Research Progress on Single-Ingredient Traditional Chinese Medicines with Exterior-Resolving, Heat-Clearing, and Cathartic Effects Based on Metabolomics-Liaoning Chaohua Pharmaceutical Co., Ltd.

Research Progress on Single-Ingredient Traditional Chinese Medicines with Exterior-Resolving, Heat-Clearing, and Cathartic Effects Based on Metabolomics

Release Date:

2021-02-04

Research Progress on Single-Ingredient Traditional Chinese Medicines with Exterior-Resolving, Heat-Clearing, and Cathartic Effects Based on Metabolomics

Abstract: Taking the names of commonly used Chinese medicinal herbs in the categories of exterior-releasing, heat-clearing, and purgative agents—as listed in the “Thirteenth Five-Year Plan” textbook on Chinese Materia Medica for higher education in the national TCM industry—as the guiding thread, we conducted a literature search in the CNKI and PubMed databases from 2009 to 2019 using the keywords “herbal name” and “metabolomics” in both Chinese and English. A total of 895 relevant studies were identified, of which 70 were selected for inclusion as single-herb research articles. This paper summarizes and synthesizes the literature on the application of metabolomics to the study of single-herb formulations in the categories of exterior-releasing, heat-clearing, and purgative agents. It is proposed that metabolomic studies of single herbs should be conducted under the guidance of TCM theory, closely integrated with their traditional therapeutic effects and clinical applications, and supported by systematic experimental and clinical research. Furthermore, a herbal characterization system consistent with the cognitive principles of TCM syndromes should be established, so as to elucidate, at the molecular level, the material basis and mechanisms of action of these herbs, scientifically define the intrinsic meaning of the “seven emotions” inherent in single-herb formulations, and provide valuable insights for research on the compatibility of herbs based on the “seven emotions” principle as well as on the patterns of drug use in classic prescriptions.

The “Seven Relationships” of traditional Chinese medicine constitute an essential component of its fundamental theoretical framework. China’s earliest specialized pharmacopoeia, the Shennong’s Classic of Materia Medica, summarized the interactions among medicinal substances into seven categories: single use, mutual reinforcement, mutual assistance, mutual inhibition, mutual destruction, mutual incompatibility, and opposition—collectively known as the “Seven Relationships” of TCM. Among these, “single use” refers to the application of a single herb alone to treat a disease characterized by a single, well-defined clinical presentation. ^[1] In the Ming dynasty, Chen Jiamo’s “Bencao Mengquan” records: “There are cases of single-drug therapy, in which a single herb is not combined with other herbs but instead exerts its therapeutic effects through both attack and tonification.” Li Shizhen, in his “Compendium of Materia Medica,” defines single-drug therapy as “a regimen in which a single herb is used without any adjuncts.” In other words, single-drug therapy involves treating disease with a single herb; when the condition is relatively simple, selecting a single agent with strong specificity can achieve the desired therapeutic outcome. Examples include Qingjin San, which uses only Scutellaria baicalensis to treat lung heat and hemoptysis; Duliang Wan, which employs only Angelica dahurica to alleviate headache associated with the Yangming meridian; and Dushen Tang, which utilizes only Panax ginseng to treat collapse of vital qi. Such formulations have been widely applied in clinical practice throughout history. As the foremost of the “seven emotions” in traditional Chinese medicine, single-drug therapy serves as a fundamental principle underlying herbal compatibility. Therefore, conducting modern research on single-drug therapy—tracking and elucidating the mechanisms of action and material basis of individual herbs—will help systematically clarify the scientific essence of herbal compatibility, while also playing a crucial role in the inheritance and development of the theory of the “seven emotions” and in the research and development of innovative traditional medicines.

Traditional Chinese medicine exhibits pharmacological characteristics of multi-component, multi-target, and multi-pathway systemic regulation; however, conventional single-discipline research approaches struggle to elucidate the complex in vivo processes and mechanisms of action underlying these effects. In recent years, the introduction and advancement of systems biology technologies such as metabolomics have provided new methodologies and innovative perspectives for evaluating the therapeutic efficacy of TCM and for investigating its bioactive constituents. ^[2-3] Metabolomics is a omics technology that emerged in the late 1990s, following genomics, transcriptomics, and proteomics. Grounded in molecular biology, it is dedicated to the systematic investigation of the types, quantities, and dynamic changes of metabolic products—endogenous metabolites—under various biological states, including physiological and pathological conditions as well as pharmacological interventions. ^[4] This research primarily employs modern bioanalytical techniques—such as nuclear magnetic resonance, liquid chromatography–mass spectrometry, and gas chromatography–mass spectrometry—to profile endogenous metabolites in biological samples, including body fluids and tissue extracts. Subsequently, multivariate statistical methods are applied to elucidate the patterns of metabolic changes, thereby uncovering the metabolic underpinnings of physiological processes. When metabolomics is integrated into traditional Chinese medicine research, it enables sensitive and comprehensive detection of endogenous metabolic responses to drug administration, allowing for the systematic extraction of holistic information on the organism’s efficacy-related responses. This approach aligns with the holistic, dynamic, and syndrome-based perspectives inherent in TCM, and it offers distinct advantages over conventional analytical methods that focus on single constituents or targets, thus providing a robust platform for the modernization of TCM research. ^[5] In recent years, with the continuous development and advancement of metabolomics and mass spectrometry technologies, metabolomics has been widely applied in modernization research on traditional Chinese medicine, including studies on pharmacological effects, material basis, quality control, and in vivo metabolism.

To systematically and comprehensively summarize the advances in single-herb Chinese medicine research based on metabolomics, this study took the commonly used herbal names listed in the “13th Five-Year Plan” national higher education textbook on Chinese Materia Medica for the TCM industry as a starting point. The focus was on three categories of herbs—those that disperse exterior pathogenic factors, those that clear heat, and those that purge the bowels. Relevant research articles from 2009 to 2019 were retrieved from the China National Knowledge Infrastructure (CNKI) and PubMed databases using the search terms “herbal name” and “metabolomics” in both Chinese and English. A total of 895 domestic and international publications were identified, of which 70 were deemed eligible for inclusion. These 70 studies were then summarized and synthesized, with particular emphasis on the application of metabolomic techniques to investigate the aforementioned three categories of herbs, thereby providing valuable insights for advancing research on the seven emotional interactions in herbal compatibility and the principles governing the use of classic formulae in TCM.

1 Current Research Status

The textbook “Chinese Materia Medica” classifies commonly used Chinese medicinal herbs into 21 categories based on their therapeutic effects, encompassing a total of 567 individual herbs. A preliminary literature search was conducted to compile studies over the past decade that have employed metabolomics to investigate single-herb preparations. The results indicate that metabolomics-based research has been carried out on 131 herbs, covering aspects such as mechanisms of action, the chemical basis of pharmacological efficacy, and toxicity assessment, accounting for 23.10% of the commonly used herbs. Among these, tonifying, heat-clearing, and blood-activating–stasis-resolving herbs are the most frequently studied, together representing 42.75% of all herbs subjected to metabolomic analysis. Herbs with exterior-releasing, heat-clearing, and purgative actions account for 6.11%, 13.74%, and 5.34%, respectively, as shown in Figures 1 and 2.

Herbs that dispel the exterior refer to those whose primary therapeutic action is to expel pathogenic factors from the body’s surface, and they are commonly used to treat exterior syndromes. The textbook “Chinese Materia Medica” lists 36 commonly used exterior-dispelling herbs (21 for dispersing wind-cold and 15 for dispersing wind-heat). Among these, eight single-herb exterior-dispelling agents have been studied using metabolomics—five for dispersing wind-cold and three for dispersing wind-heat—accounting for 22.22% of the commonly used exterior-dispelling herbs. These herbs are primarily indicated for exterior syndromes characterized by chills and fever, headache and body aches, absence of sweating or profuse but obstructed perspiration, and a floating pulse. However, current metabolomic research has mainly focused on diabetes and cardiovascular diseases, with relatively weak correlations to the traditional therapeutic effects of exterior-dispelling herbs. At the level of metabolic pathways, amino acid metabolism emerges as a common pathway targeted by these herbs, suggesting that modulation of amino acid metabolism may be one of the mechanisms underlying their pharmacological actions. Furthermore, in toxicological studies, two of the exterior-dispelling herbs—Asarum and Xanthium—are known to be toxic; metabolomic research has already investigated the mechanisms of their toxic effects, with detailed findings presented in Table 1.

1.3 Research on Cathartic Medicines Based on Metabolomics

Purgative herbs are those whose primary therapeutic action is to promote bowel evacuation and relieve constipation; they are commonly used to treat conditions such as severe constipation, stagnation of food and qi in the gastrointestinal tract, accumulation of excess heat within the body, and edema due to fluid retention. The textbook “Chinese Materia Medica” lists 17 commonly used purgative herbs (4 purgatives that attack and expel stool, 3 lubricating purgatives, and 10 potent purgatives that eliminate water). Among these, metabolic profiling techniques have been applied to study 7 single-herb purgatives (2 attack-and-expel purgatives and 5 potent purgatives that eliminate water), accounting for 41.18% of the commonly used purgative herbs. Details on the metabolic profiling studies of these single-herb purgatives are presented in Table 3.

Purgative herbs not only exert a potent laxative effect but also facilitate the downward movement of heat, thereby clearing heat and draining fire. Current metabolomics studies primarily focus on the purgative actions of rhubarb and mirabilite, which are broadly consistent with their traditional therapeutic properties. Moistening-laxative herbs are mostly plant seeds or seed kernels; they have a sweet taste and neutral nature, with a mild and gentle pharmacological profile. In clinical practice, they are often combined with other herbs, and single-use formulations are relatively rare; consequently, no relevant metabolomics studies on these herbs were identified in this review. Strong purgatives and diuretics, by contrast, are predominantly bitter, cold in nature, and toxic, with powerful and rapid effects that can easily damage vital energy and impair the spleen and stomach, thus limiting their widespread clinical application. A literature search reveals that metabolomics research on this class of drugs mainly centers on toxicity assessment and mechanisms of toxicity. Metabolomics offers significant advantages in toxicological studies—high sensitivity, high throughput, and unbiased analysis—making it an excellent platform for elucidating the mechanisms of traditional Chinese medicine toxicity and for conducting safety evaluations.

2 Challenges Faced and Corresponding Countermeasures

2.1 The extent of research coverage needs to be improved.

Although metabolomics has gained increasing attention and application in the field of traditional Chinese medicine in recent years, the statistical results of this study indicate that the number of individual TCMs for which metabolomic studies have been conducted remains relatively small, and the scope of such research still needs to be expanded. With regard to studies on three major categories of drugs—those that disperse exterior pathogens, clear heat, and purge the bowels—only 33 TCMs have been found to have undergone metabolomic investigations, with most of these focusing on popular targets such as Scutellaria baicalensis and Coptis chinensis. By contrast, metabolomic research on 98 TCMs remains entirely unexplored, a pattern that is also prevalent across other functional categories of TCMs. To advance metabolomic research on TCMs, it is essential to integrate the fundamental theoretical principles of TCM with systems biology approaches and to conduct such studies in a systematic manner based on the classification of TCM efficacy, thereby filling the existing gaps in the investigation of metabolic pathways and regulatory mechanisms at the level of individual herbs.

2.2 The types of research samples need to be diversified.

In metabolomics studies of three classes of traditional Chinese medicines—those that disperse the exterior, clear heat, and purge the bowels—researchers have typically selected a relatively limited range of sample types for analysis in disease models, often focusing on just one or two matrices such as serum, plasma, urine, feces, or tissue. Different sample types reflect metabolic information at distinct biological levels; thus, relying on a single, narrow sample type is often insufficient to comprehensively capture the complex in vivo processes and mechanisms of action of these herbal preparations. It is therefore recommended that, when conducting metabolomics research on traditional Chinese medicines, researchers should strive to collect and systematically analyze a broad spectrum of samples—including blood, urine, feces, and tissues—and integrate analyses of the distribution and compositional profiles of various biomarkers across the organism, so as to provide a comprehensive and objective elucidation of the metabolic pathways and mechanisms of action of these medicinal agents.

2.3 Analysis and detection technologies need to be improved.

A comprehensive analysis of the existing literature on traditional Chinese medicine metabolomics reveals that researchers predominantly employ conventional analytical techniques—namely nuclear magnetic resonance (NMR), liquid chromatography–mass spectrometry (LC–MS), and gas chromatography–mass spectrometry (GC–MS)—for sample analysis, with the high-throughput LC–MS platform being the most widely used. Each metabolomics analytical technique has its own strengths and limitations: NMR preserves sample integrity, is simple and rapid to operate, and offers high reproducibility, but its sensitivity is relatively low; GC–MS excels in metabolite identification, yet requires complex sample preparation and suffers from a limited detection range; LC–MS provides a broad detection scope, short analysis times, and a wide dynamic range, but relies heavily on reference standards. In recent years, continuous advances in modern instrumental analytical technologies have propelled the rapid development of metabolomics, with scholars both domestically and internationally achieving numerous innovative breakthroughs in areas such as mass spectrometry optimization and spectral data analysis. However, the application of these emerging cutting-edge technologies in the field of traditional Chinese medicine research remains relatively limited. Future research in traditional Chinese medicine metabolomics should further standardize procedures for sample collection, analysis, and processing to obtain stable, reliable, and highly reproducible results; promote the integrated application of multiple high-throughput analytical methods to maximize the detection of small-molecule metabolites and comprehensively capture changes in the metabolic profiles of traditional Chinese medicines; optimize and refine metabolomics data-analysis methodologies, while enhancing and expanding existing databases of traditional Chinese medicinal compounds and metabolites; and foster interdisciplinary integration among metabolomics, proteomics, transcriptomics, genomics, and other fields, thereby establishing a metabolomics methodological framework that aligns with the unique pharmacological characteristics of traditional Chinese medicines and better supports the modernization of this field.

2.4 The integration of experimental design with traditional efficacy remains to be strengthened.

In terms of experimental design, current metabolomics studies on traditional Chinese medicines are characterized by a predominance of animal experiments over human clinical trials, a greater reliance on Western medical disease models than on TCM syndrome models, and a focus on modern pharmacological research at the expense of studies on traditional therapeutic applications. To effectively apply metabolomics to TCM research, it is essential to proceed under the guidance of TCM theoretical principles, closely integrating traditional therapeutic effects and applications with systematic animal and clinical studies. This will enable the establishment of a comprehensive characterization system for TCM that aligns with the cognitive patterns of TCM syndromes, thereby elucidating at the molecular level the material basis and mechanisms of action of TCM. Furthermore, it will facilitate the scientific articulation of the intrinsic meanings of the “seven emotions” in TCM single-herb formulations, providing valuable insights for advancing research on the compatibility of the seven emotions in TCM and on the principles governing the use of classic renowned formulas.

3 Conclusion

Metabolomics offers unique advantages in research on traditional Chinese medicine and holds great promise for elucidating the mechanisms of action and the chemical basis of therapeutic efficacy of herbal medicines. At present, metabolomic studies of traditional Chinese medicine are still in a phase of continuous development and refinement. It is anticipated that, as metabolomic technologies continue to mature, they will provide more robust analytical tools for further uncovering the scientific underpinnings of both single herbs and compound formulations, thereby significantly advancing the modernization of traditional Chinese medicine research.

Source: Zhang Kai, Ding Liqin, Qiu Feng, and Zhang Deqin. Research Progress on Single-Ingredient Traditional Chinese Medicines with Exterior-Resolving, Heat-Clearing, and Cathartic Effects Based on Metabolomics [J]. Chinese Herbal Medicines, 2021, 52(2):585–593.

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