Isodon rubescens

Isodon rubescens: A Comprehensive Reference

1. Identity: Botanical Classification, Names, and Forms

1.1 Taxonomy and Synonymy

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. Isodon rubescens (Hemsl.) H. Hara is a perennial herb of the genus Isodon in the Labiaceae family.

The plant carries several accepted scientific synonyms and vernacular names. Its primary synonym is Rabdosia rubescens (Hemsl.) H. Hara, also known as R. dichromophylla. The plant is also locally known as "Binglingcao," "Donglingcao," and "Shanxiangcao" in China. The leaves of Isodon rubescens are known in China as "donglingcao" and are used to treat respiratory and gastrointestinal bacterial infections, inflammation, and cancer.

R. rubescens is a perennial herbaceous plant in the family Lamiaceae, mainly found in central and southern China. Rabdosia rubescens is distributed extensively in the Yellow River and Yangtze River basins located in China. Specifically, the focal area of its production is situated in the south of Taihang Mountain in Jiyuan, Henan, and had 1,400 hectares of cultivation in the year 2015. It is recognized as a "National Geographical Indication Protected Product."

1.2 Plant Parts Used and Pharmacopoeial Status

"Donglingcao" is the dry aerial part of Rabdosia rubescens (Hemsl.) Hara. The 2015 edition of the Chinese Pharmacopoeia records its efficacy of clearing away heat and detoxifying, promoting blood circulation and relieving pain.

1.3 Common Forms and Preparations

Many kinds of products related to I. rubescens, such as I. rubescens tea, have been developed in the past decades. The herb is available in multiple commercial formulations: in China, Rabdosia rubescens is a commonly available over-the-counter (OTC) herbal medicine for the treatment of inflammatory diseases. Standardized preparations include Donglingcao tablets (Donglingcao Pian), Donglingcao dropping pills, buccal/lozenge tablets, and raw herb preparations suitable for decoction. The clinical application of oridonin — the primary isolated compound — is limited due to its low solubility and poor bioavailability, and in order to overcome these shortcomings, many strategies have been explored, such as structural modification and new dosage forms. Specifically, oral bioavailability of oridonin stands at only approximately 5%.

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2. Traditional and Historical Use

2.1 Earliest Recorded History

The history of Rabdosia rubescens dates back to the Tang Dynasty in China, when the esteemed traditional medicine master Sun Simiao noted its use for treating hoarseness and sore throats. In 1406, Zhu Zhen's JiuHuang BenCao (救荒本草) described R. rubescens as a field-growing plant known for its square stems, pale purple flowers, and bitter leaves. I. rubescens was first recorded in the "Jiuhuang Bencao" compiled by Zhu Xun in the Ming Dynasty (A.D. 1368–1644), where it was often noted as a wild vegetable in ancient China.

While not explicitly recorded in texts like the Shennong Bencao Jing or Compendium of Materia Medica, Dong Ling Cao appears in regional herbal records such as the Henan Chinese Herbal Handbook and Shaanxi Chinese Herbal Medicine. These sources describe its role in treating sore throats, tonsillitis, and mouth ulcers.

2.2 Traditional Chinese Medicine Applications

In thousands of years of clinical practice, Isodon rubescens (Hemsl.) H.Hara has been widely applied as a central agent in classic traditional Chinese medicine (TCM) formulas with its efficacy of clearing away heat and detoxifying, boosting blood circulation and alleviating pain. Generally, I. rubescens is frequently utilized in the treatment of acute and chronic pharyngitis, tonsillitis, and bronchitis in clinical TCM practice.

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. 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.

In the 1970s, researchers found that tea made from R. rubescens was traditionally used in Henan province (China) to treat "Yege syndrome," which is equivalent to esophagitis, esophageal cancer, and cardia cancer in modern medicine.

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3. Phytochemistry: Key Constituents and Active Compounds

3.1 Overall Chemical Profile

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.

3.2 Principal Diterpenoids

Among the 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 most studied compound is oridonin. Oridonin (PubChem CID: 5321010, CAS No: 28957-04-2, MW: 364.4 g/mol), with the molecular formula of C₂₀H₂₈O₆, is a naturally occurring terpenoid that mainly exists in Isodon rubescens (Hemsl.) H.Hara. Oridonin (C₂₀H₂₈O₆) is a highly oxygenated 7,20-epoxy-ent-kaurane tetracyclic diterpenoid. There is an exo-methylene cyclopentanone moiety at position 16 in the D ring and a 6-hydroxyl-7-hemiacetal group in the B ring.

The botanical Rabdosia rubescens—Chinese name dong ling cao—has two very active agents, oridonin and rubescenin B. Oridonin inhibits DNA synthesis in vitro, and rubescenin B inhibited cell growth in cancer cell lines in vitro and in a mouse model.

Triterpenes and their derivatives are well-known in the research of natural phytochemistry for their excellent antitumor activity. Among the flavonoid and polyphenolic fraction, initial studies to identify and characterize the components responsible for the activity of Isodon species commenced in 1954.

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4. Established Mechanisms of Action

4.1 Anticancer Mechanisms

Oridonin has shown considerable anticancer activities, which include cell cycle arrest, apoptosis induction, and angiogenesis suppression, but the relatively moderate potency and imprecise mechanisms of action have greatly hindered its clinical applications for the treatment of cancer.

Oridonin can effectively inhibit viability of a variety of tumor cells, mainly by inhibiting cancer cell proliferation, promoting apoptosis, but also triggering autophagy. Apoptosis and autophagy were simultaneously induced by oridonin in a time-dependent manner in cancer cell lines, and inhibition of autophagy decreased oridonin-induced apoptosis, indicating that they act in synergy to mediate cell death. Treatment with oridonin caused an increase in NF-κB and p53 activities in a time-dependent manner.

Oridonin is an inhibitor of AKT1 and AKT2 (IC50s = 8.4 and 8.9 μM, respectively). Oridonin inhibits proliferation of KYSE70, KYSE410, and KYSE450 esophageal cancer cells in a dose-dependent manner, halts the cell cycle at the G2/M phase, and induces apoptosis when used at a concentration of 20 μM. It decreases the expression of cleaved poly(ADP-ribose) polymerase (PARP), caspase-3, caspase-7, and Bims, and the protein levels of phosphorylated AKT.

Oridonin, an active component isolated from Rabdosia rubescens, induced SW1990 pancreatic cancer cells to undergo apoptosis through the p53 and p38 MAPK pathways.

In the context of breast cancer, oridonin synergistically enhanced the anti-tumor effect of doxorubicin on aggressive breast cancer by promoting apoptosis and anti-angiogenesis. Additionally, this compound could inhibit angiogenesis and EMT related to VEGF-A, block Notch signaling pathway to inhibit the growth and metastasis of breast cancer, and induce autophagy to promote apoptosis.

Oridonin sensitized cisplatin-induced apoptosis via AMPK/Akt/mTOR-dependent autophagosome accumulation in A549 lung cancer cells. Moreover, it augmented the radiosensitivity of lung cancer cells by up-regulating Bax and down-regulating Bcl-2.

4.2 Anti-Inflammatory Mechanisms

Oridonin has been reported to inhibit NF-κB or MAPK activation to suppress the release of proinflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6.

A landmark finding was reported in Nature Communications: oridonin can target NLRP3 to exert its anti-inflammatory activity. On covalently binding to Cys279, oridonin blocks the NLRP3–NEK7 interaction and the subsequent NLRP3 inflammasome assembly and activation, leading to effective suppression of NLRP3-related diseases. Importantly, oridonin has both preventive and therapeutic effects on mouse models of peritonitis, gouty arthritis, and type 2 diabetes, via inhibition of NLRP3 activation. These results identify NLRP3 as the direct target of oridonin for mediating its anti-inflammatory activity.

According to the literature, oridonin can exert protective effects on LPS-induced acute lung injury (ALI) through Nrf2-independent anti-inflammatory and Nrf2-dependent anti-oxidative activities. It also protects against chemically induced pulmonary fibrosis.

Experimental evidence indicates that oridonin significantly inhibits the protein expression of TLR4, phosphorylated NF-κB, IL-1β, NLRP3, Caspase-1, ASC, and related proteins, and that oridonin may inhibit inflammatory responses by inhibiting TLR4/NF-κB/NLRP3 inflammasome activation.

4.3 Neuroprotective Mechanisms

In animal studies, oridonin inhibited glial activation and decreased the release of inflammatory cytokines in the hippocampus of Aβ_1–42-induced Alzheimer's disease mice. In addition, it inhibited the NF-κB pathway and Aβ_1–42-induced apoptosis, and could attenuate memory deficits in these mice, suggesting that oridonin might be a promising candidate for AD treatment.

According to the literature, oridonin can markedly inhibit experimental autoimmune neuritis (EAN) by lessening local inflammatory reaction and increasing the proportion of immune-regulating macrophages in peripheral nerves, possibly by the Notch pathway, which indicates it can be developed as a potential therapeutic agent for human Guillain-Barré syndrome (GBS) and neuropathies.

4.4 Multidrug Resistance Modulation

In the past decades, pharmacological studies have shown that I. rubescens has significant biological activities, especially in the modulation of antitumor and multidrug resistance.

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5. Scientific Evidence by Area of Use

5.1 Oncology (Cancer)

In vitro and in vivo (preclinical) evidence:

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, pancreatic, intestinal, and breast cancers. The most widely studied and important anticancer active compound 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.

The compound 14-O-acetyl-oridonin showed a significant influence on the viability of 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.

Oridonin reduces tumor growth in patient-derived mouse tumor models when administered at doses of 40 and 160 mg/kg.

Traditional/clinical use context:

Tea made from R. rubescens was traditionally used in Henan province (China) to treat "Yege syndrome," historically equivalent to esophagitis, esophageal cancer, and cardia cancer in modern medicine. In recent years, I. rubescens has received increasing attention due to its diverse chemical constituents and extensive biological activities, as well as its clinical antitumor efficacy.

Evidence strength:

Most of these studies have been conducted in vitro. In-depth in vivo studies on the quality control of crude extracts and active ingredients, as well as metabolite identification, are still very limited. More well-designed preclinical and clinical studies are needed to confirm the reported therapeutic potential of I. rubescens. Overall, the evidence remains preliminary; robust phase II/III randomized controlled trials in human cancer populations are absent from the current published literature.

5.2 Respiratory Tract Conditions (Pharyngitis, Tonsillitis, Bronchitis)

In thousands of years of clinical practice, Isodon rubescens (Hemsl.) H.Hara has been widely applied as a central agent in classic TCM formulas with its efficacy of clearing away heat and detoxifying, boosting blood circulation and alleviating pain. Generally, I. rubescens is frequently utilized in the treatment of acute and chronic pharyngitis, tonsillitis, and bronchitis in clinical practice.

Oridonin is the primary active component in the traditional Chinese medicine Rabdosia rubescens. It is widely employed in clinical therapy for acute and chronic pharyngitis, tonsillitis, as well as bronchitis.

Evidence strength:

Use for pharyngitis, tonsillitis, and bronchitis has longstanding TCM documentation and is recognized by the Chinese Pharmacopoeia (2015 edition). However, large-scale, double-blind randomized clinical trials in Western-standard design are not evidenced in the available literature. The evidence base consists primarily of historical and TCM clinical use plus preclinical pharmacological data.

5.3 Inflammation (General and NLRP3-Related Conditions)

Besides their antitumor activity, Rabdosia rubescens and oridonin have also possessed anti-inflammatory activity. In China, Rabdosia rubescens is a commonly available over-the-counter (OTC) herbal medicine for the treatment of inflammatory diseases.

The discovery that oridonin is a direct covalent inhibitor of NLRP3 — a druggable target relevant to gout, type 2 diabetes, peritonitis, and other inflammatory conditions — was published in Nature Communications (2018). Oridonin has both preventive and therapeutic effects on mouse models of peritonitis, gouty arthritis, and type 2 diabetes via inhibition of NLRP3 activation. This finding remains preclinical; direct translation to human NLRP3-driven diseases requires clinical validation.

5.4 Oral Conditions and Recurrent Aphthous Ulcers

The PMC review of I. rubescens cites a clinical study (Ren et al., 2009) on Donglingcao Dropping Pills in the treatment of recurrent aphthous ulcer, suggesting some clinical-level investigation has occurred for oral mucosal applications. Research has found that oridonin can induce cytotoxic effects in oral squamous cell carcinoma (OSCC) via TNF, NF-κB, and cytokine-cytokine receptor interaction signaling pathways, though further clinical trial validation is stated to be necessary.

5.5 Cardiovascular and Hemostatic Activity

Modern pharmacological studies have shown that oridonin has anti-tumor, anti-bacterial, anti-inflammatory, anti-oxidant, cardiovascular protective, immunomodulatory, and other effects. Compounds including oridonin and ponicidin are best known for their antitumor, antioxidant, anti-inflammatory, antibacterial, anti-cardiovascular, anti-dementia, and immune regulatory activities. Evidence for cardiovascular benefit currently rests on preclinical studies; no dedicated human cardiovascular trials have been identified in the published literature.

5.6 Neuroprotection and Cognitive Function

In an animal model of Alzheimer's disease, oridonin inhibited glial activation and the release of inflammatory cytokines in the hippocampus, inhibited the NF-κB pathway and Aβ_1–42-induced apoptosis, and attenuated memory deficits in Aβ_1–42-induced mice. This evidence is preclinical (animal model) only, and clinical studies in humans with cognitive decline have not been identified in the current literature.

5.7 Antimicrobial Activity

The leaves of Isodon rubescens are used in China to treat respiratory and gastrointestinal bacterial infections. In recent years, numerous achievements have been witnessed on the exploration of pharmacological effects of oridonin, including anti-microbial effects. The antimicrobial evidence is predominantly preclinical (cell and animal studies); rigorous human antimicrobial clinical trials specific to I. rubescens have not been identified in the available literature.

5.8 Hepatoprotective and Renal Protective Activity

Oridonin, found in traditional Chinese herbal medicine Isodon rubescens, possesses a wide range of pharmacological properties, including anticancer, anti-inflammatory, hepatorenal activities, as well as cardioprotective activities, and is widely present in numerous Chinese medicine preparations. The hepatorenal evidence is currently limited to in vitro and animal studies. The paradox of hepatotoxicity and hepatoprotection at different doses is discussed separately under safety (see Section 7).

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6. Body Systems and Health Areas of Association

• Oncology: Oridonin has been proven to have significant cytotoxicity against various cancers including liver, larynx, colon, pancreatic, breast, leukemia, lung, stomach, ovarian, and bladder cancers.
• Respiratory system: Frequently utilized in the treatment of acute and chronic pharyngitis, tonsillitis, and bronchitis in clinical TCM practice.
• Immune and inflammatory system: Covalent binding to Cys279 of NLRP3 blocks NLRP3–NEK7 interaction and subsequent inflammasome assembly and activation.
• Nervous system: Preclinical evidence for attenuation of neuroinflammation and memory deficits associated with amyloid-beta pathology.
• Cardiovascular system: Preclinical cardioprotective effects documented; clinical evidence absent from the current literature.
• Gastrointestinal system: Used in China to treat gastrointestinal bacterial infections.
• Hepatic and renal systems: Preclinical hepatorenal protective effects reported; dose-dependent hepatotoxic risk also documented (see Section 7).
• Musculoskeletal / rheumatological system: Traditional use includes joint rheumatism.
• Oral mucosa: Traditional and early clinical use for sore throat, tonsillitis, and recurrent aphthous ulcers.

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7. Dosage Forms and Dosages Reported in Studies

7.1 Traditional and Registered Pharmaceutical Preparations

The 2015 edition of the Chinese Pharmacopoeia records the efficacy of "Donglingcao" (the dry aerial part of Rabdosia rubescens) for clearing away heat and detoxifying, promoting blood circulation and relieving pain. Registered commercial preparations include Donglingcao Tablets and Donglingcao Dropping Pills, produced and regulated under Chinese pharmaceutical standards. The herb is prepared in TCM as a decoction of the dried aerial parts.

7.2 Preclinical Dosages Referenced in Research

Following rat oral administration of Herba Isodi Rubescentis extract containing oridonin (1.68 mg/kg), pharmacokinetic parameters in rat plasma were obtained with the LC-MS-MS method, revealing an AUC_0-t at 78.45 ± 33.83 ng/mL/h, AUC_0-∞ at 79.29 ± 34.26 ng/mL/h, t_1/2 at 0.19 ± 0.05 h, T_max at 0.69 ± 0.13 h, and C_max at 164.51 ± 58.42 ng/mL.

Oridonin reduces tumor growth in patient-derived mouse tumor models when administered at doses of 40 and 160 mg/kg.

Oridonin exhibited dose-dependent inhibitory effects on caspase-1 cleavage, IL-1β secretion, and cell death when treated with nigericin at doses of 0.5–2 μM in LPS-primed bone marrow–derived macrophages.

In one study examining small cell lung cancer, HE staining revealed a certain degree of cytotoxicity in hepatic tissue after treatment with oridonin at 10 mg/kg.

Intervention of oridonin induced abnormalities in zebrafish, including uninflated swim bladder and pericardial congestion at an EC50 of 411.94 mg/L in vitro, and also decreased the body length of zebrafish.

7.3 Bioavailability Challenge

Oridonin is isolated from Chinese herb Rabdosia rubescens with various biological and pharmacological activities including anti-tumor, anti-microbial, and anti-inflammatory effects. However, the clinical application of oridonin is limited due to its low solubility and poor bioavailability. In order to overcome these shortcomings, many strategies have been explored, such as structural modification and new dosage forms. A number of oridonin derivatives (e.g., HAO472) have been designed and synthesized, and have contributed to substantial progress in the identification of new agents and relevant molecular mechanistic studies toward the treatment of human cancers and other diseases.

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8. Safety Considerations and Interactions

8.1 General Safety Profile

Several lines of evidence indicate that oridonin may exhibit adverse effects, even toxicity under specific circumstances, which has sparked debate and concern about the security of oridonin. Future research directions should emphasize investigating the interrelationship between concentration and pharmacological effects as well as toxicity, and reducing pharmacological toxicity.

8.2 Hepatotoxicity

Reports of hepatotoxicity in relation to high doses or prolonged administration in a few experimental models suggest that dose optimization and comprehensive safety evaluation are essential prior to therapeutic application. Oridonin showed both hepatotoxicity and hepatoprotective effects, which appears paradoxical. Through analysis, it is found that this is mainly related to the concentration of oridonin and the time of administration. It was discovered that oridonin showed antitumor activity on small cell lung cancer, but at the same time, HE staining revealed a certain degree of cytotoxicity in hepatic tissue after treatment with oridonin at 10 mg/kg.

Although oridonin is generally regarded as safe, recent research has revealed a certain level of cytotoxicity to liver tissue, possibly linked to the inhibition of embryonic development.

8.3 Erythrocyte Toxicity (Eryptosis)

A 48-hour exposure to oridonin (≥25 μM) significantly increased cytosolic Ca²⁺ concentration, increased ceramide formation, decreased forward scatter, and triggered annexin V-binding (in greater than 20% of erythrocytes). Oridonin did not decrease ATP concentration and hemolysed fewer than 5% of erythrocytes. These observations reveal a completely novel effect of oridonin: triggering of Ca²⁺ entry and ceramide formation as well as suicidal death of erythrocytes. This effect was observed at supratherapeutic concentrations in an in vitro experimental system; its clinical relevance at pharmacologically achieved doses is not yet established.

8.4 Reproductive and Developmental Toxicity

Recent studies have shown that oridonin can cause suicidal erythrocyte death, induce the expression and activation of CYP2C and CYP3A family, and interfere with the early embryonic development of zebrafish.

The clinical application of oridonin is significantly restricted due to its reproductive toxicity, with the exact mechanism remaining unclear. Oridonin triggered oxidative stress and mitochondrial damage, leading to a notable decrease in WNT6, β-catenin, CLDN1, CCND1, and ZO-1 protein levels, implying that the inhibition of the Wnt/β-catenin signaling pathway and disruption of tight junction may be attributed to cytotoxicity and mitochondrial dysfunction, ultimately resulting in damage to trophoblast cells.

8.5 Drug–Herb Interactions (CYP Enzyme Induction)

It has been shown that oridonin may affect CYP2C and CYP3A encoding enzymes in the body, which raises the potential for pharmacokinetic interactions with co-administered drugs that use these CYP2C and CYP3A pathways. This consideration needs to be further pursued in the context of polypharmacy. Drugs that are substrates of CYP2C or CYP3A4/5 (a very broad category including anticoagulants, immunosuppressants, cardiovascular agents, and numerous chemotherapy drugs) may thus be subject to altered plasma concentrations when co-administered with I. rubescens preparations or isolated oridonin.

8.6 Pharmacokinetic Limitations

Researchers have investigated the pharmacokinetic parameters of oridonin in vivo by means of MS-MS, LC-MS-MS, and other analytical methods with rats and rabbits, which partially interpreted the kinds of events related to the efficacy and toxicity of relevant herbal preparations. The oral bioavailability of oridonin stands at only 5%, raising questions about the extent to which oral formulations achieve pharmacologically active concentrations in tissues. The short plasma half-life observed in rat studies (t_1/2 ~0.19 h) further complicates dosing rationale in the absence of human pharmacokinetic data.

8.7 Use in PC-SPES Combination Product

With the exception of saw palmetto, the herbs in PC-SPES have been used individually or in combination in Traditional Chinese Medicine for a variety of health problems, including those of the prostate, for hundreds of years. PC-SPES was an herbal product that resulted from a collaboration between a chemist at the New York Medical College in Valhalla, New York, and a Chinese herbalist and doctor of TCM in China. Their idea was to combine TCM with the scientific techniques of Western laboratory research. In the United States, a series of in vitro and in vivo laboratory studies on the mixture of herbs used in this TCM formulation showed promising anticancer activity from PC-SPES. PC-SPES was subsequently withdrawn from the US market by the FDA due to contamination with undisclosed pharmaceutical agents, not due to safety signals attributed specifically to I. rubescens.

8.8 Summary of Evidence Gaps

Although significant advancement has been witnessed in this field, some basic and intricate issues still exist, such as the specific mechanism of oridonin against related diseases not being fully clear. Most pharmacological studies have been conducted in vitro. In-depth in vivo studies on the quality control of crude extracts and active ingredients, as well as 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.

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References

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