About this Research Topic
Liver diseases, including viral hepatitis, liver cirrhosis, liver cancer and so on, are common illnesses posing a serious threat to public health. At present, hundreds of millions of people are suffering from liver diseases around the world, which exert a negative impact on patients' quality of life.
Herbal medicine has long been associated with the treatment of liver diseases in clinical settings, especially in East Asian countries (e.g. China, Japan, Mongolia). However, multi-target and multi-functional effects, among other factors, have made fundamental mechanistic insights and general pharmacological interactions difficult to elucidate and therefore, treatment efficacy is difficult to unambiguously define. This has implications for the safety profile of treatments, and the improper use of herbal medicine (e.g. Polygonum multiflorum, Radix bupleuri, Angelica archangelica, Scutellaria baicalensis) may increase the risk of liver disease progression, and lead to deterioration of patients’ condition.
However, herbal medicine has potential advantages in the treatment of liver diseases. It can be applied to patients with liver diseases in case conventional therapies exhibit poor curative efficacy and can also be taken as adjuvant treatment for liver cancer with surgery, radiotherapy and chemotherapy. Additionally, treatment by herbal medicine for medical withdrawal can be flexible and convenient, with small risk of withdrawal reactions and relative low costs. Thus, it is necessary to conduct in vivo, in vitro, and clinical studies on herbal treatment of liver diseases, which will provide scientific basis for the clinical application of herbal medicine in this field.
The aim of this Research Topic is to encourage researchers from all over the world to explore the pharmacology and clinical efficacy of herbal medicine in treating liver diseases through a rigorous profiling of pharmacologically-relevant ingredients, laying more emphasis on pharmacodynamics and mechanisms of action. We also welcome studies on the reasonable usage (e.g. dosage and duration) of herbal products to not only improve their curative effects on liver diseases but also reduce the risk of herb-induced liver injury, as well as identification of proper combination of herbal and conventional medicine, maximizing the clinical efficacy of drugs on liver diseases. Reviews which critically assess this topic are particularly welcome. Authors are reminded that also in view of the seriousness of these conditions, scientific rigour is of particular relevance and that the studies must be based on a clearly defined hypothesis or testable research question. ‘Negative’ outcome studies are equally welcome.
Manuscripts considered for publication in this Research Topic should focus on one or more of the following 3 broad areas:
1. Discovery of new herbal formula, single botanical drugs or plant-derived compounds with therapeutic effects on liver diseases.
Herbal medicine and its active constituents have been widely used as a potential treatment for liver disease in clinical practice (e.g. Compound glycyrrhizin tablets, Bicyclol tablets and Bifendate pills derived from herbal medicine). Further studies on the diversified ingredients of herbal products, single herb or herbal prescriptions will be beneficial for the discovery of novel drugs in the treatment of liver diseases. It should be noted that preparation, structural characterization and content determination of herb-derived compounds with therapeutic effects must be clearly illustrated in the manuscripts.
2. Exploration of interactive mechanisms of the combination of herbal and conventional medicine.
Clarifying negative or positive interactions and their mechanisms of herbal medicine and conventional medicine in the treatment of liver diseases is an essential topic in this context. Such studies will also lead to enhanced understanding and avoidance of negative outcomes - such as understanding the effects of herbal metabolites on drug-associated enzyme activity. Studies on this area must be based on pharmacologically relevant in vivo or cell based models. Simple in silico and pharmacologically irrelevant assays are not acceptable as a main tool for pharmacological assessment.
3. Studies on the reasonable usage (dosage and duration) of herbal medicine in the treatment of liver diseases.
Evaluating dosage and duration of herbal medicinal products for liver diseases, so as to improve the therapeutic effects of herbal medicine, and decrease the incidence of herb-induced liver injury.
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
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.
Herbal medicine has long been associated with the treatment of liver diseases in clinical settings, especially in East Asian countries (e.g. China, Japan, Mongolia). However, multi-target and multi-functional effects, among other factors, have made fundamental mechanistic insights and general pharmacological interactions difficult to elucidate and therefore, treatment efficacy is difficult to unambiguously define. This has implications for the safety profile of treatments, and the improper use of herbal medicine (e.g. Polygonum multiflorum, Radix bupleuri, Angelica archangelica, Scutellaria baicalensis) may increase the risk of liver disease progression, and lead to deterioration of patients’ condition.
However, herbal medicine has potential advantages in the treatment of liver diseases. It can be applied to patients with liver diseases in case conventional therapies exhibit poor curative efficacy and can also be taken as adjuvant treatment for liver cancer with surgery, radiotherapy and chemotherapy. Additionally, treatment by herbal medicine for medical withdrawal can be flexible and convenient, with small risk of withdrawal reactions and relative low costs. Thus, it is necessary to conduct in vivo, in vitro, and clinical studies on herbal treatment of liver diseases, which will provide scientific basis for the clinical application of herbal medicine in this field.
The aim of this Research Topic is to encourage researchers from all over the world to explore the pharmacology and clinical efficacy of herbal medicine in treating liver diseases through a rigorous profiling of pharmacologically-relevant ingredients, laying more emphasis on pharmacodynamics and mechanisms of action. We also welcome studies on the reasonable usage (e.g. dosage and duration) of herbal products to not only improve their curative effects on liver diseases but also reduce the risk of herb-induced liver injury, as well as identification of proper combination of herbal and conventional medicine, maximizing the clinical efficacy of drugs on liver diseases. Reviews which critically assess this topic are particularly welcome. Authors are reminded that also in view of the seriousness of these conditions, scientific rigour is of particular relevance and that the studies must be based on a clearly defined hypothesis or testable research question. ‘Negative’ outcome studies are equally welcome.
Manuscripts considered for publication in this Research Topic should focus on one or more of the following 3 broad areas:
1. Discovery of new herbal formula, single botanical drugs or plant-derived compounds with therapeutic effects on liver diseases.
Herbal medicine and its active constituents have been widely used as a potential treatment for liver disease in clinical practice (e.g. Compound glycyrrhizin tablets, Bicyclol tablets and Bifendate pills derived from herbal medicine). Further studies on the diversified ingredients of herbal products, single herb or herbal prescriptions will be beneficial for the discovery of novel drugs in the treatment of liver diseases. It should be noted that preparation, structural characterization and content determination of herb-derived compounds with therapeutic effects must be clearly illustrated in the manuscripts.
2. Exploration of interactive mechanisms of the combination of herbal and conventional medicine.
Clarifying negative or positive interactions and their mechanisms of herbal medicine and conventional medicine in the treatment of liver diseases is an essential topic in this context. Such studies will also lead to enhanced understanding and avoidance of negative outcomes - such as understanding the effects of herbal metabolites on drug-associated enzyme activity. Studies on this area must be based on pharmacologically relevant in vivo or cell based models. Simple in silico and pharmacologically irrelevant assays are not acceptable as a main tool for pharmacological assessment.
3. Studies on the reasonable usage (dosage and duration) of herbal medicine in the treatment of liver diseases.
Evaluating dosage and duration of herbal medicinal products for liver diseases, so as to improve the therapeutic effects of herbal medicine, and decrease the incidence of herb-induced liver injury.
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
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: Herbal Medicine, Cholestatic Hepatitis, Efficacy, Action Mechanism, Clinical Application
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.
