Targeting Human Inflammatory Skin Diseases with Natural Products: Exploring Potential Mechanisms and Regulatory Pathways

Inflammatory skin diseases including acne, atopic dermatitis, psoriasis, ichthyosis, vitiligo, melanoma, among others encompass a major area in dermapathology. These diseases are triggered by a wide range of conditions such as genetic predisposition, allergic reactions, exposure to environmental insults, as well as autoimmunity. These skin diseases not only cause cosmetic problems, but they also negatively impact patients’ quality of life and may be fatal in some cases. While topical corticosteroids, a form of steroidal anti-inflammatory drug, remain the primary treatment option for many human skin diseases, their long-term usage however lead to high rate of recurrence and significant side effects, particularly in the pediatric age group.

There are studies reporting that wide array of natural products, ranging from whole foods such as clove, turmeric and honey, to marine-based macro- and microalgae species, as well as phenolics and many other active pure compounds, exhibit anti-inflammatory effects that can target pleotropic signaling pathways and act as preventive or therapeutic agents for treating various skin diseases. These natural products were shown to regulate oxidative stress, apoptosis, lipid metabolism, tyrosinase-related targets and pathways. Nevertheless, the mechanism by which it modulates the progression of inflammatory skin diseases remains poorly understood.

As the immune system plays a crucial pathogenetic role in human skin diseases, many studies are now gearing towards unraveling the roles of specific immune cells populations (such as tissue-resident memory T-cells) in driving inflammatory responses in the skin. The effector mechanisms of the respective immune cell subpopulations determine the molecular changes in the local tissue cells, leading to specific microscopic and macroscopic phenotypic alterations. As such, it is essential we have a comprehensive understanding of the potential protective effects of natural products on immune cells populations, which can aid the development of effective new therapies for immune-mediated cutaneous diseases.

“Omics technologies”, including systems biology, pharmacogenomics and network pharmacology, are innovative novel technologies that can be used for elucidating modes of action and relevant signaling pathways of synthetic drugs, as well as phytochemicals and complex herbal mixtures. Studies using “omics technologies” investigating the detailed pharmacological effects of natural products extracts and active pure compounds on skin diseases are required to scientifically support and validate the pathophysiology underlying their mechanisms of actions.

The present Research Topic will include manuscripts representing recent exciting progress in the field of molecular pharmacology of natural extracts and pure compounds from cellular and molecular analysis, novel natural products formulations and scaffolds for skin lesions applications, as well as characterizing the effects of natural products using physiologically-relevant skin disease models to test the full potential of natural products in treating human skin diseases. Specifically, the protective effects of natural products in targeting inflammatory effector mechanisms that regulates the immune-pathophysiological pathways in skin diseases will be the focus in this Research Topic.
Manuscripts including research articles, basic theories, methods, and reviews (mini review, review, meta-analysis) are welcomed.

Please note that all research dealing with plant extracts or other natural substances/compounds, the composition and the stability of the study material must be described in sufficient detail. Please also see the Four Pillars of Best Practice in Ethnopharmacology below, a subset of which concerning general standards in natural product research are applied to all such studies in all sections of Frontiers in Pharmacology. Please note specifically the sections concerning in vivo experiments dealing with inflammation and traditional medicinal preparations and concepts (under Section 3d).

For submissions through the Ethnopharmacology pathway, please see below:

1) Pharmacological Requirements:
a) Traditional context - The traditional context must be described in the introduction.
b) Credible experimental models - methods must be state of the art, or a credible alternative. The following have specific requirements:
Antioxidant:
- FRAP, ABTS, DPPH, and Trolox equivalent antioxidant capacity assays are not accepted.
- in silico studies are not accepted as a main method.

Antimicrobial:
- Disc diffusion experiments must be followed by in vitro or in vivo experiments.
- Specificity must be assessed to rule out general toxic effects, e.g. by including parallel cytotoxicity testing (cf. Cos et al. 2006)
- The mechanism of action must be assessed in sufficient detail (for crude extracts, the effects of contaminants should also be addressed).

Inflammation:
- Experiments on the rat hind paw oedema model are not acceptable unless they are part of a larger pharmacological – phytochemical study.

Docking studies:
- These will not be accepted unless followed by benchwork confirming affinity.
- A proposed mechanism of action is required.

in silico network pharmacology studies
-Network pharmacology studies must critically assess the evidence to evaluate the potential pharmacological effects of a preparation / herbal (medical) product.
- The identification of the compounds must be sound. This information may be derived from the existing literature or from benchwork. It is essential that the quantities of the compounds in the preparation or plant are stated and are high enough to be of pharmacological relevance.
- The bioavailability of the compounds must be assessed.
- Ubiquitous or very widely known compounds are highly unlikely to be ‘active’.
- Transcriptomic data need to be validated using RT-PCR, and proteomic data with Western blots.

Single dose studies:
- These are not accepted unless they focus on a species / compound not yet studied in detail, and can be justified on specific ethical grounds

c) Dose - ranges must be therapeutically relevant:
- Implausibly high doses will not be considered.
- Both positive and negative controls are essential.
- Multiple doses are strongly recommended, as single dose studies are rarely accepted - only in some specific complex models.


2. Composition Requirements:
Whether the material under investigation is a crude plant extract, a multi-herbal preparation, a single compound from a commercial source or extracted from plant, chemical and botanical composition must be explicitly stated.
a) Chemical:
- The concentrations of the dominating compounds must be listed, including dominant impurities if these compounds have been identified in previous studies. Stating the class of compounds present (such as “alkaloids”) is insufficient. We will usually ask for a HPLC or UPLC to establish the compounds present to ensure replicability, if this is not possible a credible alternative can be used.
- Referring to a previously used preparation in the literature is not acceptable, unless it has come from the same preparation or has the same batch number.
- For purchased compounds, purity (%) and the supplier name must be included.
- For extracted compounds, purity (%) and the method used to determine the purity must be stated.
- The structure of active compounds should be included as figures.


b) Botanical:
- Species names must be fully validated and should be described in their full taxonomy, using the Kew Medicinal plant names service.
- Samples must be deposited in a recognised herbarium, and accessible if necessary. To find out if your institution is indexed, please use the NYBG Steere Herbarium Search tool
- Voucher numbers from the herbarium must be included in the Methods.
- Coordinates of plant picking should also be included, or the commercial source of a preparation, which must include a batch number and details on the preparation’s composition.


3. Basic Experimental and Ethical Requirements:
a) The study must contribute substantially to the existing literature. How it does so must be explicitly stated. The most up-to-date surrounding literature should be discussed, including related compounds, to demonstrate the contribution of the study to the field.
b) Compliance with all international ethical standards is essential. The Convention on Biological Diversity and the Nagoya Protocol are of particular relevance. This includes that research in the field should benefit the original users and consider their traditions.
c) The use of animals must be justified. If a material is well-characterised, and its properties well-known, performing another in vivo study is considered an unethical use of animals. A thorough knowledge of the literature is essential to avoid this mistake. Conversely, if a material is not well characterised, initial experiments in cell-based models are necessary to justify moving onto animal experiments.
d) The effects of traditional medicinal preparations must be testable in scientific terms. We acknowledge the importance of the understanding of medicinal preparations in their cultural context, and it may be that the treatment of symptoms as defined by traditional practices forms a basis for such investigations. However, pharmacological studies generally do not provide evidence for such uses, but rather for the established therapeutic targets of the model. Experimental outcomes should be linked to and described in these terms. For example, a series of in vitro tests will not demonstrate relevant evidence that will contribute to a physiological understanding of traditional therapeutic concepts, e.g. “dispelling wind” or “dampness” in Traditional Chinese Medicine. A justification must therefore be given for choosing a certain model to test a certain preparation.


4. Article-type Specific Requirements:

a) FIELD STUDIES
- Data must be substantial and original.
- The study must be discussed in the context of previous studies carried out in the region. How the study contributes to the development of the field must be made explicit.
- Must comply to the ConsEFS standards, including any updates.

b) REVIEWS
- The objective of the review must be clearly defined.
- They must provide a specific, critical assessment of the literature. The scientific quality of the original articles must be critically assessed. This includes the experimental design, and reliability of the studies.
- The traditional use must be linked to scientific evidence.
- Future needs and priorities must be clearly defined.

c) SYSTEMATIC REVIEWS & META ANALYSES
- To assure the quality of the studies included, we ask for the inclusion of a summary table (templates available on the Ethnopharmacology About page).
- We ask that a chemical analysis is included, taken from one of the included studies. The chemical composition of the study material must be well defined. If the composition is poorly characterised, this must be highlighted.
- Quality control measures taken, as defined by a pharmacopoeia, must also be included.
- If the included studies do not use full botanical taxonomic names, this should be highlighted, as must any naming inconsistency between studies.