Can High-throughput Omics Techniques and Multi-dimensional Bioinformatics Methods Contribute to the Search for Chemo-preventive or Anti-cancer Medicinal Plants?

According to the latest global cancer statistics in 2018, cancer is expected to be the leading cause of death worldwide in the 21st century, giving rise to great social burden as its high morbidity and mortality. Herbal medicine is proposed to be an effective complementary and alternative solution for primary health care, but also represents a great resource for drug innovation and discovery. In recent years, with deeper investigation on ethnopharmacology, herbal medicine-derived drugs have been acknowledged to hold great potential for prevention and treatment of diverse diseases, especially complicated diseases like autoimmune disorders, cardiovascular diseases and cancers. One of the world-renowned examples of applying herbal medicine is the use of artemisinin to treat malaria, which was awarded the Nobel Prize in Physiology and Medicine in 2015. Herbal medicine, which contains multiple ingredients that can simultaneously act on multiple targets, has demonstrated its particular therapeutic efficacy by modulating biological networks of body systems. However, it is relatively difficult to illuminate active components and therapeutic mechanisms of herbal medicine on a systematic level by conventional experimental methods only, which has led to one of the biggest hurdles in utilization of herbal medicine and herbal medicine-based drug discovery.

With the rapid development of high-throughput omics techniques and the wide application of multi-dimensional bioinformatics methods in the past decade, a large number of DNA copy number, gene expression and DNA methylation aberrations with clinical significance have been elucidated. Meanwhile, thanks to integrated bioinformatics analyses on massive amounts of high-throughput omics data, the understanding of epidemiology, pathology and molecular mechanisms of cancers has been greatly promoted and numerous biomarkers developed by bioinformatics analyses have been used in clinical practice for diagnosis and treatment. More importantly, these significant data can be freely accessed from public databases such as GEO, Oncomine, TCGA, UCSC Xena, cBioPortal, Connectivity Map, CCLE and so on. Therefore, there is no doubt that if we could apply these high-throughput omics data to studies of herbal medicine, more novel and valuable chemo-preventive or anti-cancer agents could be discovered from herbal medicine with higher efficiency and lower costs.

Especially, it has been well accepted that developing pharmacological interventions that targets the immune system could be a promising solution to cancer. Recently, studies on tumor‐infiltrating immune cells (TIICs) has become a hotspot since they have been reported to be effectively targeted by drugs and to be closely associated with the prognosis of cancer patients. However, evaluation of TIICs merely based on immunohistochemistry‐based analysis is greatly limited to a very narrow view of immune response, which leads to the fact that the prognostic value of certain TIICs subpopulation is not always consistent in studies with the same experimental design. By contrast, the approaches such as CIBERSORT, based on whole genomic expression profiles, could properly determine the diversity and landscape of TIICs, which may offer important insights into the complicated relationship among the heterogeneity of TIICs, tumor molecular subtypes, and disease tumor development. As for the regulatory effects of herbal medicine on the immune system, the immunological features of 28 human heart phenotypes and 102 herbal ingredients has been developed by calculating the enrichments of each immune signature in the transcriptional profiles of heart phenotypes and herbal ingredients. In conclusion, the integration of different types of omics data shows great potential in developing novel chemo-preventive or anti-cancer agents in herbal medicine.

Our Research Topic proposal aims at taking advantage of high-throughput omics techniques and multi-dimensional bioinformatics methods to explore chemo-preventive or anti-cancer potentials of herbal medicine. We encourage Original Research papers, Reviews and Perspectives on the following topics:

1. Chemo-preventive or anti-cancer mechanisms of herbal medicine by microarray or sequencing data-based integrated bioinformatics studies.
2. Novel methods and strategies for studying chemo-preventive or anti-cancer mechanisms of herbal medicine.
3. Novel therapeutic targets and mechanisms of herbal medicine on cancers by multiple omics techniques.
4. Novel chemicals from herbal medicine with chemo-preventive or anti-cancer 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 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.