Metabolomics and Metabolism of Traditional Chinese Medicine

Evidence shows that traditional Chinese medicine (TCM) could be beneficial for the treatment of various diseases. However, the complexities present in diagnostic theory, chemical composition of Chinese medicinal plants, and therapeutic philosophy, are currently an obstacle for the progression of TCM for novel-drug discovery. These complexities include unclear bioactive compounds, mechanisms of action, undetermined targets for therapy, non-specific features for drug metabolism and toxicology, etc.

To overcome those issues, metabolomics is a potentially useful tool for future improvement and understanding of TCM from the small-molecule metabolism level. This level of resolution will contribute to rigorous hypothesis testing in terms of the effects, or lack thereof, of well-established compounds of pharmacological relevance within the TCM frame of reference, thereby optimizing treatments. In terms of TCM therapeutics, this will mostly involve the complex interactions and metabolism between small-molecules in vivo (the hosts) and small-molecules in vitro (TCM-associated compounds). It has the potential to surmount the scientific challenges currently surrounding TCM from both a general, and specifically a metabolic perspective and promote a new horizon in drug discovery.

Essentially, metabolomics is a systems biology-driven interdisciplinary approach, whose applicability requires the integrative involvement of the knowledge and techniques used in such varied fields as: chemistry, biochemistry, instrumental science, pharmaceutical sciences, pharmacology, drug metabolism, bioinformatics, etc. This collaboration provides a means to both integrate TCM with a broader audience and expose TCM to more thorough analysis, further promoting an evidence-based approach to TCM treatment.

In this Research Topic, we aim to collect high-quality reviews and research articles which take advantage of the potential for rigorous hypothesis testing that the metobolomics paradigm affords new studies in TCM, to highlight the value of metabolomics and metabolism in addressing the complexity of TCM in systems pharmacology and enhancing their biomedical value in a real world of biomedicine, shedding light on the aid that metabolomics can offer to the investigation of complex herbal extracts and, specifically, to link phytochemical analysis with the assessment of a potential pharmacological effect and therapeutic potential.

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 s 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 a valid one or justification must be provided, that, for example, a new model was developed and why.

Specifically antioxidant activity must be based on a pharmacologically relevant in vivo 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 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

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). How are these assays and extraction protocols linked to local and traditional uses?

- 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 studied pharmacological activity. 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 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.

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 oedema). 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 critical and specific assessment of the relevant information linking local and other medical uses to the biomedical and bioscientific evidence. These reviews must be comprehensive and specific. They need to define future research needs and priorities. 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: Traditional Chinese Medicine, Metabolomics, Drug Metabolism, Therapeutic Discovery, Novel Drug

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.