Changes in the epigenetic features, which occur without alterations in DNA sequence, are sufficient to regulate gene expression. Epigenetic mechanisms have been associated with normal embryogenesis and their aberrations can be involved in numerous pathologies including cancer, the regulation of inflammation, rheumatic diseases, and cardiovascular disorders among others. Thus, they are being considered as potential therapeutic targets. Complementary approaches such as, to name a few, phytochemicals, mechanical stress, pulse magnetic field including nanomagnetic particles appear to modulate mammalian epigenome through chromatin remodeling. Phytochemicals whether present in our diet or food supplements are used for prevention or treatment of many diseases such as, but not limited to cancer, Parkinson's, anti-inflammatory actions, Alzheimer's, preventing cataract and retaining a healthy heart.

A growing body of research indicates that those powerful antioxidants, i.e., the polyphenol present in fruits, green tea, curcumin, and soybean isoflavones acquire anticancer activities by modulating the patient epigenome leading to the inhibition of a proto-oncogene or the activation of a tumor suppressor. Moreover, mechanical stress is found to promote cell death and is suggested as a complementary application for cancer treatment. Pulse magnetic field stimulation is also proposed as an adjuvant treatment to various cancer types. Needless to say, epigenetic modulations will allow the development of novel biomarkers for disease activity, and response to treatment.

Although recent advances in the fields of phytochemicals and other forms of either alternative or complementary method of disease treatment are on the rise; more profound studies are still needed to understand better the effects of these phytochemicals and other forms of either alternative or complementary method and their contribution in targeting the epigenetic aberrations. The "Epigenetic Modulating Agents: Complementary and Alternative Treatment Approaches" will provide a forum for publishing and be discussing new developments in the field.

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 papers defining adequate methods. 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 need to be fully validated using http://mpns.kew.org/mpns-portal/?_ga=1.111763972.1427522246.1459077346 or http://www.plantsoftheworldonline.org/ or www.theplantlist.org. Of course, full botanical documentation is essential (i.e. a voucher specimen deposited in a recognized herbarium). A scan of the voucher(s) is welcome as supplementary material and encourage authors to include the date, season, coordinates of the location where the material had been collected.

b) Chemical

- The composition of the study material must described in sufficient detail. Chromatograms with characterization of the dominating compound(s) are preferable. If preparations are used which are based on quality parameters provided in pharmacopoeia evidence must be provided that the material under study was in fact assessed 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 structures must be drawn using a scientifically accepted structure drawing program, must be consistent and - if relevant and possible - the stereochemistry needs to be given.

c) Multiherbal preparations:

Very often multiherbal preparations are used. Full information on their qualitative and quantitative 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) characterization.

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 (http://www.sciencedirect.com/science/article/pii/S0378874117324030)

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.