About this Research Topic
Traditional Chinese Medicine (TCM) has been widely used for treating diseases over thousands of years and recognized as a valuable and readily available resource of conventional medicine with better curative effects and fewer side effects.
TCM often combines different botanicals, sometimes containing up to 50 species and thousands of chemical compounds. However, only some of them exhibit favourable pharmacokinetics (absorption, distribution, metabolism, excretion and toxicity (ADME/T) properties of a drug) with the potential of a biological effect.
Moreover, the therapeutic effects of these herbal products might arise from a cooperative action of the herbal ingredients, making it difficult to evaluate their pharmacological and toxicological effects independently.
Traditional strategies of isolation/purification/structure identification as well as the pharmacological research involved in TCM studies make it difficult to distinguish between different bioactive ingredients and to identify their potential targets. A simple quantitative analysis of one or several active components in a herb or an animal medicine does not validate its quality and action, because multiple agents may interact with each other to form a complex network contained in the formula, potentially hitting multiple targets and exerting synergistic therapeutic effects – or indeed, may have no relevant therapeutic value in vivo.
TCM research has been challenging due to its complexity. To quickly screen and analyse the druggability of TCM on molecular level, in silico ADME/T models such as human oral bioavailability (OB) and drug-likeness (DL) are involved. The development of computational methods for TCM exploration, which has a greater focus on the identification of potential TCM targets of small molecules, has become increasingly important in recent years. In addition, dissecting the mechanisms of TCM action by considering targets that exist in the context of biological networks has become an important factor to consider.
The network pharmacological analysis of biological networks associated to a given disease can identify potential targets at the systems level. As TCM exerts its action through the direct targeting of disease-associated proteins, it can also modulate various pathways involved in specific pathological processes.
With the rapidly accumulating knowledge of drug targets and disease-associated proteins, computational models of pathway analysis could be a promising strategy to investigate the therapeutic mechanisms of TCM at the pathway level. Finally, experimental technology is appreciated to be involved for confirming the reliability of the in silico methods.
Considering the above, it is necessary to develop a comprehensive method that would be able to analyse the basic theory, screen bioactive ingredients, predict compound targets, understand the molecular mechanisms related to the therapeutic efficacy, reveal rules of drug combination, and discover new drugs of TCM from a systematic point of view.
Such an approach would be represented by “Systems pharmacology, which seeks to develop a holistic understanding of the actions and adverse effects of drugs by considering targets in the context of biological networks. Systems pharmacology intends to integrate in silico ADME/T evaluation, target identification, network pharmacology, pathway analysis and experimental technology to systematically explore the complex interrelationship between compounds, pharmacological targets, pathways and diseases from molecular to systems level.
This approach offers a novel strategy for the interpretation of multi-scale mechanisms of TCM action and is therefore promising for drug discovery in the context of complex diseases and for the development of traditional medicine.
The present Research Topic welcomes high-quality Original Research as well as Review articles providing an overview of the most exciting developments in the field of systems pharmacology and TCM.
Multidisciplinary papers with a systems pharmacology approach to study TCM are welcome.
Articles focusing on clinical trials and conventional experimental methods for TCM will not be considered for review. We particularly welcome studies using interdisciplinary methods and technologies aimed to:
- evaluate the biologically active compounds from TCM based on in silico ADME/T models;
- identify the molecular/cellular targets of bioactive ingredients in TCM and relevant signalling pathways based on computer methods;
- elucidate the relationships between compounds, targets, diseases and pathways based on network pharmacology approach;
- investigate the underlying mechanisms of action of TCM on treatment of complex diseases based on computer and experimental methods.
The four pillars of best practice in ethnopharmacology
With these guidelines we define in detail what constitutes best practice for manuscripts submitted to Frontiers in Pharmacology; Section Ethnopharmacology. They provide a basis for the peer review and build on the general requirements of Frontiers in Pharmacology.
1) Pharmacology
a) The manuscript (MS) must report a substantive body of ethnopharmacological research, to be considered as an independent addition to the literature. In general, we expect that such studies are based on local / traditional uses of plants or other natural substances which need to be spelled out clearly.
b) For pharmacological studies, the model used must be one which is either generally accepted in the field as valid or a credible alternative whose general development, and application in the reported instance, has been justified.
Specifically antioxidant activity must be based on a pharmacologically relevant in vivo or cell based model. Simple in silico and pharmacologically irrelevant assays for antioxidant activity (e.g. the DPPH assay, FRAP (Ferric Reducing Ability of Plasma), ABTS (2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)) are not acceptable as a main tool for assessing an extract or a compound for activity.
c) Similarly, simple screening for anti-microbial effects of crude extracts is no longer state-of-the-art. Authors must follow the widely accepted standards for microbiological testing (cf. Cos et al. 2006 Anti-infective potential of natural products: How to develop a stronger in vitro ‘proof-of-concept’ Journal of Ethnopharmacology 106: 290–302) and subsequent methods papers. Such research is only meaningful if it contributes to our mechanistic understanding of anti-microbial effects, its specificity or identifies novel leads.
d) The dose ranges must be therapeutically relevant. While it will be impossible to define an exact cut-off, the literature in the field is now replete with studies which test extracts at implausibly high doses. Single dose studies will only be of relevance in exceptional circumstances (e.g. in case of specific complex pharmacological models). And of course, positive and negative controls must be included.
e) In order to establish therapeutic benefits, selectivity data are essential. How specific is the effect? Many compounds have non-selective in vitro effects and research on common compounds must be justified in terms of the potential therapeutic benefits. While such research may be relevant and have potential applications, authors will need to assess the specificity of a single compound or an extract rich in a well-studied compound (like rutin, curcumin, or quercitin) and provide evidence for the relevance and novelty of the approach.
f) Docking studies must be justified with affinity experiments, or other well established experimental methods to support a proposed mechanism of action. Algorithmic docking studies will not be accepted; these indicate if a compound will "fit" into a binding site but do not indicate the binding affinity or the ability to induce a conformational change.
2) Composition:
a) Botanical:
The identification of the study material must be described well. All species are fully validated using Kew MPNS portal or The Plant List initiative or Plants of the World Online Of course, full botanical documentation is essential (i.e. a voucher specimen deposited in a recognised herbarium). A scan of the voucher(s) is welcome as supplementary material and encourage authors to include the coordinates of the location where the material had been collected.
b) Chemical
- The composition of the study material must be described in sufficient detail. Chromatograms with a characterisation of the dominating compound(s) are preferable. If preparations are used which are available commercially quality parameters provided in pharmacopoeia must be provided. The material under study must be characterised using the methods of the relevant monograph
- If ‘pure’ compounds are used sufficient information on the level of purity must be included. Especially in in vitro models, the authors must be confident that the compounds are stable under the conditions used (for example, they do not degrade due to high concentrations of DMSO). A critical aspect that should be considered is how these assays and extraction protocols are linked to local and traditional uses. In this way, variables such as the solubility of the compound in the traditional preparation and in the analytical extraction protocol should be taken into consideration
- All chemical line structures must be drawn using a internationally accepted structure drawing programme, must be consistent and - if possible and relevant - the stereochemistry needs to be given.
c) Multiherbal preparations:
Very often multiherbal preparations are used. Full information on their composition (in terms of the botanical drugs / species included) and information on the rationale for studying this preparation needs to be included. It is essential that in these cases sufficient details are provided on the botanical (2a) and chemical (2b) characterisation.
3) Basic requirements and research ethics
Frontiers has very well developed guidelines relating to ethical aspects of a MS. Specifically, for Frontiers in Pharmacology (Ethnopharmacology) the following key requirements are essential:
a) The objectives of the research reported must be spelled out clearly and in detail. All MS must critically assess the scientific basis of the work and provide meaningful conclusions, which are based on a clear hypothesis / research question as defined in the introduction. Ethnopharmacological research must assess whether a compound or plant extract has a certain effect and it cannot be about ‘confirming an extract’s or compound’s effects or efficacy’.
b) Research must add new and scientifically substantive knowledge to our understanding of the pharmacology and use of medicinal plants. A key basis for this is a review of literature relevant to the pharmacological activity already reported on the species including possibly related taxa or compounds. This must be up-to-date, and clearly demonstrate the substantive addition to the literature the MS submitted represents. Simply using advanced measurements/techniques/protocols reproducing previous studies of the same plant product will only be accepted in exceptional circumstances (e.g. previously unknown, highly active components are discovered).
c) Compliance with all international ethical standards is essential. In the context of ethnopharmacology, the Convention on Biological Diversity and, most recently, the Nagoya Protocol are of particular relevance (https://www.cbd.int/abs/).
d) Research in ethnopharmacology is based on local and traditional knowledge often passed on orally over generations. Ultimately, research in this field must therefore benefit those populations who are or were the original keeper of this knowledge.
e) The use of animals must be justified in the context of novelty (see also part 1). It is ethically not acceptable to have yet another in vivo study on an already well-studied species, demonstrating some common activity (e.g. an anti-inflammatory effect studied in the rat-paw edema). The same is true for species which are chemically very similar (and generally are rich in common ingredient) to ones already studied pharmacologically. Such studies must ‘meet(s) the standards of rigor’ we expect in ethnopharmacology as defined in the Frontiers’ guidelines.
4) Other specific requirements
a) Studies focusing on local and traditional uses of plants (ethnopharmacological field studies) must be based on substantial, original data. The relevance of the MS in the context of previous studies in the geographical region must be spelled out clearly and it must contribute to the understanding of the therapeutic uses of plant species and inform experimental or clinical studies This includes an adequate presentation and discussion of the data. Also, social science centered studies (e.g. ethnobotanical studies or health system research of local and traditional medical systems) are welcome. This journal subscribes to the ConSEFS standards including any updates.
b) In case of reviews, we expect clearly defined scientific aims (objectives), a comprehensive, critical and specific assessment of the relevant information linking local and other medical uses to the biomedical and bioscientific evidence. Reviews need to define future research needs and priorities. It is essential that the scientific quality of the original articles cited is assessed. If pharmacological studies are reviewed, particular attention must be paid to assessing the quality of the studies.
c) Food plants are commonly reported to have pharmacological effects. Frontiers in Ethnopharmacology focuses on therapeutic benefits of such species and not on the general food/nutritional properties.
TCM often combines different botanicals, sometimes containing up to 50 species and thousands of chemical compounds. However, only some of them exhibit favourable pharmacokinetics (absorption, distribution, metabolism, excretion and toxicity (ADME/T) properties of a drug) with the potential of a biological effect.
Moreover, the therapeutic effects of these herbal products might arise from a cooperative action of the herbal ingredients, making it difficult to evaluate their pharmacological and toxicological effects independently.
Traditional strategies of isolation/purification/structure identification as well as the pharmacological research involved in TCM studies make it difficult to distinguish between different bioactive ingredients and to identify their potential targets. A simple quantitative analysis of one or several active components in a herb or an animal medicine does not validate its quality and action, because multiple agents may interact with each other to form a complex network contained in the formula, potentially hitting multiple targets and exerting synergistic therapeutic effects – or indeed, may have no relevant therapeutic value in vivo.
TCM research has been challenging due to its complexity. To quickly screen and analyse the druggability of TCM on molecular level, in silico ADME/T models such as human oral bioavailability (OB) and drug-likeness (DL) are involved. The development of computational methods for TCM exploration, which has a greater focus on the identification of potential TCM targets of small molecules, has become increasingly important in recent years. In addition, dissecting the mechanisms of TCM action by considering targets that exist in the context of biological networks has become an important factor to consider.
The network pharmacological analysis of biological networks associated to a given disease can identify potential targets at the systems level. As TCM exerts its action through the direct targeting of disease-associated proteins, it can also modulate various pathways involved in specific pathological processes.
With the rapidly accumulating knowledge of drug targets and disease-associated proteins, computational models of pathway analysis could be a promising strategy to investigate the therapeutic mechanisms of TCM at the pathway level. Finally, experimental technology is appreciated to be involved for confirming the reliability of the in silico methods.
Considering the above, it is necessary to develop a comprehensive method that would be able to analyse the basic theory, screen bioactive ingredients, predict compound targets, understand the molecular mechanisms related to the therapeutic efficacy, reveal rules of drug combination, and discover new drugs of TCM from a systematic point of view.
Such an approach would be represented by “Systems pharmacology, which seeks to develop a holistic understanding of the actions and adverse effects of drugs by considering targets in the context of biological networks. Systems pharmacology intends to integrate in silico ADME/T evaluation, target identification, network pharmacology, pathway analysis and experimental technology to systematically explore the complex interrelationship between compounds, pharmacological targets, pathways and diseases from molecular to systems level.
This approach offers a novel strategy for the interpretation of multi-scale mechanisms of TCM action and is therefore promising for drug discovery in the context of complex diseases and for the development of traditional medicine.
The present Research Topic welcomes high-quality Original Research as well as Review articles providing an overview of the most exciting developments in the field of systems pharmacology and TCM.
Multidisciplinary papers with a systems pharmacology approach to study TCM are welcome.
Articles focusing on clinical trials and conventional experimental methods for TCM will not be considered for review. We particularly welcome studies using interdisciplinary methods and technologies aimed to:
- evaluate the biologically active compounds from TCM based on in silico ADME/T models;
- identify the molecular/cellular targets of bioactive ingredients in TCM and relevant signalling pathways based on computer methods;
- elucidate the relationships between compounds, targets, diseases and pathways based on network pharmacology approach;
- investigate the underlying mechanisms of action of TCM on treatment of complex diseases based on computer and experimental methods.
The four pillars of best practice in ethnopharmacology
With these guidelines we define in detail what constitutes best practice for manuscripts submitted to Frontiers in Pharmacology; Section Ethnopharmacology. They provide a basis for the peer review and build on the general requirements of Frontiers in Pharmacology.
1) Pharmacology
a) The manuscript (MS) must report a substantive body of ethnopharmacological research, to be considered as an independent addition to the literature. In general, we expect that such studies are based on local / traditional uses of plants or other natural substances which need to be spelled out clearly.
b) For pharmacological studies, the model used must be one which is either generally accepted in the field as valid or a credible alternative whose general development, and application in the reported instance, has been justified.
Specifically antioxidant activity must be based on a pharmacologically relevant in vivo or cell based model. Simple in silico and pharmacologically irrelevant assays for antioxidant activity (e.g. the DPPH assay, FRAP (Ferric Reducing Ability of Plasma), ABTS (2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)) are not acceptable as a main tool for assessing an extract or a compound for activity.
c) Similarly, simple screening for anti-microbial effects of crude extracts is no longer state-of-the-art. Authors must follow the widely accepted standards for microbiological testing (cf. Cos et al. 2006 Anti-infective potential of natural products: How to develop a stronger in vitro ‘proof-of-concept’ Journal of Ethnopharmacology 106: 290–302) and subsequent methods papers. Such research is only meaningful if it contributes to our mechanistic understanding of anti-microbial effects, its specificity or identifies novel leads.
d) The dose ranges must be therapeutically relevant. While it will be impossible to define an exact cut-off, the literature in the field is now replete with studies which test extracts at implausibly high doses. Single dose studies will only be of relevance in exceptional circumstances (e.g. in case of specific complex pharmacological models). And of course, positive and negative controls must be included.
e) In order to establish therapeutic benefits, selectivity data are essential. How specific is the effect? Many compounds have non-selective in vitro effects and research on common compounds must be justified in terms of the potential therapeutic benefits. While such research may be relevant and have potential applications, authors will need to assess the specificity of a single compound or an extract rich in a well-studied compound (like rutin, curcumin, or quercitin) and provide evidence for the relevance and novelty of the approach.
f) Docking studies must be justified with affinity experiments, or other well established experimental methods to support a proposed mechanism of action. Algorithmic docking studies will not be accepted; these indicate if a compound will "fit" into a binding site but do not indicate the binding affinity or the ability to induce a conformational change.
2) Composition:
a) Botanical:
The identification of the study material must be described well. All species are fully validated using Kew MPNS portal or The Plant List initiative or Plants of the World Online Of course, full botanical documentation is essential (i.e. a voucher specimen deposited in a recognised herbarium). A scan of the voucher(s) is welcome as supplementary material and encourage authors to include the coordinates of the location where the material had been collected.
b) Chemical
- The composition of the study material must be described in sufficient detail. Chromatograms with a characterisation of the dominating compound(s) are preferable. If preparations are used which are available commercially quality parameters provided in pharmacopoeia must be provided. The material under study must be characterised using the methods of the relevant monograph
- If ‘pure’ compounds are used sufficient information on the level of purity must be included. Especially in in vitro models, the authors must be confident that the compounds are stable under the conditions used (for example, they do not degrade due to high concentrations of DMSO). A critical aspect that should be considered is how these assays and extraction protocols are linked to local and traditional uses. In this way, variables such as the solubility of the compound in the traditional preparation and in the analytical extraction protocol should be taken into consideration
- All chemical line structures must be drawn using a internationally accepted structure drawing programme, must be consistent and - if possible and relevant - the stereochemistry needs to be given.
c) Multiherbal preparations:
Very often multiherbal preparations are used. Full information on their composition (in terms of the botanical drugs / species included) and information on the rationale for studying this preparation needs to be included. It is essential that in these cases sufficient details are provided on the botanical (2a) and chemical (2b) characterisation.
3) Basic requirements and research ethics
Frontiers has very well developed guidelines relating to ethical aspects of a MS. Specifically, for Frontiers in Pharmacology (Ethnopharmacology) the following key requirements are essential:
a) The objectives of the research reported must be spelled out clearly and in detail. All MS must critically assess the scientific basis of the work and provide meaningful conclusions, which are based on a clear hypothesis / research question as defined in the introduction. Ethnopharmacological research must assess whether a compound or plant extract has a certain effect and it cannot be about ‘confirming an extract’s or compound’s effects or efficacy’.
b) Research must add new and scientifically substantive knowledge to our understanding of the pharmacology and use of medicinal plants. A key basis for this is a review of literature relevant to the pharmacological activity already reported on the species including possibly related taxa or compounds. This must be up-to-date, and clearly demonstrate the substantive addition to the literature the MS submitted represents. Simply using advanced measurements/techniques/protocols reproducing previous studies of the same plant product will only be accepted in exceptional circumstances (e.g. previously unknown, highly active components are discovered).
c) Compliance with all international ethical standards is essential. In the context of ethnopharmacology, the Convention on Biological Diversity and, most recently, the Nagoya Protocol are of particular relevance (https://www.cbd.int/abs/).
d) Research in ethnopharmacology is based on local and traditional knowledge often passed on orally over generations. Ultimately, research in this field must therefore benefit those populations who are or were the original keeper of this knowledge.
e) The use of animals must be justified in the context of novelty (see also part 1). It is ethically not acceptable to have yet another in vivo study on an already well-studied species, demonstrating some common activity (e.g. an anti-inflammatory effect studied in the rat-paw edema). The same is true for species which are chemically very similar (and generally are rich in common ingredient) to ones already studied pharmacologically. Such studies must ‘meet(s) the standards of rigor’ we expect in ethnopharmacology as defined in the Frontiers’ guidelines.
4) Other specific requirements
a) Studies focusing on local and traditional uses of plants (ethnopharmacological field studies) must be based on substantial, original data. The relevance of the MS in the context of previous studies in the geographical region must be spelled out clearly and it must contribute to the understanding of the therapeutic uses of plant species and inform experimental or clinical studies This includes an adequate presentation and discussion of the data. Also, social science centered studies (e.g. ethnobotanical studies or health system research of local and traditional medical systems) are welcome. This journal subscribes to the ConSEFS standards including any updates.
b) In case of reviews, we expect clearly defined scientific aims (objectives), a comprehensive, critical and specific assessment of the relevant information linking local and other medical uses to the biomedical and bioscientific evidence. Reviews need to define future research needs and priorities. It is essential that the scientific quality of the original articles cited is assessed. If pharmacological studies are reviewed, particular attention must be paid to assessing the quality of the studies.
c) Food plants are commonly reported to have pharmacological effects. Frontiers in Ethnopharmacology focuses on therapeutic benefits of such species and not on the general food/nutritional properties.
Keywords: Systems pharmacology, Traditional Chinese Medicine, Complex diseases, bioactive ingredients, mechanism of action
Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.
