic pharyngitis, and oral ulcers (Deng and Lv, 2017). Overall, I. rubescens may be further studied and applied as a dietary supplement and therapeutic agent.

TABLE 1

TABLE 1. The prescriptions and efficacy indications of I. rubescens in China.

Phytochemical Constituents

Many studies on the isolation and identification of I. rubescens have shown that I. rubescens contains a variety of secondary metabolites, including diterpenoids (1–255), triterpenoids (256–266), phenols (267–301), alkaloids (302–311), essential oils (312–317) and other compounds (318–324). The most important and abundant biologically active components isolated from I. rubescens are diterpenoids, which have excellent antitumor activity. These components should be considered as promising candidates for the future development. The phytochemicals present in I. rubescens, including their names, CAS numbers, formulas of the isolated compounds, are summarized in Table 2. The structures of compounds isolated from I. rubescens are illustrated in Figure 3 showing that diterpenoids are the main components of I. rubescens. To document the advances in the pharmacological study of the listed compounds, these active compounds are shown in Table 3.

TABLE 2

TABLE 2. The chemical constituents isolated from the I. rubescens.

FIGURE 3

FIGURE 3. The chemical structure of compounds from I. rubescens.

TABLE 3

TABLE 3. Biological activities of bioactive compounds and extracts of I. rubescens.

Diterpenoids

Diterpenoids are the main compounds identified from I. rubescens, and 255 diterpenoids have been isolated and identified from the whole plant of I. rubescens. Enantio-kaurikane diterpenes are the most diverse type of terrestrial plant diterpenes with the most diverse molecular structures and biological activities among natural products. Recent studies have shown that some members of this family have antibacterial and antitumor activities. The structural feature of the enantiomer-kauritan type is that the rings A and B share two carbon atoms at positions 5 and 10, forming a bridged ring (Li et al., 2019). Such tetracyclic diterpene molecules can be transformed into complex molecular skeletons through intramolecular cyclization, oxidative cleavage and degradation rearrangement. Therefore, more than 1,500 natural enantiomer-kauritan diterpenoids have been isolated and identified. Among these enantiomer-kauritan diterpenoids, 7, 20-epoxy enantiomer kaureane diterpene has the largest number of isolated compounds and the best activity. The most widely studied enantiomer-kauritan diterpenoid is oridonin (1), and it has been reported that it has an inhibitory effect on a variety of tumor cells including liver cancer, laryngeal cancer, esophageal cancer, colon cancer, gastric cancer, breast cancer, leukemia, pancreatic cancer and other cancers. Oridonin also has anti-dementia, antidepressant, antibacterial and antiviral activities (Ding et al., 2016; Pi et al., 2017; Yang et al., 2018; Zhang D. et al., 2019). Among these bioactive constituents, oridonin (1), ponicidin (2), lushanrubescensin H (46), lushanrubescensin J (48), rabdosin A (130), isodocarpin (135), rabdoternin F (152), shikokianin (153), lasiodin (154), parvifoline AA (161), lasiodonin (173), lasiodoninacetonide (175), rosthorin (203), isojiangrubesin C (227), isojiangrubesin E (229), rabdoternin E (234), 11-O-acetylangustifolin (236), jaridonin (246), 14-O-acetyl-oridonin (247), isodonoiol (248), isodonal (249), rabdosin B (250), effusanin A (251), xerophinoid B (253), and 7,14-O-(1-methylethylidene) oridonin (254), are best known for their antitumor, antioxidant, anti-inflammatory, antibacterial, anti-cardiovascular, anti-dementia, and immune regulatory activities. The components of diterpenes and their derivatives are shown in Table 2, and their structures are shown in Figure 3.

Triterpenes

Triterpenes and their derivatives are well-known in the research of natural phytochemistry for their excellent antitumor activity. Before 2009, 11 triterpenoids (256–266), including ursolic acid (256), oleanic acid (257), β-sitosterol (258), α-amyrin (259), daucosterol (260), betulin (261), eryihrodiol (263), and stigmasterol (265), were isolated and identified from I. rubescens. Among these triterpenoids, ursolic acid is a common triterpenoid compound that exists in natural plants. It has sedative, anti-inflammatory, antibacterial, anti-diabetic, anti-ulcer, blood sugar lowering, and other pharmacological activities and can be used as medicine or emulsifier (Cai, 2009). However, few studies have been recently reported on the biological activities of other triterpenoids.

Phenols

Phenols are important secondary metabolites in nature with a wide range of pharmaceutical activities, such as antioxidant, anti-inflammatory, antibacterial, and antiviral activities. At present, 35 phenolic compounds (267–301) have been separated from the whole plant of I. rubescens and structurally characterized. Salicylic acid (267) is an important raw material for aspirin, salicylamide and other drugs, and can also be used as a disinfectant. Caffeic acid (268), danshensu (271), ferulic acid (276), and other compounds with catechol structure have strong antibacterial, antiviral, antioxidant, and anti-cardiovascular biological activities.

Flavonoids are an important component of phenols. The flavonoid structure is characterized by two benzene rings (A and B-rings) with phenolic hydroxyl groups connected with each other through the central three carbon atoms, with 2-phenylchromone as the basic nucleus. Biologically important secondary metabolites have attracted wide attention due to their extensive pharmacological activities. Up to date, 24 flavonoids (278–301) have been isolated and identified from the whole plant of I. rubescens. Some of these flavonoids form flavonoid glycosides with the hydroxyl groups of monosaccharides or disaccharides at positions 3, 5, 6 and 7 through O-glycosidic bonds. Compounds (282–284, 286, and 289–290) are flavonoids and compounds (278–281, 285, 287–288, and 291–301) are flavonoid glycosides. Among these flavonoid glycosides, 5, 8, 4′-trihydroxyl-6, 7, 3′-trimethoxyl-flavone (294) and pedalitin (279) are modestly active in the inhibition of the nitrite production in macrophages, and 5, 4′- trihydroxy-6, 7, 8, 3′ trimethoxyflavone (297) was demonstrated to be selectively active against HL-60 cells with an IC₅₀ value of 7.55 μM (Bai N. et al., 2010). Phenols are also an important material basis for the antioxidant effect of I. rubescens. A focus of future research should be on the phenols of I. rubescens and the promotion of their development for cosmetics, functional foods and medicine.

Alkaloids

Approximately nine alkaloids (302–311) have been isolated from the whole plant of I. rubescens (Guo et al., 2010). However, the pharmacological activity of most of these alkaloids is still unclear.

Essential Oil and Other Compounds

The stalks and leaves of I. rubescens also contain a series of essential oils. These volatile oils are mainly divided into monoterpenes and sesquiterpene compounds such as α-pinene (312), β-pinene (313), cinene (314), 1,8-cineole (315), p-cymene (316), and β-elemene (317) (Cai, 2009). In addition, fatty compounds (318–320, 323–324) have also been identified from the essential oil of I. rubescens by GC-MS. Moreover, inositol (321) and α-D-fructofuranose (322) have also been identified from I. rubescens (Cai, 2009).

Pharmacological Activities

The crude extracts and several compounds isolated from I. rubescens have been evaluated for their antitumor, antioxidant, anti-inflammatory, antibacterial, anti-dementia, and immune regulatory effects as well as their abilities in the prevention and treatment of cardiovascular and cerebrovascular diseases. Among these effects, the antitumor, antibacterial and anti-inflammatory activities of diterpenoids are the most important and also the most studied effects. Modern pharmacological studies are discussed below, and the main active ingredients are summarized in Table 3. In addition, the main molecular mechanism of the biological activity of I. rubescens is shown in Figure 4.

FIGURE 4

FIGURE 4. Graphical summary of pharmacological properties of I. rubescens.

Antitumor Activity

In several published papers, aqueous and alcoholic extracts of I. rubescens have shown inhibitory activity against a variety of cancer cells, including esophageal, gastric, liver, bladder pain, pancreatic, intestinal, and breast cancers (Ding et al., 2016). The most widely studied and important anticancer active compound in I. rubescens is oridonin (1), whose pharmacological activity has been proven to have significant cytotoxicity against various cancers such as liver, larynx, colon, pancreatic, breast, leukemia, lung, stomach, ovarian and bladder cancers (Ding et al., 2016; Jiang et al., 2017). The compound 14-O-acetyl-oridonin (247) showed a significant influence on the viability of the human cancer cell lines (HepG2, COLO 205, MCF-7, and HL-60), with IC₅₀ values of 30.96, 14.59, 56.18, and 11.95 μM, respectively. Rosthorin (203) exhibited a better activity than 14-O-acetyl-oridonin under the same conditions, with IC₅₀ values of 27.85, 6.63, 51.52, and 10.86 μM, respectively (Bai N. S. et al., 2010). Lushanrubescensin H (46) has significant anti-proliferative activity against tumor cell lines (K562, Bcap37, BGC823, and CA) at the concentrations of 100, 10, 1, 0.1, and 0.01 mg/ml after incubation for 48 or 72 h, and the corresponding IC₅₀ values were 3.56, 13.42, 8.91, and 8.25 μM, respectively (Feng et al., 2008). Lushanrubescensin J (48) is a novel asymmetric ent-kauranoid dimer, which exhibited potent inhibitory activity against K562 cells with IC₅₀ is 0.93 μg/ml (Han et al., 2005). In 2012, Liu et al. conducted a large number of phytochemical studies on I. rubescens and isolated 47 new diterpenoids. Pharmacological studies have shown that rabdosin A (130), isodocarpin (135), shikokianin (153), and lasiodin (154) showed in vitro cytotoxic activity against five species HL-60, SMMC-7721, A-549, MCF-7, and SW-480, which was equal to or stronger than that of the positive drug cisplatin. The structure-activity relationship confirms that unsaturated cyclopentanone is the active center responsible for the cytotoxic activity of enantio-kauri diterpene. The structure of kaurine A (87) is identical to that of oridonin (1) exhibiting unsaturated cyclopentanone fragments, but the nitrogen of kaurinea is replaced with oxygen in oridonin, which results in a greatly different activity. We speculate that the acid pK_a value of the imine conjugate is around 9, which leads to cell culture conditions around pH 7, where only about one percent of the unprotonated molecules can cross the membrane and enter the interior of the cell, such as other enantiotopic kauri diterpenes, which do not contain nitrogen (Liu, 2012). The drug resistance caused by chemotherapy during the treatment of malignant tumors has an important effect on the efficacy and prognosis of tumor patients. Jaridon 6 (200) is a novel diterpenoid isolated from I. rubescens, which can promote the early apoptosis of MGC803/5-FU cells. At the same time, it inhibited the proliferation of MGC-803 cells in a dose and time-dependent manner by blocking the G0/G1 phase. It decreased the protein expression levels of p-PI3K, p-AKT and p-GSK-3β in MGC803/5-Fu cells, increased the expression of cleaved caspase-9, cleaved caspase-3, and cleaved caspase-7 cleaved PARP-1 protein activated the intracellular caspase pathway and promoted apoptosis (Han, 2018). Jaridonin (246) exhibited strong anti-proliferative and pro-apoptotic effects in human EC cell lines by the activation of the mitochondria mediated apoptotic pathway, induction of G2/M arrest, as well as increased expression of p53 and p21 (Ma et al., 2013). Similarly, isojiangrubesin B (226), isojiangrubesin E (229), effusanin A (251), and 7, 14-O-(1-methylethylidene) oridonin (254) exhibited a significant inhibitory ability against all cell lines (HL-60, A-549, SMMC-7721, MCF-7, and SW-480), with IC₅₀ values ranging from 0.5 to 6.5 μM. Their cytotoxic activity was better than that of cisplatin, but worse than that of paclitaxel (Zhang L. et al., 2017). These reported antitumor activities are consistent with the traditional usage such as the treatment of liver cancer, esophageal cancer, cardia cancer, lung cancer, prostate cancer, bladder cancer, colon cancer, breast cancer, cervical cancer, and gastric cancer. The pharmacological studies of the inhibition of tumor cells of esophageal cancer and oral cancer by I. rubescens also confirmed the traditional application of I. rubescens in the treatment of sore throat, tonsillitis, pharyngitis and stomatitis. Therefore, I. rubescens tea can be consumed as a daily health drink by patients with pharyngitis.

In short, I. rubescens has significant antitumor activity and good health and medical effects on humans. However, it is worth noting that most of the research on its antitumor activity is still in its infancy, and the use of in vitro methods, further in-vivo and mechanism of action investigations and clinical research should therefore be encouraged and strengthened. Among the compounds isolated from I. rubescens, diterpenoids showed excellent antitumor activity in vitro, but the specific mechanism of action is not well understood yet, and further studies on the mechanism of action are needed in the later stage. The antitumor activity of other compounds, such as flavonoids and triterpenoids, needed to be urgently enhanced.

Antibacterial Activity

Ethanol extract of I. rubescens has an obvious antibacterial effect on Staphylococcus aureus and Streptococcus A hemolyticus. The minimum effective concentration was in the range of 1:128–1:256. The effect of the ethanol extract of I. rubescens on Escherichia coli was very weak, and the inhibitory effect of the water extract of I. rubescens on Staphylococcus aureus and Escherichia coli indicated that the effective antimicrobial component of I. rubescens was soluble in alcohol. Total diterpenes of I. rubescens also showed a strong inhibitory activity against Staphylococcus aureus and Staphylococcus albicans, and 80% acetone and ethanol extracts of I. rubescens had relatively higher antibacterial activities against Gram-positive strains with the lowest minimum inhibitory concentration and minimum bactericidal concentrations of 5 and 10 mg/ml, respectively (Feng and Xu, 2014). In vitro experiments showed that the extracts of I. rubescens had a certain inhibitory effect on Verticillium groundnut, and its n-butanol site had the best inhibitory activity with an inhibition rate of 94.61% and an EC₅₀ value of 0.67 mg/ml which is the focus of antibacterial activity tracking. Extracts of I. rubescens had the best inhibitory activity against Zygomycetes of maize, wheat, tobacco, apple with EC₅₀ values of 0.261, 0.689, 0.487, and 0.419 mg/ml, respectively. The efficacy of I. rubescens against Rhizoctonia verticillioides was studied, showing that the n-butanol part had the best control effect with an efficacy of 75.52%, and the ethyl acetate part had a better effect on powdery mildew of goldenrod with a long effect time. The possible mechanism is the inhibition of the bacterial growth by the I. rubescens extract by disrupting cell membrane permeability while disrupting the cellular metabolism (Li, 2020). The K-B method was used to screen the antibacterial active ingredients of I. rubescens, and the ethyl acetate part with the highest activity was separated by chromatography.

Several studies have demonstrated a significant inhibitory activity of the isolated compound of I. rubescens against a variety of bacterial strains. Of particular importance is the application of oridonin (1) to prevent methicillin resistance of Staphylococcus aureus (SA), Methcillin-resistant Staphylococcus aureus (MRSA), and β-lactamase-positive Staphylococcus aureus (ESBLs-SA), showing a certain antibacterial activity (MIC is 3.125, 6.25, 6.25 μg/disc) which is strong but still weaker than that of the positive control berberine (MIC is 0.156 μg/disc). Ferulic acid (276) has a certain antibacterial activity against SA and MRSA (MIC is 50 and 50 μg/disc), while salicylic acid (267) has only antibacterial activity against SA (MIC is 50 μg/disc) (Li et al., 2014). The MIC and MBC values of oridonin (1) against the MRSA strain USA300 were 64 and 512 μg/ml, respectively, and the mechanism underlying the antibacterial activity was related to changes in the cell membrane and cell wall permeability, disturbance in the protein and DNA metabolism, and influence on the bacterial morphology (Yuan et al., 2019). In addition, the combination of oridonin (1) and azoles has a synergistic effect on drug-resistant Candida albicans. The mechanism of reversing FLC resistance comprises changes of the expression level of efflux-related genes, inhibition of drug efflux, and induction of apoptosis upon entry of Candida albicans into cells (Chen et al., 2020). The results suggest its potential to provide new leads for the development of highly antimicrobial drugs, which are a source of new lead compounds for the development of novel antimicrobial agents.

Cholera is an acute diarrheal infectious disease caused by the contamination of ingested food or water with Vibrio cholerae. Each year, there are an estimated 3–5 million cases of cholera. CFTR chloride channels are new molecular targets for the treatment of secretory diarrhea. It was shown that oridonin (1) significantly reduced the inward flow of iodine ions in wt-CFTR and F508-CFTR FRT epithelial cells in a dose-dependent manner, and also reduced cholera toxin-induced humoral secretion, making it a candidate compound for the treatment of cholera toxin-induced secretory diarrhea (Luan et al., 2015).

However, many antimicrobial studies have only provided preliminary information. The isolation of bioactivity-oriented antimicrobial compounds and their potential mechanisms of antimicrobial action need to be further investigated.

Anti-Inflammatory Activity

Studies have shown that I. rubescens shows better efficacy on some inflammatory diseases. In the xylene induced auricular edema mouse model, the aqueous extract of I. rubescens was administered orally at a dose of 0.32 g/kg, and the results showed that the anti-inflammatory activity of aspirin was significantly higher than that of the blank group, while the anti-inflammatory activity of the aqueous extract at this dose was significantly higher than that of aspirin at a dose of 30 mg/kg (Tang et al., 2011). The compounds, oridonin (1), hubeirubesin I (111), rabdosin A (130) and lasiokaurin (174) isolated from I. rubescens exhibited obvious NO production inhibitory effects with IC₅₀ values of 6.51, 1.48, 2.25, and 1.36 μM, respectively. In the present study, 6, 7-seco-ent-kaurane diterpenoids, such as compounds 225 and 130 with an α, β-unsaturated ketone moiety, exhibited NO production inhibitory effects, indicating that the α, β-unsaturated ketone moiety is an essential pharmacophore (Wen et al., 2019). The therapeutic effect of the oral administration of oridonin (1) on acetic acid-induced ulcerative colitis in mice was reported in the literature related to the anti-inflammatory effect of oridonin. In addition, the expression levels of TNF-α, IL-1β and IL-6 mRNA in RAW 264.7 cells were significantly reduced after administration of oridonin (10 μmol/L), and Western blot assay showed significantly reduced the expression levels of TNF-α, IL-1β and IL-6 mRNA in RAW 264.7 cells. These results suggest that oridonin can down-regulate the expression of LPS-induced pro-inflammatory factors in RAW 264.7 cells, and its anti-inflammatory immune mechanism is related to the activation of the TLR4-NF-κB signaling pathway. In vivo experimental results suggest that oridonin may target the p38-MAPK and NF-κB signaling pathways to inhibit the development of inflammation and significantly reduce the clinical symptoms of kidney injury in diabetic mice, including increased urine protein, creatinine and blood urea nitrogen levels, thus protecting from diabetic nephropathy (Kang and Liu, 2019). These findings suggest that I. rubescens diterpenoids are potent inhibitors of inflammation and may be useful in the development of anti-inflammatory drugs for the treatment of various inflammation-related diseases. However, studies on the crude extracts of I. rubescens and in vivo models are very limited, and more in-depth studies on the anti-inflammatory effects as well as possible mechanistic studies are urgently needed.

Antioxidant Activity

The crude extracts of I. rubescens have a certain scavenging activity for DPPH radicals, hydroxyl radicals and superoxide anion radicals. Studies showed that the scavenging rate of ethyl acetate extract was better than those of petroleum ether, chloroform and n-butanol extracts for DPPH radicals, hydroxyl radicals and superoxide anion radicals. At a mass concentration of 800 μg/ml, the ethyl acetate extraction site showed better scavenging of DPPH radicals, hydroxyl radicals and superoxide anion radicals of 94.30%, 89.46%, and 87.47% respectively. At the same mass concentration, the scavenging rates of DPPH radicals, hydroxyl radicals and superoxide anion radicals were 72.89%, 71.99%, and 50.60% for the n-butanol extraction site, but only 84.47%, 65.21%, and 20.37% for petroleum ether extraction site, respectively, while the scavenging rates of DPPH radical, hydroxyl radical and superoxide anion radical for the chloroform extraction site were only 62.47%, 63.03%, and 46.31%, respectively. The scavenging rates of DPPH radical, hydroxyl radical and superoxide anion radical by chloroform extraction site were only 62.47%, 63.03%, and 46.31%, respectively. The IC₅₀ values of the ethyl acetate extraction site for DPPH radicals, hydroxyl radicals and superoxide anion radicals was significantly lower than those of the petroleum ether, chloroform and n-butanol extraction sites, but slightly higher than those of VC on DPPH radicals and hydroxyl radicals. The active ingredients of the ethyl acetate extract of I. rubescens were mostly identified by GC-MS as polyphenols, ketones and organic acids, among which the percentage of polyphenols reached 39.15%, which was consistent with the antioxidant activity (Jiu et al., 2018). In 2014, Feng et al. found that the 80% acetone extracts had the highest content of total polyphenols (equivalent to 8.09 mg GAE/g) and flavonoids (equivalent to 5.69 mg RE/g) and the strongest antioxidant activities, followed by those of 80% methanol and 80% ethanol, and finally hexane extracts (Feng and Xu, 2014). Determination of the total phenolic and flavonoid contents revealed that the ethanol extract of I. rubescens was equivalent to 8.40 mg GAE/g and 9.51 mg QE/g of dry weight, and the radical scavenging activities of the ethanol extracts were evaluated based on DPPHC and ABTSC⁺ radicals. The free radical scavenging capacities of the ethanol extracts were 198.90 and 303.74 μM, respectively, equivalent to the amount of ascorbic acid. Phenolic and total flavonoid contents are important factors that determine the antioxidant activity of the extracts which lays the foundation for the development and utilization of antioxidant products of I. rubescens (Zhang Y. et al., 2017). In addition, oridonin isolated from I. rubescens has antioxidant properties and protects human keratin-forming cells from hydrogen peroxide-induced oxidative stress. Low doses of oridonin (1–5 µM) protected keratin-forming cells from hydrogen peroxide-induced apoptosis in a concentration and time-dependent manner and significantly reduced the production of H₂O₂-induced reactive oxygen species in cells (Bae et al., 2014).

Natural antioxidants have attracted much attention because of their high efficiency and low toxicity. It has become an inevitable trend in the development of modern medicine and health care industries to find new antioxidants from natural products that can remove free radicals in the body. Numerous antioxidant experiments have confirmed that I. rubescens has the potential to become a natural antioxidant. It can eliminate free radicals or inhibit the activity of free radicals, thereby helping the body maintain sufficient antioxidant status.

Hypoglycemic Activity

In 2020, Xue et al. found that ethanolic and aqueous extracts (0.06–1.00 g/L) of I. rubescens could increase the activity of DMEM-treated human umbilical vein endothelial cells (HUVECs). Treatment with the aqueous extract (0.13–1.00 g/L) resulted in a higher cell viability (101.37%–114.18%) than the positive control (102.49%), while the cell viability of the positive control was higher than that of cells treated with alcohol extracts (90.07%–103.44%). Furthermore, the ethanol extract did not reduce fasting blood glucose in diabetic rats. The results of cell and animal experiments showed that the main hypoglycemic components of I. rubescens are hydrophilic substances (polar components), while alcohol-soluble substances I. rubescens (non-polar components) have no significant hypoglycemic effect. Based on network pharmacology screening, 25 hypoglycemic components of I. rubescens, such as rabdoternin A (148), rabdoternin B (149), and epinodosinol (137), were identified. These components activate six hypoglycemic targets, including 3-hydroxy-3-methyl glutaraldehyde coenzyme A reductase (HMGCR), integrin α-L (ITGAL), integrin β-2 (ITGB2), progesterone receptor (PGR), glucocorticoid receptor (NR3C1) and nuclear receptor subfamily 1I member 2 (NR1I2). These targets are involved in 94 signaling pathways, such as Rap1, PI3K-Akt and HIF-1 signaling pathways (Jintao et al., 2020).

Hepatoprotective Activity

The Global Hepatitis Report 2017, published by the World Health Organization, shows that approximately 325 million people worldwide were infected with chronic hepatitis B virus or hepatitis C virus in 2017. Moreover, 80% of liver cancers are caused by hepatitis B. Chronic hepatitis is the prevalent disease in China, usually caused by liver injury, which evolves into liver fibrosis and eventually leads to cirrhosis and liver cancer. Therefore, the prevention and treatment of liver injury and liver fibrosis receive much research attention. In 2010, Yao et al. found that I. rubescens extract had a protective effect against carbon tetrachloride-induced chronic liver injury and early hepatic fibrosis in mice. It significantly reduced the levels of serum alanine aminotransferase (ALT) and glutathione aminotransferase (AST), decreased the levels of total protein (TP), albumin (ALB), and malondialdehyde (MDA), increased the activity of superoxide dismutase (SOD), reduced the degree of liver tissue degeneration and necrosis, and alleviated the pathological changes of liver tissue (Yao et al., 2010). In 2019, Liu et al. discovered that oridonin (1) can reduce ALT levels in model mice and the expression of α-smooth muscle actin (α-SMA) in the liver of mice with fibrosis. It also reduced the expression of NLRP3, caspase-1, and IL-1β and the infiltration of inflammatory cells. Therefore, oridonin (1) is a potential drug for the treatment of liver fibrosis (Liu et al., 2020). Overall, the findings of these studies lay a research direction that points to prospective therapeutic efficacy of I. rubescens against hepatitis.

Cardiovascular Protective Activity

Cardiovascular disease is a common disease that seriously threatens human health and is characterized by a high prevalence, disability rate, and mortality rate. Cardiovascular diseases kill up to 15 million people worldwide each year, ranking first among all causes of death. In 2017, Kang et al. demonstrated that total flavonoids of I. rubescens can stimulate endogenous protective mechanisms and induce the release of low levels of the cytokines NO and NOS, thereby reducing the release of serum NSE, alleviating ischemia-reperfusion injury in brain tissue and further improving the protective effect of ischemic preconditioning on brain injury (Kang et al., 2017). Moreover, oridonin (1) ameliorated the abnormal elevation of ECG ST segment caused by myocardial ischemia-reperfusion injury. Furthermore, the myocardial infarct area was significantly reduced and serum CK-MB levels were decreased. Oridonin (1) exerted significant cardioprotective effects by regulating energy and amino acid metabolism. Research on the composition and mechanism of action of other components of I. rubescens for cardiovascular protection should be enhanced.

Anti-Alzheimer’s and Antidepressant Activity

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by β-amyloid aggregation, tau protein hyperphosphorylation, and neuroinflammation. In 2013, Zhang et al. found that oridonin significantly attenuated β-amyloid deposition, plaque-associated APP expression and microglial activation in the brain of transgenic mice, and additional in vitro studies indicated that oridonin effectively attenuated the inflammatory reaction of macrophages and microglial cell lines (Zhang et al., 2013). In 2014, Wang et al. found that oridonin could inhibit the mRNA levels of IL-1β, IL-6, COX-2, iNOS, TNF-a, and MCP-1 induced by Aβ, which also up-regulated the expression of IL-10 in Aβ_1-42-induced AD mice (Wang et al., 2014). Oridonin (1) was also found to rescue Aβ_1-42-induced synaptic loss, increase the expression of PSD-95 and synaptophysin in the synaptosomes of AD mice, and promote mitochondrial activity. In addition, oridonin also activated the BDNF/TrkB/CREB signaling pathway in the hippocampus of AD mice and improved the behavioral symptoms of AD mice (Wang et al., 2016). In summary, oridonin is a candidate compound with anti-Alzheimer’s activity. Recently, oridonin was reported to regulate the PPAR-γ/AMPA receptor signaling pathway in the prefrontal cortex and identified as a novel antidepressant with clinical potential (Liu et al., 2020).

Immunomodulatory Activity

In 2011, Liu et al. isolated the polysaccharide fraction RPPSIIa from I. rubescens, analyzed its structural properties and explored its immunological activity. Structure analysis revealed that the polysaccharide RPPSIIa is a homogeneous compound composed of the monosaccharides rhamnose and glucose in the ratio of 7: 93. It can effectively stimulate the proliferation of mouse spleen lymphocytes in a concentration range of 5–100 μg/ml. Moreover, RPPSIIa at the concentrations of 5 and 50 μg/ml can effectively enhance lymphocyte proliferation induced by Con A (Liu et al., 2011). Moreover, oridonin also inhibits the transcriptional activation of the BAFF promoter in macrophages by significantly suppressing BAFF expression and secretion in macrophages. Lupus symptoms and tissue damage in MRL-lpr/lpr mice were effectively reduced by inhibiting BAFF (Zhou et al., 2013).

Quality Control

In the past decades, different methods including TLC, HPLC, UPLC, and UV have been used to analyze the chemical constituents of and control the quality of derivatives isolated from I. rubescens. In 2007, Zou et al. established a reversed-phase high performance liquid chromatography (RP-HPLC) method to determine the content of ursolic acid and oleanolic acid in I. rubescens by using the chromatographic column NUCLEO-DURC18RP (250 × 4.6 mm, 5 μm), a methanol-water mobile phase (87: 13), a flow rate of 0.8 ml/min, and a photodiode array detector (detection wavelength: 210 nm; column temperature: 25°C). The sample recovery rates of ursolic acid and oleanolic acid were 96.2% and 98.7%, and the RSD were 1.9% and 0.9%, respectively (Zou and Chen, 2007). In the 2020 edition of the Chinese Pharmacopoeia, only oridonin was used as the standard for the evaluation of the I. rubescens quality in the pharmaceutical market. According to this source, chromatography was performed using octadecylsilane bonded silica gel as filler and methanol-water (55: 45) as the mobile phase, and the detection wavelength was 239 nm. HPLC analysis of oridonin in the dried aboveground parts of I. rubescens revealed a content of more than 0.25% (Chinese Pharmacopoeia, 2020). In fact, diterpenoids especially oridonin (1) and ponicidin (2), are considered to be the main active ingredients of I. rubescens. Therefore, ponicidin (2) should be also used as quality control marker for I. rubescens and its medicinal extracts.

Due to different cultivation areas and climatic conditions, significant differences in the chemical compositions of Chinese herbal medicines may be found, and the interactions of multiple chemical compounds may contribute to the therapeutic effects of Chinese medicine. Therefore, a simple quantitative analysis of one or two active ingredients in herbal medicines cannot represent their overall quality, and the simultaneous quantitative analysis of active ingredients has become the most direct and important method for the quality of drugs control of TCM. Thus, it is necessary to establish standards for controlling the quality because of the need for its clinical application. In 2011, Zhang et al. established an ultra-high performance liquid chromatography (UPLC) method for the simultaneous determination of the contents of the five main active ingredients in I. rubescens by using a Waters UPLC chromatographic system, an ACQUITY BEH Shield PR18 column (2.1 × 100 mm, 1.7 μm), a mobile phase of 0.1% formic acid methanol solution (A)-0.1% formic acid aqueous solution (B) with a flow rate of 0.2 ml/min (detection wavelengths: 250 and 210 nm; column temperature: 23°C). The chromatographic analysis of the five components of oridonin, ponicidin, rosmarinic acid, oleanolic acid and ursolic acid could be completed within 22 min, the chromatographic peak of each component had a good resolution, and all calibration curves showed good linearity (r² > 0.9991) in the test ranges (Zhang et al., 2011). In 2013, Yuan et al. established an HPLC method for the simultaneous determination of rosmarinic acid, oridonin and chrysoplenetin in I. rubescens. With this method, phenolic acids, diterpenes and flavonoids can be simultaneously determined to obtain more comprehensive information about the intrinsic quality of I. rubescens (Yuan et al., 2013).

I. rubescens has complex components, some of which are low in content, and most diterpenes have weak or no UV absorption. It is particularly difficult to use conventional quality control methods for TCM such as HPLC, UPLC, UV, and TLC for the simultaneous determination of to determine more active ingredients. HPLC-MS/MS provides a good alternative for routine analysis due to its rapidness, sensitivity and specificity, and can be used as a reliable method for the quality evaluation of I. rubescens. In 2010, Du et al. established a new HPLC-MS/MS method for the qualitative identification and quantitative determination of 19 diterpenoids, 6 phenolic acids, and 3 flavonoids in I. rubescens (Du et al., 2010). The separation was carried out on a C₁₈ column with a linear gradient of 0.1% formic acid/methanol containing 0.1% formic acid at a flow rate of 0.7 ml/min. This method has been successfully applied to the qualitative and quantitative analysis of 28 chemical components in natural and planted I. rubescens samples from different sources, providing strong support for the quality control of I. rubescens. Although the commonly used method for the determination of the content of I. rubescens is HPLC, considering the multiple components and efficacy of TCM, new determination methods should be studied and developed.

Toxicity

Information on the side effects and safety evaluations of I. rubescens and its active ingredients is limited, and no major side effects have yet been discovered. The 2020 edition of the Chinese Pharmacopoeia recommends an exact dose of 30–60 g per day of I. rubescens (China Pharmacopoeia, 2020). In 2000, the chronic toxicity of I. rubescens tablets was measured by the intragastric administration of SD mice with a dose of 20 or 40 g/kg/day for 21 days, the results showed that the long-term administration of I. rubescens tablets had no toxic side effects on the organism (Hu et al., 2000). In 2011, Hu et al. observed the acute toxicity of the active parts of I. rubescens, and the mass fraction of oronidin in I. rubescens extract determined by HPLC was 62.4%. The maximum tolerated dose (MTD) of the effective parts of I. rubescens was 20 g/kg/d, which is 480 times the dose commonly used in human clinical administration, suggesting that the effective parts of I. rubescens had no toxicity in mice (Hu et al., 2011). In another safety evaluation experiment, the results of the acute oral toxicity test showed that the MTD of a concentrated solution of I. rubescens was greater than 20.3 g/kg/bw in Kunming mice of both sexes. The genetic toxic effects of different I. rubescens concentrations were verified in the three genetic toxicity tests of micronucleus test, sperm malformation test and Ames test of the cells, in vivo and in vitro in three aspects, revealing negative results. The 90 days feeding test showed that I. rubescens powder had no obvious toxic and side effects on the observed indexes of rats, and the maximum dose of I. rubescens powder was 5.0 g/kg/bw (Ma, 2010). In conclusion, the toxicity study of I. rubescens and its active components and traditional Chinese medicine preparations showed no toxicity, allowing for the development of I. rubescens related drugs and health food.

Conclusion and Future Perspectives

TCM is an important part of ancient medicine because of its wide range of uses, numerous types of chemical components, extensive pharmacological activity and reliable clinical effects. Moreover, it is an important source of lead compounds from numerous types of chemical components for modern drug development. In this review, we summarize the research progress in botany, ethnobotanical uses, phytochemistry, pharmacology, quality control and toxicity of I. rubescens. In ancient and modern China, I. rubescens was widely used to treat various diseases. Traditionally and ethnobotanically, I. rubescens was used for the treatment of esophageal, cardiac, liver, breast, rectal and other cancers, as well as sore throat, cold and headache, tracheitis, chronic hepatitis and snake and insect bites. To date, 324 compounds have been isolated and identified from this plant. A variety of biological activities have been reported for these components, especially their excellent and broad antitumor activity. Among these components, diterpenoids are the major bioactive component, but a large number of studies have focused on the pharmacology of enantio-kaurane type diterpenoids, such as oridonin (1) and ponicidin (2), and oridonin was touted as the second best bioactive component after paclitaxel. A variety of Chinese medicinal preparations including I. rubescens tablets and dropping pills, have been marketed, and clinical studies on the effective ingredient oridonin have also been carried out. It can be expected that further studies may reveal more enantio-kaurane type diterpenes. Based on the described pharmacological activities of I. rubescens, many studies have been conducted using different in vivo and in vitro experimental biological techniques that support most of its traditional medicinal uses. However, scientific research on I. rubescens still exhibits gaps. Therefore, we summarize several topics herein that should be prioritized for future detailed investigation.

Firstly, diterpenoids have always been considered to be the most important active compounds in I. rubescens, because of their wide variety and extensive pharmacological studies. However, research on new saponins, alkaloids and flavonoids isolated from I. rubescens is still neglected, which seriously limits the diversity of I. rubescens research and application. Secondly, current research mainly focuses on antitumor pharmacological activities, and research on other traditional applications of I. rubescens in the treatment of bronchitis, rheumatic joint pain, snake and insect bites, etc. needs to be strengthened. Thirdly, the metabolism and serum pharmacology of I. rubescens and its active components should be further studied by in vivo and in vitro methods. Fourth, the diterpenoids in I. rubescens generally have antitumor activity. Research on structure-activity relationships should be increased to find the core chemical structure of antitumor drugs, and provide effective molecules for the creation of new drugs of I. rubescens. Last but not least, similar pharmacological activities of these different components that contribute to the pharmacological activity of crude I. rubescens have been reported, but the relationship between these components including synergistic or antagonistic effects should be clarified in future studies.

In conclusion, I. rubescens is a valuable medicinal resource. However, more comprehensive studies on the pharmacodynamics, metabolism, pharmacokinetics, toxicity and side effects as well as clinical trials are required to demonstrate the efficacy and safety of extracts of active compounds of I. rubescens. We also expect to find new skeletons and new active molecules of I. rubescens.

Author Contributions

XD and YL obtained the literatures. XC wrote the manuscript. XH and GG gave ideas and edited the manuscript. All authors approved the paper for publication.

Funding

This work was supported by the Program for the Science and technology projects of Guizhou Province (Qian Kehe foundation-ZK (2021) General-550; Qian Kehe Platform Talents (2018)5772–074; Qian Kehe Platform Talents (2019)-017), and the Science and Technology Project of Zunyi (Grant No. ZSKH-HZ-(2020)-78). Logistics Support Department of the Military Commission, (Grant No. CCD16J001; Grant No. CLB19J051).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

Bae, S., Lee, E. J., Lee, J. H., Park, I. C., Lee, S. J., Hahn, H. J., et al. (2014). Oridonin Protects Hacat Keratinocytes against Hydrogen Peroxide-Induced Oxidative Stress by Altering Microrna Expression. Int. J. Mol. Med. 33 (1), 185–193. doi:10.3892/ijmm.2013.1561

CrossRef Full Text | Google Scholar

Bai, N., He, K., Zhou, Z., and Lai, C.-S. (2010). Flavonoids from Rabdosia Rubescens Exert Anti-inflammatory and Growth Inhibitory Effect against Human Leukemia HL-60 Cells. Food Chem. 122 (3), 831–835. doi:10.1016/j.foodchem.2010.03.071

CrossRef Full Text | Google Scholar

Bai, N. S., He, K., Zhu, Z., Tsai, M. L., Zhang, L., Quan, Z., et al. (2010). Ent-Kaurane Diterpenoids from Rabdosia Rubescens and Their Cytotoxic Effects on Human Cancer Cell Lines. Planta Med. 76 (02), 140–145. doi:10.1055/s-0029-1186002

PubMed Abstract | CrossRef Full Text | Google Scholar

Cai, M. L. (2009). Study on the Constituents from Rabdosia Rubescens Hemsl. [Master dissertations]. Xi′an: Shaanxi University of Chinese Medicine.

Google Scholar

Cai, M. L., Gao, H. Y., Huang, J., Sun, B. H., Song, X. M., and Wu, L. J. (2008). Chemical Constituents from the Aerial Part of Dongling. J. Shenyang Pharm. Univ. 25 (11), 856–874. doi:10.14066j.cnki.cn21-1349/r.2008.11.003

CrossRef Full Text | Google Scholar

Chen, H., Li, H., Duan, C., Song, C., Peng, Z., Li, H., et al. (2021). Reversal of Azole Resistance in Candida Albicans by Oridonin. J. Glob. Antimicrob. Resist. 24 (24), 296–302. doi:10.1016/J.JGAR.2020.10.025

CrossRef Full Text | Google Scholar

Chinese Pharmacopoeia (2020). Editorial Committee of Chinese Pharmacopoeia, 2020. Beijing: China Medical Science and Technology Press.

Google Scholar

Dai, Y., Song, Z. R., and Li, J. (2015). Extraction Characteristics of Polysaccharides, Total Flavonoids and Oridonin from Rabdosia Rubescens. J. Jinggangshan Univ. (Natural Science). 36 (03), 93–98. doi:10.3969/j.issn.1674-8085.2015.03.019

CrossRef Full Text | Google Scholar

Deng, X. X., and Lv, X. (2017). Comparison of the Efficacy of Donglingcao Dripping Pills and Compound Donglingcao Buccal Tablets in the Treatment of Recurrent Oral Ulcer. He’nan traditional Chin. Med. 37 (04), 733–735. doi:10.16367/j.issn.1003-5028.2017.04.0261

CrossRef Full Text | Google Scholar

Ding, Y., Ding, C. Y., Ye, N., Liu, Z. Q., Wold,Chen, E. A. H. Y., et al. (2016). Discovery and Development of Natural Product Oridonin-Inspired Anticancer Agents. Eur. J. Med. Chem. 2016, 122. doi:10.1016/j.ejmech.2016.06.015

CrossRef Full Text | Google Scholar

Du, Y. F. (2008). Quality Control of Rabdosia Rubescens and Pharmacokinetics of Two Mushroom Components. [Doctor dissertations]. Hebei: Hebei Medical University.

Google Scholar

Du, Y. F., Liu, P. W., Yuan, Z. F., Jin, Y. R., Zhang, X. W., Sheng, X. N., et al. (2010). Simultaneous Qualitative and Quantitative Analysis of 28 Components in Isodon Rubescens by HPLC-ESI-MS/MS. J. Separation Sci. 33 (4–5), 545–557. doi:10.1002/jssc.200900704

PubMed Abstract | CrossRef Full Text | Google Scholar

Feng, S. S., and Xu, J. G. (2014). Profile of Antioxidant and Antibacterial Activities of Different Solvent Extracts from. Rabdosia Rubescens. Int. J. Food Sci. Tech. 49 (11), 2506–2513. doi:10.1111/ijfs.12576

CrossRef Full Text | Google Scholar

Feng, W. S., Li, H. W., Zheng, X. K., and Wang, Y. Z. (2008). Progress in Studies of Chemical Compositions from. Isodon Rubescens. Chin. J. New Drugs. 17 (23), 2003–2007.

Google Scholar

Gao, S. Y., and Wang, L. (2014). Chemical and Pharmacological Effects of Rabdosia Rubescens. J. Harbin Univ. Commerce (Natural Sci. Edition). 30 (01), 1–6. doi:10.19492/j.cnki.1672-0946.2014.01.001

CrossRef Full Text | Google Scholar

Guo, P., Li, Y. S., and Guo, Y. Q. (2010). Research Progress on Chemical Constituents and Pharmacological Activities of. Rabdosia Rubescens. Drug Evaluation Research. 33 (2), 144–147. doi:10.7501/j.issn.0253-6376

CrossRef Full Text | Google Scholar

Han, B. K. (2018). The Antitumor Mechanism of a Novel Diterpene Jaridon 6 from Isodon Rubescens on Gastric Cancer Resistant Cell MGC803/5-Fu. Master, Zhengzhou University, Zhengzhou.

Google Scholar

Han, Q. B., Mei, S. X., Jiang, B., Zhao, A. H., and Sun, H. D. (2003a). Kaurane Diterpenoids from. Rabdosia Rubescens. Chin. J. Org. Chem. 23 (3), 270–273.

Google Scholar

Han, Q. B., Zhao, Q. S., Li, S. H., Peng, L. Y., and Sun, H. D. (2003b). Enantiokaurane Diterpenoids from. Rabdosia Rubescens. Huaxue Xuebao. 04 (07), 1077–1082. doi:10.3321/j.issn:0567-7351.2003.07.021

CrossRef Full Text | Google Scholar

Han, Q. B., Zhao, A. H., Zhang, J. X., Lu, Y., Zheng, L. L., Zhang, Q. T., et al. (2003c). Cytotoxic Constituents of Isodon Rubescens Var. Lushiensis. J. Nat. Prod. 66 (10), 1391–1394. doi:10.1021/np030165w

CrossRef Full Text | Google Scholar

Han, Q. B., Li, M. L., Li, S. R., Mou, Y. K., Lin, Z. W., and Sun, H. D. (2003d). Ent-kaurane Diterpenoids from Isodon Rubescens Var. Lushanensis. Chem. Pharm. Bull. 51 (07), 790–793. doi:10.1248/cpb.51.790

PubMed Abstract | CrossRef Full Text | Google Scholar

Han, Q., Lu, Y., Wu, L., He, Z. D., Qiao, C. F., Xu, H. X., et al. (2005). An Asymmetric Ent-Kauranoid Dimer from Isodon Rubescens Var. Lushanensis. Tetrahedron Lett. 46 (32), 5373–5375. doi:10.1016/j.tetlet.2005.06.004

CrossRef Full Text | Google Scholar

Hu, Y. J., Zhang, J. C., Wang, L., and Cheng, L. (2011). Acute Toxicity Test of Active Parts of Rabdosia Rubescens. Guangming J. Chin. Med. 26 (11), 2216–2217. doi:10.3969/j.issn.1003-8914.2011.011.025

CrossRef Full Text | Google Scholar

Hu, Y. X., Wang, D. P., and Yang, H. (2000). Chronic Toxicity Test of Donglingcao Buccal Tablets. J. Med. Forum 8 (12), 39–40.

Google Scholar

Huang, S. X., Zhou, Y., Pu, J. X., Li, R. T., Li, X., Xiao, W. L., et al. (2006). Cytotoxic Ent-Kauranoid Derivatives from. Isodon Rubescens. Tetrahedron 62 (20), 4941–4947. doi:10.1016/j.tet.2006.02.079

CrossRef Full Text | Google Scholar

Huang, S. X., Pu, J. X., Xiao, W. L., Li, L. M., Weng, Z. Y, Zhou, Y., et al. (2007). Ent-Abietane Diterpenoids from Isodon Rubescens Var. Rubescens. Phytochemistry. 68 (5), 616–622. doi:10.1016/j.phytochem.2006.11.007

PubMed Abstract | CrossRef Full Text | Google Scholar

Jiang, P., Jin, H., Jiang, J. H., Yang, F., Cai, H. H., Yang, P. H., et al. (2017). Single Molecule Force Spectroscopy for In-Situ Probing Oridonin Inhibited ROS-Mediated EGF-EGFR Interactions in Living KYSE-150 Cells. Pharmacol. Res. 119, 479–489. doi:10.1016/j.phrs.2016.11.036

PubMed Abstract | CrossRef Full Text | Google Scholar

Jintao, X., Shasha, Y., Jincai, W., Chunyan, L., Mengya, Y., and Yongli, S. (2020). Network Pharmacological Screening of the Active Ingredients and Hypoglycemic Effect of Isodon Rubescens in the Treatment of Diabetes. Planta Med. 86 (08), 556–564. doi:10.1055/a-1147-9196

PubMed Abstract | CrossRef Full Text | Google Scholar

Jiu, M., Liu, G. C., Zhao, Y. M., Yuan, J. F., and Wang, L. J. (2018). Antioxidant Activity and Component Analysis of. Rabdosia Rubescens. Food Sci. Tech-brazil. 43 (05), 239–244. doi:10.13684/j.cnki.spkj.2018.05.042

CrossRef Full Text | Google Scholar

Kang, J. J., and Liu, X. N. (2019). The New Progress of Oridonin's Anti-inflammatory Effect in the Treatment of many Diseases. Wild Plant Resources of China,. Chin. Wild Plant Resour. 38 (02), 47–51. doi:10.3969/j.issn

CrossRef Full Text | Google Scholar

Kang, L., Miao, M. S., Bai, M., and Tian, S. (2017). Effect of Total Flavonoid in Rabdosia Rubescens on Tolerant Mice Models under Cerebral Anoxia - Sciencedirect. Saudi J. Biol. Sci. 24 (8), 1798–1802. doi:10.1016/j.sjbs.2017.11.015

CrossRef Full Text | Google Scholar

Li, B. L., Shi, Z. X., and Pan, Y. J. (2002). A New Diterpenoid, Taibairubescensin C, from. Isodon Rubescens. Pol. J. Chem. 76 (5), 721–724. doi:10.1002/chin.200235171

CrossRef Full Text | Google Scholar

Li, G. S., Zhang, W., Peng, T., and Guo, M. Z. (2014). Antibacterial Activity of Compounds from Rabdosia Rubescens. World Sci. Technology-Modernization Traditional Chin. Med. 3, 610–613. doi:10.11842/wst.2014.03.031

CrossRef Full Text | Google Scholar

Li, J. S., Bao, L. P., Zha, D. Q., Zhang, L., Gao, P., Zhang, J., et al. (2017). Oridonin Protects against the Inflammatory Response in Diabetic Nephropathy by Inhibiting the TLR4/p38-MAPK and TLR4/NF-Κb Signaling Pathways. Int. Immunopharmacol 55, 9–19. doi:10.1016/j.intimp.2017.11.040

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, M. R., Lu, Y. H., Zhou, M., and Ding, Z. J. (2001). Determination of Oridonin in Donglingcao Syrup by RP-HPLC. Chin. J. Chin. Materia Med. 26 (11), 64–65.

Google Scholar

Li, Q. F., Feng, B. K., Li, W. M., and Xiao, F. (2011). Study on Dissolution Determination of Rabdosia Rubescens Dispersible Tablets. Chin. Traditional Patent Med. 33 (03), 442–445. doi:10.3969/j.issn.1001-1528.2011.03.021

CrossRef Full Text | Google Scholar

Li, S., Zhang, Q., Li, X., Xu, J., and Guo, Y. Q. (2019). Studies on the Chemical Constituents of Rabdosia Rubescens. J. Pharm. Res. 38 (4), 194–197. doi:10.13506/j.cnki.jpr.2019.04.002

CrossRef Full Text | Google Scholar

Li W, W., Wang, J. J., and Ma, D. W. (2019). Synthesis of Enantiokaurane Diterpenes. Prog. Chem. 031 (011), 1460–1471. doi:10.7536/PC190809

CrossRef Full Text | Google Scholar

Li, X. X. (2020). Preliminary Study on Anti-fungal and Insecticidal Activities and Anti-fungal Mechanism of Isodon Rubescens Extract. Master, Zhengzhou University, Zhengzhou.

Google Scholar

Liu, D., Qin, H. L., Yang, B. X., Du, B., and Yun, X. L. (2020). Oridonin Ameliorates Carbon Tetrachloride-Induced Liver Fibrosis in Mice through Inhibition of the NLRP3 Inflammasome. Drug Dev. Res. 81 (04), 526–533. doi:10.1002/ddr.21649

PubMed Abstract | CrossRef Full Text | Google Scholar

Liu, F., Liu, G. Y., Zhou, J., Che, X. P., and Han, R. F. (2011). Purification and Characterization of Rabdosia Rubescens Polysaccharide Rppsiia. Zhongcaoyao Zazhi. 42 (02), 241–243.

Google Scholar

Liu, J., Liang, J. Y., and Xie, T. (2004a). Development of Rabdosia Rubescens (Hemsl.) Hara. Strait Pharm. J. 04 (02), 1–7.

Google Scholar

Liu, J., Xie, T., Wei, X. L., Yang, H., Yang, C. H., and Liang, J. Y. (2004b). Studies on Chemical Constituents of. Rabdosia Rubescens. Chin. J. Nat. Med. 02 (05), 276–279.

Google Scholar

Liu, P., and Du, J. (2020). Oridonin Is an Antidepressant Molecule Working through the PPAR-γ/AMPA Receptor Signaling Pathway. Biochem. Pharmacol. 180 (23), 114136. doi:10.1016/j.bcp.2020.114136

PubMed Abstract | CrossRef Full Text | Google Scholar

Liu, X. (2012). Studies on Chemical Constituents and Bioactivity of Isodort Rubescens and I. Flexicaulis. [Master dissertations]. Wuhan: Huazhong University of Science and technology.

Google Scholar

Liu, X., Xue, Y. B., Dong, K., Li, X. N., Li, Y., Pu, J. X., et al. (2012). Three New Ent-Kaurane Diterpenoids from Isodon Rubescens and Their Cytotoxicities. Chin. J. Nat. Med. 10 (6), 464–470. doi:10.1016/S1875-5364(12)60088-0

CrossRef Full Text | Google Scholar

Lu, F., and Xu, X. J. (2008). Chemical Constituents of Rabdosia Rubescens. Zhongyaocai Zazhi 09, 1340–1343. doi:10.13863/j.issn1001-4454.2008.09.021

CrossRef Full Text | Google Scholar

Lu, H. Y., and Liang, J. Y. (2012). A New Asymmetric Ent-Kauranoid Dimer from. Rabdosia Rubescens. Zhongcaoyao Zazhi 4.01 (2012), 4–7. doi:10.3969/j.issn.1674-6384.2012.01.002

CrossRef Full Text | Google Scholar

Lu, H. Y., Liang, J. Y., and Chen, R. (2007). Studies on the Chemical Constituents of. Rabdosia Rubescens. Chin. J. Nat. Med. 04 (04), 269–271.

Google Scholar

Lu, H. Y., Liang, J. Y., Chen, R., and Yu, J. (2008). Chemical Constituents of. Rabdosia Rubescens. Chem. Industry For. Prod. 04 (03), 7–12.

Google Scholar

Lu, H. Y., Wang, M. H., Zhang, X. Q., Wu, F. H., and Liang, J. Y. (2013). Studies on the Chemical Constituents of. Rabdosia Rubescens. Strait Pharm. J. 25 (12), 193–196.

Google Scholar

Luan, J., Zhang, Y. F., Yang, S., Wang, X., Yu, B., and Yang, H. (2015). Oridonin: A Small Molecule Inhibitor of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Isolated from Traditional Chinese Medicine. Fitoterapia. 100, 88–94. doi:10.1016/j.fitote.2014.11.001

PubMed Abstract | CrossRef Full Text | Google Scholar

Luo, G. Y., Deng, R., Zhang, J. J., Ye, J. H., and Pan, L. T. (2017). Two Cytotoxic 6,7-seco-spiro-lacton-ent-kauranoids from Isodon Rubescens. J. Asian Nat. Prod. Res. 20 (3), 1. doi:10.1080/10286020.2017.1317754

PubMed Abstract | CrossRef Full Text | Google Scholar

Luo, X., Pu, J. X., Xiao, W. L., Zhao, Y., Gao, X. M., Li, X. N., et al. (2010). Cytotoxic Ent-Kaurane Diterpenoids from Isodon Rubescens Var. Lushiensis. J. Nat. Prod. 73 (6), 1112–1116. doi:10.1021/np100110u

CrossRef Full Text | Google Scholar

Ma, Y. C., Ke, Y., Zi, X. L., Zhao, W., Shi, X. J., and Liu, H. M. (2013). Jaridonin, a Novel Ent-Kaurene Diterpenoid from Isodon Rubescens, Inducing Apoptosis via Production of Reactive Oxygen Species in Esophageal Cancer Cells. Curr. Cancer Drug Targets 13 (06), 611–624. doi:10.2174/15680096113139990030

PubMed Abstract | CrossRef Full Text | Google Scholar

Ma, Z. (2010). Study on Immune Regulation of Rabdosia Rubescens and its Safety Assessment. [Master dissertations]. Changsha: Central South University.

Google Scholar

Pi, J., Jin, H., Jiang, J. H., Yang, F., Cai, H. H., Yang, P. H., et al. (2017). Single Molecule Force Spectroscopy for In-Situ Probing Oridonin Inhibited ROS-Mediated EGF-EGFR Interactions in Living KYSE-150 Cells. Pharmacol. Res. 119, 479–489. doi:10.1016/j.phrs.2016.11.036

PubMed Abstract | CrossRef Full Text | Google Scholar

Ren, W., Zhu, S. R., Tao, X. J., Chen, W. M., Ma, J. Z., and Zhu, G. X. (2009). Clinical Study of Donglingcao Dropping Pills in the Treatment of Recurrent Aphthous Ulcer. J. Clin. Stomatol. 25 (12), 40–41.

Google Scholar

Shi, J. F. (1984). Fifty Cases of Chronic Tracheitis Treated with Frost Eggplant Seedling. J. GuiZhou Univ. Traditional Chin. Med. 04 (02), 44–45.

Google Scholar

Shu, J. W., Yuan, F., Wen, C. M., and Yang, G. Z. (2017). Studies on Diterpenoids from Rabdosia Rubescens. J. Green Sci. Technology. 04 (18), 216–218.

Google Scholar

Si, X. W., Li, S. Y., Chen, S. H., and Tan, G. H. (1993). Clinical Report of Yantejia Buccal Tablets in Treating 120 Cases of Diseases in Department of Facial Features. J. GuiZhou Univ. Traditional Chin. Med. 06 (02), 31–32. doi:10.16588/j.cnki.issn1002-1108.1993.04.017

CrossRef Full Text | Google Scholar

Song, F. J., Gao, J., Yang, G. Z., and Wang, S. T. (2011). Chemical Constituents of. Rabdosia Rubescens. Lishizhen Med. Materia Med. Res. 22 (05), 1069–1070. doi:10.3969/j.issn.1008-0805.2011.05.013

CrossRef Full Text | Google Scholar

Sun, H. D., Lin, Z. W., Fu, J., Zheng, X. R., and Gao, Z. Y. (1985). Studies on the Structures of Oridonin and Oridonin B from Xinyang. Acta Chim. Sinica 04 (04), 353–359.

Google Scholar

Tang, J. C., Zhao, M., Wang, Y. J., Kang, G. F., Wu, J. H., Zheng, M. Q., et al. (2011). One Single HPLC-PDA/(-)ESI-MS/MS Analysis to Simultaneously Determine 30 Components of the Aqueous Extract of Rabdosia Rubescens. J. Chromatogr. B Analyt Technol. Biomed. Life Sci. 879 (26), 2783–2793. doi:10.1016/j.jchromb.2011.07.046

PubMed Abstract | CrossRef Full Text | Google Scholar

The Plant List (2013). Version 1.1. Published on the Internet. Available at: http://www.theplantlist.org/(Accessed January 1.

Google Scholar

Wang, D. H., Ji, Z. Q., Wei, S. P., Guo, Z. Y., and Wu, W. (2010). JStudy on Antibacterial Constituents of. Rabdosia Rubescens. Agrochemicals. 49 (06), 410–412. doi:10.16820/j.cnki.1006-0413.2010.06.005

CrossRef Full Text | Google Scholar

Wang, S. L., Yang, H., Yu, L. J., Jin, J. L., Qian, L., Zhao, H., et al. (2014). Oridonin Attenuates Aβ1–42-Induced Neuroinflammation and Inhibits NF-kB Pathway. PLoS One 9 (8), e104745. doi:10.1371/journal.pone.0104745

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, S. L., Yu, L. J., Yang, H., Li, C. S., Hui, Z., Xu, Y., et al. (2016). Oridonin Attenuates Synaptic Loss and Cognitive Deficits in an Aβ1–42-Induced Mouse Model of Alzheimer′s Disease. Plos One 11, e0151397. doi:10.1371/journal.pone.0151397

PubMed Abstract | CrossRef Full Text | Google Scholar

Wei, J. J. (2012). Primary Study on the Formation Mechanism of Chemotype in Isodon Rubescens (Hemsl.) H. Hara. [Master dissertations]. Zhengzhou: Zhengzhou University.

Google Scholar

Wen, C., Chen, S., Yuan, F., Liu, X. M., Song, F. J., Mei, Z. N., et al. (2019). Diterpenoids from Isodon Rubescens and Their Nitric Oxide Production Inhibitory Activity. RSC Adv. 9 (69), 40628–40635. doi:10.1039/C9RA08831H

CrossRef Full Text | Google Scholar

Wu, Q. J., Zheng, X. C., Wang, T., and Zhang, T. Y. (2018). Effects of Oridonin on Immune Cells, Th1/Th2 Balance and the Expression of BLys in the Spleens of Broiler Chickens Challenged with Salmonella Pullorum. Res. Vet. ence. 119, 262–267. doi:10.1016/j.rvsc.2018.07.008

PubMed Abstract | CrossRef Full Text | Google Scholar

Xie, R. J. (2012). Studies on the Chemical Constituents and Bioactivities of Isodon Rubescens and Isodon Serra. [Master dissertations]. Xinxiang: Xinxiang Medical University.

Google Scholar

Xie, R. J., Yan, F. L., Hai, G. F., Hou, R. J., Ding, M. M., and Bai, Y. X. (2011). Two New Diterpenoids and Other Constituents from Isodon Rubescens. Fitoterapia 82, 726–730. doi:10.1016/j.fitote.2011.03.003

PubMed Abstract | CrossRef Full Text | Google Scholar

Xiong, H. (2014). Study on Modern Pharmacological and Chemical Components and Clinical Medication of Isodon Rubescens. Inner Mongolia traditional Chin. Med. 33 (22), 2. doi:10.3969/j.issn.1006-0979.2014.22.081

CrossRef Full Text | Google Scholar

Xue, J., Song, J., and Shen, C. X. (2007). Study on Antitumor Effect of. Isodon Rubescens. Lishizhen Med. Materia Med. Res. 2007 (9), 2277–2278. doi:10.3969/j.issn.1008-0805.2007.09.138

CrossRef Full Text | Google Scholar

Yan, X. B., Lei, M., Ke, Y., Qu, H. L., Yin, P., and Liu, H. M. (2006). Chemical Constituents of Rabdosia Rubescens. J. Chem. Res. 17 (03), 80–82.

Google Scholar

Yang, H. T., and Shen, C. L. (1997). Development of Rabdosia Rubescens Medicated Toothpaste. Oral Care Industry 04 (04), 16–18.

Google Scholar

Yang, J., Ren, X. Y., Zhang, L. P., Li, Y. Y., Cheng, B., and Xia, J. (2018). Oridonin Inhibits Oral Cancer Growth and PI3K/Akt Signaling Pathway. Biomed. Pharmacother. 100, 226–232. doi:10.1016/j.biopha.2018.02.011

PubMed Abstract | CrossRef Full Text | Google Scholar

Yao, H. Z., Li, J. X., and Zheng, H. N. (2010). Protective Effect of Rabdosia Rubescens Extract on CCl₄ Induced Chronic Liver Injury in Mice. Lishizhen Med. Materia Med. Res. 03, 575–577. doi:10.3969/j.issn.1008-0805.2010.03.032

CrossRef Full Text | Google Scholar

Yuan, X. L., Yan, L. H., Zhang, Q. W., and Wang, Z. M. (2013). HPLC Determination of Rosmarinic Acid, Oridonin and Cat's Eye Flavin in Rubescens Vulgaris. Chin. J. Chin. Materia Med. 14, 2343–2347. doi:10.4268/cjcmm20131426

CrossRef Full Text | Google Scholar

Yuan, Z. W., Ping, O. Y., Gu, K. X., Rehman, T., Zhang, T. Y., Yin, Z. Q., et al. (2019). The Antibacterial Mechanism of Oridonin against Methicillin-Resistant staphylococcus Aureus (Mrsa). Pharm. Biol. 57 (1), 710–716. doi:10.1080/13880209.2019.1674342

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, D., Zhou, Q., Huang, D. D., He, L., Zhang, H., Hu, B., et al. (2019). ROS/JNK/c-Jun axis Is Involved in Oridonin-Induced Caspase Dependent Apoptosis in Human Colorectal Cancer Cells. Biochem. Biophys. Res. Commun. doi:10.1016/j.bbrc.2019.04.011

CrossRef Full Text | Google Scholar

Zhang, J. H, Zhou, Y. Y., Sun, Y. X., Yan, H., Han, W. C., Wang, X. Y., et al. (2019). Beneficial Effects of Oridonin on Myocardial Ischemia/reperfusion Injury: Insight Gained by Metabolomic Approaches. Eur. J. Pharmacol. 861, 172587. doi:10.1016/j.ejphar.2019.172587

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, H., Du, X., Pu, J. X., Wang, Y. Y., He, F., and Zhao, Y. (2010a). Two Novel Diterpenoids from Isodon Rubescens Var. Lushanensis. Tetrahedron Lett. 51, 4225–4228. doi:10.1016/j.tetlet.2010.06.015

CrossRef Full Text | Google Scholar

Zhang, H., Pu, J. X., Wang, Y. Y., He, F., Zhao, Y., Li, X. N., et al. (2010b). Four New Ent-Kauranoids from Isodon Rubescens Var. Lushanensis and Data Reassignment of Dayecrystal B. Chem. Pharm. Bull. (Tokyo). 41 (26), 56. doi:10.1248/cpb.58.56

CrossRef Full Text | Google Scholar

Zhang, J. Q., Li, L., and Li, S. J. (2008). Clinical Observation on 160 Cases of Acute Pharyngitis Treated with Donglingcao Tablet. Chin. Med. Mod. Distance Education China 002, 119. doi:10.3969/j.issn.1672-2779.2008.02.016

CrossRef Full Text | Google Scholar

Zhang, J., Yuan, K., Jin, Y. C., and Liu, Y. (2011). Simultaneous Determination of 5 Active Ingredients in Rubescens by UPLC Method. Chin. J. Pharm. Anal. 04, 641–644. doi:10.1142/s1793604711002202

CrossRef Full Text | Google Scholar

Zhang, L., Khoo, C. S., Koyyalamudi, S. R., Pedro, N. D., and Reddy, N. (2017). Antioxidant, Anti-inflammatory and Anticancer Activities of Ethanol Soluble Organics from Water Extracts of Selected Medicinal Herbs and Their Relation with Flavonoid and Phenolic Contents. Pharmacologia 8, 59–72. doi:10.5567/pharmacologia

CrossRef Full Text | Google Scholar

Zhang, Y., Jiang, H. Y., Liu, M., Hu, K., Wang, W. G., Du, X., et al. (2017). Bioactive Ent-Kaurane Diterpenoids from. Isodon Rubescens. Phytochemistry. 143, 199–207. doi:10.1016/j.phytochem.2017.08.009

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, X. H. (2019). Clinical Effect of Donglingcao Capsule Combined with Western Medicine in the Treatment of Chronic Pharyngitis. Chin. J. Clin. Rational Drug Use. 12 (20), 85–86. doi:10.15887/j.cnki.13-1389/r.2019.20.055

CrossRef Full Text | Google Scholar

Zhang, Z. Y., Daniels, R., and Schluesener, H. J. (2013). Oridonin Ameliorates Neuropathological Changes and Behavioural Deficits in a Mouse Model of Cerebral Amyloidosis. J. Cell. Mol. Med 17 (12), 1566–1576. doi:10.1111/jcmm.12124

CrossRef Full Text | Google Scholar

Zhou, L., Sun, L. J., Wu, H. K., Zhang, L. Z., Chen, M. C., Liu, J. W., et al. (2013). Oridonin Ameliorates Lupus-like Symptoms of MRLlpr/lpr Mice by Inhibition of B-Cell Activating Factor (BAFF). Eur. J. Pharmacol. 715 (1-3), 230–237. doi:10.1016/j.ejphar.2013.05.016

CrossRef Full Text | Google Scholar

Zou, J., Pan, L. T., Li, Q. J., Pu, J. X., Yao, P., Zhu, M., et al. (2012). Rubesanolides C-E: The Abietane Diterpenoids Isolated from Isodon Rubescens and Evaluation of Their Anti-biofilm Activity. Org. Biomol. Chem. 10 (26), 5039–5044. doi:10.1039/c2ob25192b

PubMed Abstract | CrossRef Full Text | Google Scholar

Zou, J., Pan, L. T., Li, Q. J., Zhao, J. H., Pu, J. X., Yao, P., et al. (2011). Rubesanolides A. B: Diterpenoids Isodon Rubescens. Org. Lett. 13 (6), 1406–1409. doi:10.1021/ol200086k

CrossRef Full Text

Zou, S. Q., and Chen, W. (2007). Determination of Ursolic Acid and Oleanolic Acid in Rubescens by Reversed-phase High Performance Liquid Chromatography. Lishizhen Traditional Chin. Med. Materia Med. 07, 1577–1578. doi:10.3969/j.issn.1008-0805.2007.07.018

CrossRef Full Text | Google Scholar

Glossary

A549 Human alveolar basal epithelial cells

ALT Alanine aminotransferase

AST Aspartate aminotransferase

ABTS 2, 2′-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid

Aβ amyloid

A.D Anno domini

AKT Proteinkinase B

Aβ1-42 Human amyloid beta peptide 1-42

BAFF B-cell-activating factor

Bcap37 Human breast cancer cells

BGC823 Human gastric cancer cell line

BDNF Brain-derived neurotrophic factor

COX-2 Cyclooxygenase-2

CREB Cyclic-AMP response binding protein

COLO 205 Colorectal cancer line 205

DPPH 2,2-diphenyl-1-picrylhydrazyl

DMEM Dulbecco’s modified eagle medium

EC₅₀ Concentration for 50% of maximal effect

ECG Electrocardiogram

GAE Gallic acid equivalents

GC-MS Gas chromatography-mass spectrometer

GSK-3β Glycogen synthese kinase-3β

HPLC High performance liquid chromatography

HPLC-MS High performance liquid chromatography-mass spectrometer

HL-60 Human promyelocytic leukemia cells

HaCaT Human immortalized keratinocytes

HepG2 Liver hepatocellular cells

HIF-1 Hypoxia inducible factor

HUVECs Human umbilical vein endothelial cells

IC₅₀ Half maximal inhibitory concentration

IL-1β Interleukin-1β

IL-6 Interleukin-6

IL-10 Interleukin-10

iNOS Inducible nitric oxide synthase

K562 Human chronic myeloid leukemia cells

MCF-7 Human breast adenocarcinoma cell line

MDA Malondialdehyde

MIC Minimum inhibitory concentration

MAPK Mitogen-activated protein kinase

MCP-1 Human macrophage chemoattractant protein-1

NLRP3 NOD-like receptor protein 3

NF-κB Nuclear factor-kappa B

NO Nitric oxide

PI3K Phosphatidylinositol 3-kinase

PPAR-γ Peroxisome proliferators-activated receptors

PSD-95 Postsynaptic density protein 95

pKa Dissociation constant

QE Quercetin equivalents

RAW 264.7 Mouse leukaemic monocyte macrophage cell line

RSD Relative standard deviation

SMMC-7721 Human hepatocellular carcinoma cells

SOD Superoxide dismutase

SW480 Human colon cancer cell line

TNF-α Tumor necrosis factor alpha

TLR4 Toll-like receptor 4

TrkB Tyrosine kinase receptor B

TLC Thin layer chromatography

TCM Traditional chinese medicine

UV Ultraviolet-visible spectroscopy

UPLC Ultra-high-performance liquid chromatography.