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Systematic Review
Revised

A Review of Wound Healing Mechanisms of Natural Products in Keratinocyte Cells

[version 2; peer review: 1 approved with reservations, 2 not approved]
Adryan Fristiohady
https://orcid.org/0000-0002-3499-0511
1,2, Rathapon Asasutjarit1, La Ode Muh Julian Purnama1, Lidya Agriningsih Haruna2, Wirhamsah Al-Ramadan2
Adryan Fristiohady
https://orcid.org/0000-0002-3499-0511
1,2, Rathapon Asasutjarit1, [...] La Ode Muh Julian Purnama1, Lidya Agriningsih Haruna2, Wirhamsah Al-Ramadan2
PUBLISHED 17 Nov 2022
Author details Author details
OPEN PEER REVIEW
REVIEWER STATUS

This article is included in the Cell & Molecular Biology gateway.

This article is included in the Faculty of Medicine – Thammasat University collection.

Abstract

Background: Wound-healing in the skin is one mechanism that maintains homeostasis. Ineffective skin wound healing is a significant health problem that ultimately causes morbidity and mortality. The process of wound healing using traditional medicine has a good effect with various mechanisms of action. This review aims to provide insights related to the wound-healing mechanisms of several plants in HaCat cells.
Methods: The literature study method was used from primary and secondary libraries. The library search was conducted using online-based library search instruments from 1988 to 2021, such as NCBI-PubMed, Google Scholar, and Elsevier.
Results: The wound-healing mechanism includes processes that restore skin integrity through four stages: hemostasis, inflammation, multiplication, and remodeling. Many plants have been studied to have activity in wound healing by various mechanisms.
Conclusions: Several compounds in plants have shown the activity in wound healing in keratinocyte cells  by various mechanisms.

Keywords

Wound-healing, Keratinocyte, Natural Products

Corresponding author: Adryan Fristiohady
Competing interests: No competing interests were disclosed.
Grant information: This research has been funded by the Thammasat Postdoctoral Grant 2021 contract no. TUPD 18/2021.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Copyright:  © 2022 Fristiohady A et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite: Fristiohady A, Asasutjarit R, Julian Purnama LOM et al. A Review of Wound Healing Mechanisms of Natural Products in Keratinocyte Cells [version 2; peer review: 1 approved with reservations, 2 not approved]. F1000Research 2022, 11:528 (https://doi.org/10.12688/f1000research.121813.2) First published: 16 May 2022, 11:528 (https://doi.org/10.12688/f1000research.121813.1) Latest published: 17 Nov 2022, 11:528 (https://doi.org/10.12688/f1000research.121813.2)

Revised Amendments from Version 1

We have revised the abstract, introduction and fixed the methods as requested by the reviewers. We added the figures to show the mechanisms of the compounds that involved in the wound healing process in Keratinocyte cells. On this revised version, we added more discussion to strengthen the activity of the compounds in wound healing.

To read any peer review reports and author responses for this article, follow the "read" links in the Open Peer Review table.

Introduction

Skin is the human body’s largest organ,1 about 15% of the body weight consisting of the epidermis, dermis, and subcutaneous (Figure 1). The epidermis is the outermost layer of the skin and maintains a vital barrier against external trauma. The main cellular content of the epidermis is keratinocytes (about 95% of the epidermis), and fibroblasts are the main cellular components of the dermis.2,3 The epidermis, mainly composed of keratinocytes, is classified into stratum corneum, granular layer, spinous layer, and basal layer, based on the stages of keratinocyte differentiation. Keratinocytes have an essential role in inflammation.4 The skin’s primary function is to protect the body from exogenous factors by forming a protective barrier that covers the body; therefore, any injury or damage to the skin must be repaired immediately to provide continuous protection to our body systems.5 The skin protects against environmental factors such as harmful UV rays and pathogens and prevents water loss.6

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure1.gif

Figure 1.

The structure of skin.

Wound healing is one of the functions of skin.7 Wound healing maintains homeostasis. The physiological healing system involves four stages, which include homeostasis (blood clotting), inflammation, proliferation (new tissue growth), and maturation (remodeling).8 A wound-healing response is initiated when the epidermis is injured.3 Keratinocytes, the main cellular component of the epidermis, are responsible for restoring the epidermis after injury through epithelialization.9,10 Epithelialization is an essential component of wound healing and is a critical success parameter. Epithelialization is defined as the process of covering a denuded epithelial surface. The cellular and molecular processes involved in initiating, maintaining, and completing epithelialization are critical to successful wound closure. Without re-epithelialization, the wound cannot be considered healed.11 The successful step of re-epithelialization is considered an essential indicator of wound closure to prevent further infection and chronic wound development. Re-epithelialization is triggered to restore the damaged epidermis in response to skin damage. The most important cell types responsible for re-epithelialization are keratinocytes, which proliferate, differentiate, and migrate to heal open wounds.12–14

The study of folklore medicine is recognized as one way to explore medicine’s potential in the future. Researchers have identified 122 compounds used in primary medicine derived from “ethnomedical” plant sources, and 80% of these compounds are used or closely related to traditional ethnomedical uses.15 Because the skin healing process is quite complex, there are limits to treating skin wounds entirely with a single compound. Thus, developing wound healing agents with natural ingredients can be an option for skin wound treatment. Using natural products as a wound healing agent has several advantages, such as low cost and high safety compared to other synthetic products.6 A large number of plants have been used, by tribes and folklore, in many countries to treat wounds and burns.15 The wound healing process is promoted efficiently using traditional medicine, mainly sourced from plants. These drugs have been shown to affect one or more stages of the healing process. In this context, traditional medicine provides a comprehensive source for discovering native bioactive compounds and developing new pharmaceutical applications.16 Especially for the treatment of plant origin, both topical and systemic herbal medicines have been widely used in wound healing. Several properties, including anti-inflammatory, antioxidant, and antimicrobial activity, are required to be effective wound-healing agents. Thus, any herb with these properties should be investigated and used to develop effective wound-healing agents.10 Various health-supporting constituents in this plant have attracted scientists to examine it to know its potential wound-healing properties.15

The epidermis is mainly composed of keratinocytes. Keratinocytes are known to have an essential role in inflammation. Keratinocytes are also a significant source of inflammatory mediators, including a group of the tumor necrosis factor (TNF)-α and interleukin (IL) families. Overproduction of pro-inflammatory mediators can lead to abnormal inflammatory responses.4 Therefore, in vitro studies of human skin’s epidermis and dermis have been commonly performed using HaCaT cells.5 HaCaT cells are immortalized human keratinocytes used to study dermatological conditions such as contact dermatitis, psoriasis, or skin cancer due to their high availability and ease of cell culture.8 HaCaT is the primary epithelial cell line from adult human skin to show normal differentiation and provides a promising tool for studying the regulation of keratinization in human cells. The HaCaT cell line has an altered phenotype in vitro (clonogenic on plastics and agar) but remains nontumorigenic. Despite the altered and unrestricted growth potential, HaCaT cells, similar to normal keratinocytes, reform the structured and differentiated epidermal tissue in an orderly manner when transplanted into model mice.17 Therefore, this review article aims to determine the wound-healing mechanism of several plant extracts on HaCaT cells.

Methods

Protocol and registration

The results are reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.18 Scoping reviews purpose to; establish evidence available, elucidate key ideas, establish how research is done and determine knowledge gaps for a particular topic.

Eligibility criteria

Articles were included based on the following criteria:

  • 1. Problem: Papers that match the research topic, namely the molecular mechanism of wound-healing of several compounds and extracts in HaCaT cells

  • 2. Intervention: The studies using an in vitro approach

  • 3. Outcome: Plants with wound-healing activity in HaCat cells

  • 4. Design study: Literature non-experimental dan systematic review

  • 5. Year published: 1988 - 2021

  • 6. Language: English

Articles were excluded based on the following criteria:

  • 1. Problem: Papers that were not matched with the topic, namely the molecular mechanism of wound-healing of several compounds and extracts in HaCaT cells

  • 2. Intervention: The studies using an in vitro and in vivo approach

  • 3. Outcome: Plants with no activity as wound healing agents in HaCat cell lines

  • 4. Design study: Experimental

  • 5. Year published: -

  • 6. Language: non-English

Information sources

Articles relevant to the study were searched and retrieved electronically from PubMed (https://pubmed.ncbi.nlm.nih.gov/advanced/) and Google Scholar (https://scholar.google.com/) using advanced search builders. The search from the databases was lastly collected on 10th December 2021.

Search strategy

An advanced search in three databases, NCBI-PubMed, Google Scholar, and Elsevier, was searched to identify peer-reviewed articles on wound-healing and wound-healing mechanisms using compounds and extracts against HaCaT cells. Specifically, the search queries consisted of relevant medical subject titles (MeSH) and relevant keywords. The Search terms included:

Wound-healing AND HaCaT Cells AND Compounds AND Extracts

Selection of sources of evidence

The articles obtained were further verified using the search strategy and filters outlined in the search strategy section. Assessment of the resulting articles was done independently by all the reviewers. Disagreements between them were resolved through consensus. First, articles from the initial search were obtained. Duplicate references were removed through manual deduplication. The titles and abstracts of the retrieved articles were screened for relevance to the study topic. Full-text reports were examined for compliance with eligibility criteria.

Data chatting process

Data from the evidence sources was assessed independently and then discussed by the team to reach a consensus. The information abstracted was as shown in the table.

Data items

The selection of the review articles based on the molecular mechanism of action as the primary outcome domain was guided by the following items:

  • 1. Title of study

  • 2. Year of publication – 1988 - 2021

  • 3. Study objectives – wound-healing mechanism in HaCaT cells

  • 4. Study design – review

  • 5. Results – summary of findings on molecular mechanisms

  • 6. Discussion – detailed explanation of the results and limitations of the review

  • 7. Conflict of interest – Authors declare no conflict of interest

Synthesis of results

Results from the selected articles were tabulated in the summary of findings. The methodologies and molecular mechanisms of action (interventions) were summarized.

Results

Wound-healing

Wound healing is a complex biological mechanism involving cellular interactions between cells, including smooth muscle cells, fibroblasts, endothelial cells, myofibroblasts, keratinocytes, and immune cells.19 Wound-healing processes restore skin integrity through four stages: The coagulation phase and forming of a platelet scab to cover the wound opening to prevent further blood loss or entry of pathogens. The inflammatory phase is the flow of inflammatory cells to the wound site for protection against pathogens and activates skin cells. During this phase, neutrophils and macrophages are activated by releasing pro-inflammatory cytokines such as Interleukin-1β, 6, 8, Tumor necrosis factor (TNF), and growth factors such as Platelet-derived growth factor (PDGF), Transforming growth factor (TGF-α, β, 1) and Fibroblast growth factor (FGF) (Figure 2).12 During the proliferation phase, skin cells multiply rapidly to replace lost cells. Restoring the basal keratinocyte layer in the basement membrane between the epidermis and the dermis begins to proliferate through various signaling molecules during the proliferative stage. When a certain level of repair is reached, the cytoplasmic shape of the keratinocytes is altered to move to the upper layers of the epidermis, differentiate, and transform through different cell layers to reach the final maturation stage. Thus, the proliferation and migration of keratinocytes suture the wound site during wound healing.11 Remodeling Phase, In this phase, fibroblast and a vascular density decrease, old collagen fibers from the initial scar are replaced with matrix, and new collagen fibers are synthesized to form new tissue.12,20,21

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure2.gif

Figure 2.

Wound-healing involving cytokines.

Inflammation

Tissue injury causes disruption of blood vessels and extravasation of blood. It will require hemostasis and provides a temporary extracellular matrix for cell migration by blood coagulation. Coagulation pathways activate complement pathways. In addition, the injured or activated parenchymal cells produce several vasoactive mediators and chemotactic factors. These substances carry inflammatory leukocytes to the site of injury. Neutrophil infiltration clears the wound site of foreign particles and bacteria and is then extruded with eschar or phagocytized by macrophages. Macrophages bind to specific extracellular matrix proteins by their integrin receptors, stimulating the phagocytosis of microorganisms and extracellular matrix fragments by macrophages. The extracellular matrix also stimulates monocytes to undergo metamorphosis into inflammatory macrophages and express colony-stimulating factor 1, a cytokine required for the survival of monocytes and macrophages; tumor necrosis factor-α, a potent inflammatory cytokine; and platelet-derived growth factor, a potent chemoattractant and mitogen for fibroblasts. Other important cytokines expressed by monocytes and macrophages are transforming growth factor a, interleukin-1, transforming growth factor b, and insulin-like growth factor I. Monocyte and macrophage-derived growth factors are required to initiate and propagate new tissue formation.22

Epithelialization

Wound re-epithelialization begins within hours of injury. Epidermal skin cells, such as hair follicles, rapidly remove clotted blood and damaged stroma from the wound site. At the same time, the cells undergo phenotypic changes characterized by intracellular tonofilament retraction, dissolution of cellular desmosomes, which provide physical connections between cells, and formation of peripheral cytoplasmic actin filaments, which allow cell movement. Furthermore, the epidermal and dermal cells no longer adhere to each other due to the severance of the connection between the epidermis and the basement membrane, which allows lateral movement of the epidermal cells. Integrin receptors’ expression on cells interacts with various extracellular matrix proteins (e.g., fibronectin and vitronectin) with type I collagen in the wound stroma and thus form a fibrin clot. Plasminogen activator activates collagenase (matrix metalloproteinase 1) and facilitates the degradation of collagen and extracellular matrix proteins. One to two days after injury, epidermal cells at the wound margins begin to proliferate behind actively migrating cells. The absence of neighboring cells at the wound edges may signal migration and proliferation of epidermal cells. As re-epithelialization occurs, basement membrane proteins reappear in a highly ordered sequence from the wound edge inward, like a zipper. Epidermal cells return to their normal phenotype, firmly adherent to the regenerated basement membrane and the underlying dermis.22

Formation of granulation tissue

New stroma, often called granulation tissue, begins to invade the wound site approximately four days after injury. Many new capillaries give new stroma with their granularity. Macrophages, fibroblasts, and blood vessels move into the wound site at the same time. Macrophages provide a source of growth factors needed to stimulate fibroplasia and angiogenesis, fibroblasts produce new extracellular matrix needed to support growth into cells, and blood vessels carry oxygen and nutrients needed to maintain cell metabolism. Primarily platelet-derived growth factor and transforming growth factor b1, together with extracellular matrix molecules, stimulate tissue fibroblasts around the wound to proliferate, express integrin receptors, and migrate into the wound site. The structural molecules of the newly formed extracellular matrix, called the transient matrix, contribute to the formation of granulation tissue by providing a scaffold or channel for cell migration. These molecules include fibrin, fibronectin, and hyaluronic acid. Movement of cells into the blood clot from fibrin crosslinks or into the extracellular matrix requires an active proteolytic system that can open pathways for cell migration. In addition to serum-derived plasmin, various fibroblast-derived enzymes include plasminogen activator, collagenase, gelatinase A, and stromelysin. After migrating into the wound, fibroblasts initiate extracellular matrix synthesis. The collagen matrix gradually replaces the temporary extracellular matrix. Once an abundant collagen matrix has been deposited in the wound, fibroblasts stop producing collagen, and the fibroblast-rich granulation tissue is replaced by relatively acellular scar tissue. Cells in the wound undergo signal-induced apoptosis.22

Neovascularization

Angiogenesis is a complex process that depends on the extracellular matrix in the wound bed and the migration and mitogenic stimulation of endothelial cells. Induction of angiogenesis is associated with acidic or basic fibroblast growth factors. Furthermore, many other molecules were also found to have angiogenic activity, including vascular endothelial growth factor, transforming growth factor b, angiogenins, angiotropins, angiopoietin 1, and thrombospondins. Low oxygen tension and increased lactic acid can also stimulate angiogenesis. The mentioned molecules induce angiogenesis by stimulating the production of essential fibroblast growth factors and vascular endothelial growth factors by macrophages and endothelial cells. Activated wound epidermal cells secrete large amounts of vascular endothelial cell growth factor. Essential fibroblast growth factor regulates the site for angiogenesis during the first three days of wound healing. In contrast, the vascular endothelial cell growth factor is critical for angiogenesis during granulation tissue formation at days 4 to 7. cell disruption and the production of vascular endothelial cell growth factor by epidermal cells is stimulated by hypoxia. Proteolytic enzymes released into connective tissue degrade extracellular matrix proteins. These protein fragments carry peripheral blood monocytes to the site of injury, where macrophages are activated and release angiogenic factors. Certain macrophage angiogenesis factors, such as essential fibroblast growth factors, stimulate endothelial cells to release plasminogen activators and procollagenase. The plasminogen activator converts plasminogen to plasmin and procollagenase to activate collagenase, and together these two proteases digest the basement membrane. Fragmentation of the basement membrane allows endothelial cells stimulated by angiogenesis factors to migrate and form new blood vessels at the injury site. Once the wound is filled with new granulation tissue, angiogenesis stops, and many new blood vessels are destroyed due to apoptosis. This programmed cell death is regulated by various matrix molecules, such as thrombospondins 1 and 2, and antiangiogenic factors, such as angiostatin, endostatin, and angiopoietin 2.22

Wound contraction and extracellular matrix reorganization

Wound contraction involves complex interactions of cells, extracellular matrix, and cytokines. During the second week of healing, fibroblasts assume a myofibroblast phenotype characterized by extensive collections of actin-containing microfilaments placed along the cytoplasmic surface of the cell plasma membrane. The appearance of myofibroblasts corresponds to the initiation of connective tissue compaction and wound contraction. Contraction requires stimulation by altering growth factor b1 or b2 and platelet-derived growth factor, attachment of fibroblasts to the collagen matrix via integrin receptors, and crosslinking between collagens. Collagen remodeling during the transition from granulation tissue to scar tissue depends on the continuous synthesis and low levels of collagen catabolism. The degradation of collagen in wounds is controlled by several proteolytic enzymes called matrix metalloproteinases, secreted by macrophages, epidermal and endothelial cells, and fibroblasts. In the first three weeks, fibrillar collagen accumulates relatively rapidly and has been reshaped by wound contraction. After that, the rate of collagen accumulation is much slower, and collagen remodeling with the formation of larger collagen bundles and an increase in the number of intermolecular crosslinks increases. However, a wound never reaches its normal strength (the tension at which the skin breaks) like uninjured skin. The scar is only 70 percent stronger at maximum strength than normal skin.22

Plants are the potential to provide wound-healing activities. Many studies reported the activity of plants for wound-healing and its mechanism. Thereby, this study review several plants that exhibit wound-healing activity below.

Aristolochia bracteolata

Aristolochia bracteolata contains aristoctam, aporphines, protobiberberines, flavonoids, alkaloids, tannins, sterols, steroids, and several other compounds used for skin treatments, as well as utilized for its anti-inflammatory properties (Figure 3).23 A. bracteolata extract selectively inhibited cell proliferation at higher concentrations (>100 μg/mL) and lower concentrations (<25 μg/mL). This extract showed linear and dose-dependent cell proliferation. The wound healing study showed that wound closure was 50.38% ± 1.39 and 69.81% ± 1.89, respectively, at a 25 μg/mL concentration after 24 and 48 h. The extract was tested for anti-inflammatory activity by determining the inhibitory activity on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in 264.7 RAW cells. The results found that A. bracteolata had a strong inhibitory effect on the production of NO and tumor necrosis factor-α/TNF-α. A. bracteolata extract inhibited the expression of the inducible nitric oxide synthase (iNOS) gene by lipopolysaccharide (LPS). A. bracteolata showed decreased pro-inflammatory cytokine mRNA expression concentration-dependent, indicating a mechanism for iNOS inhibition, gene expression analyzed by Real-Time PCR.24

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure3.gif

Figure 3.

Wound healing mechanism of Aristolochia bracteolata.

Boerhavia diffusa

The methanol extract (EM) of the leaves of Boerhavia diffusa significantly increased the viability and migration of human keratinocytes (HaCaT) cells. GC-MS analysis revealed the presence of caffeic acid, ferulic acid, and D-pinitol as the primary bioactive metabolites (Figure 4). The content of secondary metabolites in the extract of punarvana, such as phenolics and flavonoids, reduces lipid peroxidation, increases collagen fibrils’ survival by increasing collagen fibers’ strength, prevents cell damage, and accelerates DNA synthesis. Due to their antioxidant and antimicrobial properties, phenolics, flavonoids, and terpenoids enhance wound healing. Antioxidants enhance the healing process by reducing the damage caused by free oxygen radicals. D-pinitol, which is an insulinomimetic. Apply topical insulin promotes diabetic wound-healing by regulating wound inflammatory cells and improving cellular function. Bioactive insulin activates the IR/IRS/PI3K/AKT pathway in skin wound-healing, leading to tissue regeneration, growth, proliferation, and migration of keratinocytes and fibroblasts.25 A previous study demonstrated tgat insulin applied topically enhances diabetic wound healing by regulating wound inflammatory cells and improving cellular function.26 In addition, Chen et al. (2012) reported that excision wound closure time was reduced from 7 to 5 days in insulin-treated animals. This finding was associated with increased inflammatory response, re-epithelialization, and collagen remodeling in the wound group of animals treated with the insulin solution.27 Azevedo et al. (2016) also investigated the effect of insulin cream (0.5 U/100 g) applied daily for 26 days on second-degree burns in control rats and diabetic rats; results showed that insulin cream increased inflammatory cell infiltration and collagen deposition in diabetic rats, whereas non-diabetic rats showed no such effect.28 In addition, caffeic and ferulic acids can promote wound healing mainly due to their potent antioxidant and anti-inflammatory properties.25

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure4.gif

Figure 4.

Wound healing mechanism of Boerhavia diffusa.

Achyrocline satureioides (Lam.)

Achyrocline satureioides (Lam.) extracts are medicinal plants from Brazil, Uruguay, Argentina, and Paraguay. This plant contains quercetin, luteolin and 3-O-methylquercetin (Figure 5).29 The results showed a significant increase in the viability of HaCaT cells on ASE-loaded nanoemulsions (NEASE) (up to 5 μg/mL of flavonoids). Preliminary tests showed that NEASE was able to increase cell migration at low flavonoid concentrations. ASE did not induce HaCaT cytotoxicity and tended to increase keratinocyte cell viability compared to controls after 24 h of treatment for all concentrations tested (0.625-10 μg/mL). Luteolin decreases in protein expressions of inflammatory factors, including matrix metalloproteinase-9 (MMP-9), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL1-β and downregulation of nuclear factor-κB (NF-κB).30,31

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure5.gif

Figure 5.

Wound healing mechanism of Achyrocline satureioides (Lam.).

Calophyllum inophyllum Linn.

Anti-inflammatory and wound healing activities of calophyllolide (CP) have been reported isolated from Calophyllum inophyllum Linn (Figure 6). CP was tested on model rats by performing surgical wounds and treated with phosphate buffer saline (PBS), povidone-iodine (PI), and CP to evaluate the wound healing rates. In addition, the anti-inflammatory activity was indicated with the MPO test. The results showed that CP did not affect the viability of HaCaT cells in the indicated concentrations. CP extract at 10-1000 ng/ml had a non-significant difference in cell viability. CP reduced fibrosis formation and effectively promoted wound healing in a mouse model without causing weight loss (p-value = 0,6524). CP decreased the fibrosis formation and accelerated the wound closure in the epidermis and dermis, which ultimately closed 14 days after treatment. The molecular mechanisms underlying wound repair reduce MPO activity and increase M2 macrophages. CP prevents a prolonged inflammatory process by downregulating pro-inflammatory cytokines-IL-1β, IL-6, and TNF-α but upregulating anti-inflammatory cytokines, IL-10.32

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure6.gif

Figure 6.

Wound healing mechanism of Calophyllum inophyllum Linn.

Ulmus parvifolia

The bark of Ulmus parvifolia contains phenolic compounds and steroid glucosides, used to treat edema. This plant has been isolated, containing catechin-7-O-β-D-apiofuranoside (Figure 7).33 The results showed that HaCaT cells grown in the presence of U. parvifolia root bark extract showed a faster and dose-dependent growth rate than untreated cells. Collagen protein remodeling during wound healing may be affected by proteolytic activity in the extracellular matrix by matrix metalloproteinases (MMPs). MMPs play an essential role in all stages of wound healing during normal tissue remodeling and morphogenesis by modifying the wound matrix. Understanding the role of MMPs during infection and chronic tissue repair could pave the way for identifying potential targets for chronic wounds. In addition, MMPs also regulate cell-cell and cell-matrix signaling by releasing cytokines and growth factors sequestered in the extracellular matrix (ECM). TGF-β is a family of growth factors that play an essential role in wound healing by regulating the inflammatory response, keratinocyte proliferation and migration, angiogenesis, collagen synthesis, and ECM remodeling.6

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure7.gif

Figure 7.

Wound healing mechanism of Ulmus parvifolia.

Aloe vera

Aloe vera extract contains mannose-6-phosphate, increasing wound contraction and collagen synthesis. Isolated polysaccharides from Aloe vera also induce matrix metallopeptidase (MMP)-3 and metallopeptidase inhibitor-2 gene expression during wound repair (Figure 8).34 The gel was tested non-cytotoxic against nauplii and compatible with human blood and skin cells. Aloe vera promotes the attachment and proliferation of HaCaT and HFF1 cells. It also significantly accelerated wound closure through reepithelialization and wound.35 Aloe vera gel exhibited significant wound healing properties, as indicated by the statistically significant increase in the percentage of wound closure and migration rate for the two highest concentrations used.36

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure8.gif

Figure 8.

Wound healing mechanism of Aloe vera.

Hibiscus syriacus

Hibiscus syriacus (HS) contains flavonoids, including dihydroquercetin, herbacetin, and kaempferol (Figure 9). HS ethanol extract accelerated wound-healing activity in epithelial formation and fibronectin production. Fibronectin expression analysis with immunostaining revealed that fibronectin value after being treated with HS was 19,4 ±6,7%. It was significant compared to the control group.37 During tissue repair, fibronectin is converted from a soluble inactive form to biologically active extracellular matrix (ECM) fibrils via a cell-dependent process. ECM fibronectin promotes many cellular processes essential for tissue repair and regulates the assembly of other proteins into the matrix. Reduced ECM fibronectin levels were indicated by unhealed wounds.38

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure9.gif

Figure 9.

Wound healing mechanism of Hibiscus syriacus.

In addition, HS enhances the expression of genes involved in skin hydration and homeostasis. HS contains compounds which stimulate the expression of biomarkers relevant to skin regeneration and hydration, thereby counteracting the molecular pathways that cause skin damage and aging. Fibroblasts and keratinocytes are the keys to the wound-healing process in the skin. Treatment of HaCaT cells with 0,002% HS for 24 h significantly improved the wound healing response. 0,002 and 0,01% of HS increased by 50% and 20% of wound healing rate, respectively. Aquaporin 3 (Aqp3) is an integral membrane pore protein expressed more in the basal than in the upper layers of the epidermis. Specifically, the Aqp3 and filaggrin genes were increased by 20 and 58%, respectively. Aqp3 selectively conducts water molecules in and out of cells and prevents the passage of ions and other solutes. Filaggrin is a filament-associated protein that binds to keratin fibers and is responsible for the integrity and waterproofing capacity of the top layer of skin.37,39

Sideroxylon obtusifolium (Roem. & Schult.)

N-Methyl-(2S,4R)-trans-4-Hydroxy-L-Proline (NMP) from the leaves of Sideroxylon obtusifolium (Brazilian medicinal species) has acted as an anti-inflammatory and wound-healing management (Figure 10).40 A previous study showed that the methanol fraction of Sideroxylon obtusifolium (MFSO) (50 μg/ml) stimulated HaCaT cells by increasing proliferation and migration rates in keratinocytes during wound-healing. MFSO demonstrated stimulation of human keratinocytes (HaCaT) cells and enhanced wound healing through modulation of inflammation in burns.40,41

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure10.gif

Figure 10.

Wound healing mechanism of Sideroxylon obtusifolium (Roem. & Schult.).

Alternanthera sessilis

Alternanthera sessilis contains 2,4-dihydroxy-2,5-dimethyl-3(2H)-furan-3-one (8,92%), hexadecanoic acid (7,21%), palmitate (5,65%), and L-glutamic acid (5,04 %) (Figure 11). The highest concentration of extract treatment (50 μg/ml) showed a migration rate of 99%. The extract showed a strong positive result of 65%, with a difference of 14% in the migration rate between the two. The extract may act on broad signaling receptors to promote proliferation and migration in HaCat. Higher concentrations are required for epithelial barrier stimulation, while lower doses are sufficient to trigger connective tissue cellular compounds.5

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure11.gif

Figure 11.

Wound healing mechanism of Alternanthera sessilis.

Wedelia trilobata L.

Grandiflorenic acid from Wedelia trilobata leaves was assessed for its possible activity on HaCaT keratinocyte proliferation and its effects on in vitro scratch tests, collagen content, TGF-β2 levels, and nitric oxide, TNF- and IL-1β determinations using Raw 264.7 cells. Grandiflorenic acid (2.5 μg/ml) resulted in a 106% percentage of HaCaT keratinocyte viability, induced a migration rate of 100% in the initial in vitro assay, and the collagen content increased to 171.2 μg/ml compared to the control (61.1 μg/mL) with human fibroblasts. Grandiflorenic acid has potential wound-healing activity due to fibroblast stimulation and inhibition of prolongation of the inflammatory phase of wound healing, as evidenced by a decrease in inflammatory cytokine levels from Raw 264.7 macrophage cells. Grandiflorenic acid and proteoglycans increased collagen production (Figure 12).15

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure12.gif

Figure 12.

Wound healing mechanism of Wedelia trilobata L.

Aegle marmelos L.

The active compounds isolated from the Maja flower (Aegle marmelos L.) are cineol, eugenol, cuminaldehyde, aegelin, 1-hydroxy-5,7-dimethoxy-2 naphthalene-carboxaldehyde (HDNC), and Luvangetin, which had been purified >98% (Figure 13). Treatment with Maja flowers for 24 h drastically increased cell motility and expression of keratinocytes in specific cell lines. It enhances protein expression in loricrin, filaggrin, and involucrin (a keratinocyte differentiation marker). Keratinocyte motility is enhanced by the ERK and Akt signaling pathways.42

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure13.gif

Figure 13.

Wound healing mechanism of Aegle marmelos L.

Eriobotryae folium

The leaves of Eriobotrya japonica contain amygdalin (laetrile and vitamin B1) which has antioxidant activity with an IC50 value of 56.59 μg/ml (Figure 14).43 The ethanolic extract of Eriobotryae folium (EF) increases intracellular and extracellular PGE2 levels in HaCaT cells and inhibits 15-PGDH (ED50: 168,4 μg/ml) with relatively low cytotoxicity (IC50: 250.0 μg/ml). In the other study, EF extract suppressed LPS-induced nitric oxide and PGE2 production by inhibiting inducible nitric oxide synthase and COX-2 expression in lipopolysaccharides that stimulated RAW264 cells decreased MRP4 and PGT expression.44

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure14.gif

Figure 14.

Wound healing mechanism of Eriobotryae folium.

Glycyrrhiza glabra

Glycyrrhiza glabra (GG) has a positive proliferative effect on keratinocytes. The larger the dose, the higher the rate of proliferation. GG inhibits abnormal cell proliferation and is anticarcinogenic. Although GG has been shown to increase the rate of cell proliferation and migration of keratinocytes and promote wound healing, the underlying mechanism is unclear. However, GG helps activate proliferation and cytoskeletal rearrangement proteins and promotes wound-healing. The antioxidant effect of some GG constituents, such as glycyrrhizin and glabridin, may also help enhance the wound healing ability of keratinocytes (Figure 15).45 G. glabra aqueous extract ointment could significantly (p ≤ 0.05) decrease the level of the wound site, total cell, macrophage, lymphocyte, and neutrophil, and enhance the level of wound contracture, fibrocyte, hexuronic acid, and hydroxyproline as compared with the basal ointment and control groups.46

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure15.gif

Figure 15.

Wound healing mechanism of Glycyrrhiza glabra.

Calabrian honey

BL1 (multifloral) and BL5 (orange) honey showed the best healing properties among the five kinds of honey tested. Pinocembrin, revealed in honey samples BL1 and BL5, is a flavanol with known biological activities, including wound-healing. At high concentrations or after prolonged contact, polyphenols can reduce the production of pro-inflammatory cytokines and interact with metabolism and cell proliferation, thereby healing wounds. Pinocembrin in vitro modulates the production of inflammatory cytokines, such as TNF-, IL-1β, IL-6, and IL-10, by suppressing NF-κB and MAPK activation.47 Pinocembrin and its 7-linolenoyl derivative were found to be innovative wound-healing agents. Immunofluorescence and functional assays showed that GPR120 mediated the activity. Pinocembrin produced wound-healing of HaCaT cells after 6 and 24 h by about +30% compared to untreated. In contrast, the 7-linolenoyl derivative increased HaCaT wound closure by about +40% compared to untreated controls. Activation of GPR120 can impair by increasing levels of TGF-β, which triggers the synthesis of components of the extracellular matrix, thereby contributing to wound-healing induced by keratinocytes. Complex signaling pathways involved in the upregulation of MMPs and the turnover of extracellular matrix components stimulated by attendants can lead to tissue damage or repair processes. In particular, MMP-9 plays an essential role in cell migration and reepithelialization (Figure 16).48

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure16.gif

Figure 16.

Wound healing mechanism of Calabrian honey.

Thymus vulgaris L.

Previous studies showed that Thyme oleoresin at 25 μg/ml and 50 μg/ml significantly promoted HaCaT cell migration, leading to wound closure. The upper part of the plant is reported to have significant components such as p-cymene, α-terpinene, and thymol (Figure 17). The possible mechanisms in wound healing are its ability to maintain wound moisture, increase oxygenation by increasing blood supply, increase epithelial cell migration, rapid maturation of collagen and reduce inflammation, increase collagen synthesis, increase the synthesis of hyaluronic acid and dermatan sulfate in wound tissue.49

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure17.gif

Figure 17.

Wound healing mechanism of Thymus vulgaris L.

Trapa japonica

Trapa japonica contains fiber and polyphenols, such as ellagic acid, eugeniin, and gallic acid, which have antioxidant and anti-inflammatory activities (Figure 18). The results showed that the extract of T. japonica decreased the TNF-α, thus significantly decreasing MMP-1 and MMP-9 mRNA expression.50

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure18.gif

Figure 18.

Wound healing mechanism of Trapa japonica.

Gracilaria lemaneiformis

Gracilaria lemaneiformis contains sulfated galactan, anti-inflammatory, and antioxidant (Figure 19). The purified Gracilaria lemaneiformis (GLP-2) fraction promoted cell proliferation and migration of HaCat cells through activation of PI3K/aPKC signaling during wound-healing of human keratinocytes. GLP-2 significantly increased wound-healing activity when compared to control cells. The results showed that GLP treatment could increase lamellipodium formation in migrating HaCaT cells. GLP-2 promotes cell migration with cell polarity and directional migration to accelerate wound healing of keratinocytes using early migration and transwell assays. GLP-2 significantly increased wound healing activity compared to control cells.38 Horikoshi et al. reported that upstream (upstream) regulation of the PI3K/aPKC signaling pathway promotes cell polarization in HaCaT cells. Increased Akt phosphorylation is considered an index of activation of the PI3K signaling pathway after injured cells. GLP-2 activates the PI3K/aPKC signaling pathway and promotes cell polarization in HaCaT cells. GLP-2 positively regulates Cdc-42, Rac-1, Par-3, and aPKC in HaCaT cells. Cdc42 induces filopodial extension at the cell periphery, which aids in directional cell migration. Par-3 and aPKC are considered proteins that regulate cell polarity involved in the regulation of cell polarization. Increased Akt phosphorylation was considered an index of activation of the PI3K signaling pathway after injured cells. The present study observed a significant increase in Akt phosphorylation in GLP-2-treated cells compared to control cells at 12 h during the wound-healing process.51

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure19.gif

Figure 19.

Wound healing mechanism of Gracilaria lemaneiformis.

Nerium indicum

Nerium indicum (NI) contains oleandrin, flavonoids, and tannins (Figure 20).52 These plants may vary on keratinocyte activity at the wound site at specific doses. Studies have shown that the test materials used, either alone or in combination, positively affect keratinocyte proliferation and migration, an essential factor required for proper wound closure and wound-healing.46

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure20.gif

Figure 20.

Wound healing mechanism of Nerium indicum.

Urtica dioica L.

Urtica dioica L (UD) extract contains saponins, flavonoids, carbohydrates, ketoses, resins, and coumarins (Figure 21). The UD extract increased the proliferation rates of HEK-293 and HaCaT cells by 39% and 30% after 24 h, respectively, compared to control cells. The viability of extract-treated HEK-293 cells was increased compared to untreated (control) cells after 24 h of incubation (Figure 21). Maximum cell viability (i.e., 139 ± 2%) was achieved by the addition of 150 μg/ml of the extract. This value was statistically significant for p < 001. In the case of HaCaT cells (keratinocytes from human skin), cell viability was increased by 30% upon incubation with 100 μg/mL extract for 24 h. The extract increased the cell population in the G2/M phase by almost 10%. Moreover, the extract caused a twofold increase in the rate of cell migration of both cell lines compared to the control cells. In addition, the extract was found to have moderate anti-inflammatory and antioxidant properties that enhance the overall wound-healing potential.53

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure21.gif

Figure 21.

Wound healing mechanism of Urtica dioica L.

Curcuma amarissima

Curcuma amarissima (CA) contains curcumenol, curdione and curzerenone (Figure 22). The cell viability test showed that the CA extract increased the viability of HaCaT cells. MTT cell viability test was performed to monitor changes in the viability of Hacat cells in media containing CA extract (CA extract in DMSO as solvent from stock solution) in the presence of 10% fetal bovine serum, FBS. The results showed that the CA extract at concentrations lower than 40 g/mL had no significant effect on cells cultured in FBS-rich media viability. However, extracts at 80 and 160 μg/ml caused a significant reduction in cell viability to about 30% and 10%, respectively. However, DMSO at all concentrations used did not cause changes in the viability of HaCaT cells. A similar experiment was also conducted in which treatment with CA extract was carried out in FBS-free media. The results showed that the viability of HaCaT cells in a serum-free medium was more sensitive to CA treatment. In particular, cell viability was significantly reduced when cells were treated with CA at 20 μg/mL, and cell viability was maximally decreased to about 20% in cells treated with CA at 40 μg/ml or more. This increase in cell viability was related to the CA extract’s pharmacological activity in inducing cell proliferation. CA extract rapidly induces ERK1/2 and Akt activation. Consistently, CA extract accelerated cell migration, rapidly healing the injured human keratinocyte monolayer. In particular, MEK inhibitors (U0126) or PI3K inhibitors (LY294002) blocked CA-induced enhancement of cell monolayer wound-healing. In addition, CA extract induces the expression of Mcl-1, an antiapoptotic protein, supporting that the CA extract enhances the survival of human keratinocytes.10

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure22.gif

Figure 22.

Wound healing mechanism of Curcuma amarissima.

Clausena excavata

The methanol extract of Clausena excavate contains coumarins, flavonoids, and glycosides with various biological properties.54–56 C. excavata exhibits diverse therapeutic activities, which include anticancer, insecticidal, antifungal, antiplasmodial antiplatelet, antinociceptive, immunomodulatory, antimycobacterial, and anti-HIV-1 activity.57–59 These compounds regulate inflammation through inhibition of the MAPK/NF-κB pathway. In addition, it was shown that methanol extract treatment increased TGF-β1 expression, the cytokine increased wound contraction, extracellular matrix deposition, and collagen formation in wound healing (Figure 23).54

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure23.gif

Figure 23.

The wound healing mechanism of Clausena excavate.

Angelica gigas

Angelica gigas contains Coumarin, decursin, and decursinol angelate (Figure 24), which improves wound-healing with HaCaT human keratinocytes. ERK1/2 phosphorylation is essential for cell survival, proliferation, and inhibition of apoptosis. The expression of genes encoding ECM remodeling proteins, inflammatory cytokines, and growth factors is an essential step in human wound healing. The simultaneous expression of these genes can accelerate this process.60

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure24.gif

Figure 24.

Wound healing mechanism of Angelica gigas.

Salvia haenkei

Salvia haenkei contains rosmarinic acid (Figure 25). Hydroalcoholic extract of S. haenkei effectively increases the wound closure rate in cultured keratinocytes with the almost total invasion of the scrapes after 48 h of treatment. Gene expression analysis showed that S. haenkei regulates the nuclear factor-κB (NF-κB) transcription factor signaling pathway. The results showed that the S. haenkei extract does not cause a statistically significant increase in the rate of fibroblast migration. Specifically, this study analyzed the mRNA levels of several genes involved in the early inflammatory phase of skin repairs, such as the transcriptionally active subunit of the transcription factor NF-κB (RelA), the inflammatory cytokine interleukin-6 (IL-6), and tumor necrosis factor-alpha. (TNF-α), inducible nitric oxide synthase (iNOS or NOS2), and the inducible prostaglandin synthesis enzyme cyclooxygenase-2 (COX-2). Tn with S. haenkei increases the IL-6 in fibroblasts and keratinocytes (83.6 and 19.7-fold induction, respectively), whereas TNFα levels only have a mild increasing trend.16

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure25.gif

Figure 25.

Wound healing mechanism of Salvia haenkei.

Crassocephalum crepidioides

Crassocephalum crepidioides (Benth.) S. Moore contains β-cubebene, α-farnesene, and α-caryophyllene, which exhibit antioxidant and anti-inflammatory activities (Figure 26). C. crepidioides (CC) extract exhibited anti-inflammatory in vitro assays on the macrophage cell line RAW 246.7. In addition, reduced inflammatory cell density in granulation tissue in 7-days wounds, combined with decreased TNF-α and NF-B1 mRNA expression. NF-B1 and TNF-α are essential markers for the degree of inflammation. High levels of TNF-α have been reported to inhibit wound re-epithelialization, myofibroblast formation, and smooth muscle actin (SMA-α). The results showed that CC could improve the wound-healing process through its anti-inflammatory activity. TGF-β1 mRNA was also found to be elevated in granulation tissue. TGF-β1 is involved in many essential effects on the wound-healing process. The activities of TGF-β1 include the induction of fibroblast proliferation, motivating the differentiation of fibroblasts into myofibroblasts, and increasing the synthesis, deposition, and maturation of collagen. The increase in the TGF-β1 gene may explain the increase in fibroblasts and the wound-healing effect.61

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure26.gif

Figure 26.

Wound healing mechanism of Crassocephalum crepidioides.

Withania somnifera

Withania somnifera contains withaferin A, which has anti-inflammatory, antiangiogenic, antimetastatic, and anticancer activities (Figure 27). The results showed that ashwagandha extract (AE) significantly inhibited mRNA expression of inflammatory cytokines, including interleukin IL-8, IL-6, TNF-α, IL-1β, IL-12, and promoted mRNA expression of the anti-inflammatory cytokine TGF-β1 in HaCaT cells. Cytokine expression levels were investigated in ASH-WEX-treated HaCaT cells by RT-qPCR. The results showed that when cells were treated with ASH-WEX at concentrations <5 mg/ml, which was non-toxic in HaCaT cells, the mRNA expression levels of the inflammatory cytokines IL-8, IL-6, and IL-12 were significantly decreased. TNF- and IL-1β mRNA levels were also decreased. In contrast, treatment with ASH-WEX at concentrations < 5 mg/ml significantly increased the mRNA expression level of the anti-inflammatory cytokine TGF-β1. These results indicate that ASH-WEX has an anti-inflammatory effect on keratinocytes. In addition, AE inhibited lipopolysaccharide-induced phosphorylation of p38 and c-Jun N-terminal kinase, as well as NF-κB p65. The results showed that EA was not toxic to HaCaT cells up to a dose of 10 mg/mL. AE inhibits the MAPK/NF-κB pathway. The NF-κB and MAPK signaling pathways are strongly associated with the expression of inflammatory cytokines in HaCaT cells.4

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure27.gif

Figure 27.

Wound healing mechanism of Withania somnifera.

Anemarrhena asphodeloides

Mangiferin has been isolated from the plant Anemarrhena asphodeloides (Figure 28). A. asphodeloides (AA) extract promoted inhibiting Th2-type cytokines, pro-inflammatory cytokines, and filaggrin restoration in HaCaT cells. TNF-α/IFN-γ significantly increased mRNA expression of IL-4 in HaCaT keratinocytes. However, pretreatment with AA significantly suppressed the mRNA expression of IL-4. AA pretreatment of TNF-α/IFNγ-stimulated HaCaT keratinocytes reduced IL-13 mRNA expression. However, pretreatment with AA significantly suppressed the mRNA expression of IL-6 in a dose-dependent manner. These results suggest that AA has a protective effect on skin keratinocytes by inhibiting the transcription of inflammatory cytokine levels associated with skin barrier dysfunction. TNF-α/IFN-γ co-stimulation decreased filaggrin protein expression and mRNA levels, but pretreatment with AA significantly increased filaggrin protein levels, although mRNA levels increased slightly. The results showed that AA had a filaggrin-recovery effect on TNF-α/IFN-γ-stimulated HaCaT keratinocytes. Treatment with AA increased Keratinocyte HaCaT migration and inhibited the expression of iNOS protein levels. It is possible to assume that AA facilitates wound-healing in the skin barrier by inhibiting overexpression.62

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure28.gif

Figure 28.

Wound healing mechanism of Anemarrhena asphodeloides.

Sasa veitchii

Sasa veitchii is a traditional plant that contains lignin, polysaccharides, and chlorophyll (Figure 29). It has many pharmacological activities such as antioxidant, anti-inflammatory, antibacterial and anticancer. HaCaT cells treated with S. veitchii extract for 72 h showed significantly higher AQP3 expression and mitogen-activated p38 phosphorylated protein kinase (MAPK) than control cells. S. veitchii extract increases AQP3 expression and provides wound-healing and healing effects. The increase in AQP3 expression elicited by the Kumazasa extract may be due to increased transcription via activation of p38 MAPK signaling. It was also found that S. veitchii extract had a proliferative effect on HaCaT cells.63

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure29.gif

Figure 29.

Wound healing mechanism of Sasa veitchii.

Periplaneta americana

Periplaneta americana contains polyalcohols, amino acids, pyrimidines, uracils, and proteoglycans (Figure 30). P. americana extract showed effects in wound-healing that depend on the Janus-activated kinase/signal transducer pathway and transcriptional activator 3 (JAK/STAT3) and Smad3 activity. Pretreatment with STAT3 inhibitors blocked cell proliferation and migration. This extract promotes the proliferation and migration of immortalized human keratinocyte HaCaT cells. The results showed increased keratinocyte proliferation and migration after treatment (0,3125 mg/mL) for 48 h. After treatment, JAK/STAT3 signaling expression and Smad3 activation, NF-κB/p65, and β-catenin were significantly upregulated in HaCaT cells and wound tissue. However, NF-κB and Wnt signaling appear to be minimally activated regardless of the limited expression of NF-κB/P65 and β-catenin upregulation or cell nuclear translocation.64

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure30.gif

Figure 30.

Wound healing mechanism of Periplaneta americana.

Angelica tenuissima

Angelica tenuissima root contains decursin and Z-ligustilide (Figure 31). The root extract of A. tenuissima accelerates wound filling under basal conditions in the keratinocytes that make up the epidermal layer. It inhibits the mRNA expression of MMP-1 and elastase. It also increases the collagen content as indicated by the production and secretion of type I procollagen with or without UVB exposure. This extract could be beneficial in suppressing UVB-mediated wrinkling of skin formation and photoaging by increasing PIP levels and decreasing MMP-1 and elastase activity. A. tenuissima can play a role in attenuating the inflammatory response caused by UVB irradiation through upregulation of photo-protective hemeoxygease-1 and suppressing pro-inflammatory cyclooxygenase-2 expression.65

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure31.gif

Figure 31.

Wound healing mechanism of Angelica tenuissima.

Astragali radix

Astragaloside VI (AS-VI) and cycloastragenol-6-O-beta-D-glucoside (CMG) (Figure 32) from Astragali radix enhance skin cell proliferation and migration via activation of the EGFR/ERK signaling pathway, resulting in enhanced wound-healing in vitro. AS-VI actively promotes the proliferation of human keratinocytes (HaCaT) by activating the ERK1/2 pathway rather than the JNK and p38 pathways. This plant shows that astragaloside can activate cellular processes involved in wound-healing. It is mediated, at least in part, by EGFR/ERK1/2, which could be beneficial in wound closure.66

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure32.gif

Figure 32.

Wound healing mechanism of Astragali radix.

Mimosa tenuiflora (Willd)

Mimosa tenuiflora bark contains high amounts of saponins and polyphenols such as arabinogalactan (Figure 33). Mimosa tenuiflora (Willd) aqueous extract at concentrations of 10 and 100 μg/ml indicated a loss of cell viability and proliferation of dermal fibroblasts. Isolated, ethanol-precipitated compounds (EPC) (10 μg/ml) have shown strong potential to increase viability by stimulating mitochondrial activity and dermal fibroblast proliferation. Stimulation of human keratinocytes was only found at a concentration of 100 μg/ml. EPC did not influence the expression of specific proliferation and differentiation-related genes. Fibroblasts in the connective tissue are the main targets of the arabinogalactan polymer compound from Mimosa tenuiflora. Intense fibroblast stimulation can initiate wound closure and production of extracellular and filling materials within the wound.67

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure33.gif

Figure 33.

Wound healing mechanism of Mimosa tenuiflora (Willd).

Fitzroya cupressoides

Fitzroya cupressoides, commonly called allerce, contains fatty acids, mono and sesquiterpenes, diterpenes, lignans, and phytosterols. Diterpenes and lignans were the most active compounds, with the biomolecules matairesinol, podophyllotoxin, and ferruginol (Figure 34). Allerce extract has a significant effect on wound healing. The results showed that the extract stimulated cell division in human skin epidermal cells in the context of wound healing. These results also indicated that allerce extract accelerated the healing process after 24 and 48 h treatment. This effect was promoted by stimulating HaCaT cell division in wound healing.68

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure34.gif

Figure 34.

Wound healing mechanism of Fitzroya cupressoides.

Plantago australis

The hydroethanolic extract of Plantago australis contains verbascoside (Figure 35). P. australis extract and verbascoside decreased cell viability at 1000 μg/mL and 100 μg/mL, respectively. The results showed approximately 81,06% wound closure (P. australis extract 25 μg/mL) and 58,7% and 57,77% (Verbascoside 5 and 10 μg/mL). P. australis extract showed a significant reduction in TNF-α level. These compounds have wound-healing activity, increase cell migration, and reverse the effects of oxidation in lipopolysaccharide-activated N9 cells. This effect may also be associated with decreased TNF-α, IL-6, IL-12p70, INF-γ, and MCP-1.69

ddf470f0-1e57-4d2e-9cef-2d4bc8a7e0b3_figure35.gif

Figure 35.

Wound healing mechanism of Plantago australis.

Conclusion

Several compounds in plants have been studied to have activity in wound healing by various mechanisms (Table 1). The wound-healing mechanism includes processes that restore skin integrity through four stages: hemostasis, inflammation, multiplication, and remodeling. Antioxidant and anti-inflammatory activities play an essential role in wound-healing mechanisms. Many compounds in plants have been studied to have activity in wound healing by various mechanisms.

Table 1.

Plants with wound healing activity and its compounds.

NoPlantsSolventCompoundsReferences
1.Aristolochia bracteolatamethanolAristoctam, Aporphines, Protobiberberines24
2.Boerhavia diffusamethanolcaffeic acid, ferulic acid, and D-pinitol26
3.Achyrocline satureioides (Lam.)ethanolluteolin and 3-O-methylquercetin30
4.Calophyllum inophyllum Linnethanolcalophyllolide32
5.Ulmus parvifoliaethanolcatechin-7-O-β-D-apiofuranoside33
6.Aloe veraaqueousmannose-6-phosphate35
7.Hibiscus syriacusethanoldihydroquercetin, herbacetin, and kaempferol37
8.Sideroxylon obtusifoliummethanol fractionN-Methyl-(2S,4R)-trans-4-Hydroxy-L-Proline41
9.Alternanthera sessilisethanol2,4-dihydroxy-2,5-dimethyl-3(2H)-furan-3-one, hexadecanoic acid, palmitate, and L-glutamic acid5
10.Wedelia trilobatethanolGrandiflorenic acid15
11.Aegle marmelos L.cineol, eugenol, cuminaldehyde, aegelin, 1-hydroxy-5, 7-dimethoxy-2 naphthalene-carboxaldehyde (HDNC), and Luvangetin42
12.Eriobotrya japonicaethanolicamygdalin44,43
13.Glycyrrhiza glabraaqueousglycyrrhizin and glabridin45,46
14.Calabrian honeymethanolPinocembrin48
15.Thymus vulgaris L.-p-cymene, α -terpinene, and thymol49
16.Trapa japonicaaqueousellagic acid, eugeniin, and gallic acid50
17.Gracilaria lemaneiformis-galactan51
18.Nerium indicummethanololeandrin52
19.Urtica dioica L.methanolketoses, resins, and coumarins53
20.Curcuma amarissimaethanolcurcumenol, curdione and curzerenone10
21.Clausena excavatemethanolcoumarins54
22.Angelica gigas-decursin, and decursinol angelate60
23.Salvia haenkeiHydroalcoholicrosmarinic acid16
24.Crassocephalum crepidioides (Benth.) S.Hydroalcoholicβ-cubebene, α-farnesene, and α-caryophyllene61
25.Withania somnifera-withaferin A4
26.Anemarrhena asphodeloidesethanolMangiferin62
27.Sasa veitchiiethanollignin63
28.Periplaneta americanaethanolpyrimidines, uracils64
29.Angelica tenuissimaethanolZ-ligustilide65
30.Astragali radixmethanolAstragaloside VI (AS-VI) and cycloastragenol-6-O-beta-D-glucoside (CMG)66
31.Mimosa tenuifloraaqueousarabinogalactan67
32.Fitzroya cupressoides-matairesinol, podophyllotoxin, and ferruginol68
33.Plantago australishydroethanolicverbascoside69

Acknowledgements

The authors would like to thank Thammasat University for the grant Thammasat Postdoctoral Fellowship contract number: TUPD/18 2021.

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Fristiohady A, Asasutjarit R, Julian Purnama LOM et al. A Review of Wound Healing Mechanisms of Natural Products in Keratinocyte Cells [version 2; peer review: 1 approved with reservations, 2 not approved] F1000Research 2022, 11:528 (https://doi.org/10.12688/f1000research.121813.2)
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ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
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Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
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Reviewer Report 30 Nov 2022
David Leavesley, Skin Research Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore;  The University of Newcastle, Newcastle, NSW, Australia 
Not Approved
VIEWS 13
https://doi.org/10.5256/f1000research.140131.r156037
This document claims to be a systematic review of human keratinocyte cell line (HaCaT) wound healing assays in response to exogenously applied products derived from products manufactured from plants. This is an important topic. Traditional and Complementary Medicine (T&CM) practices ... Continue reading
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Leavesley D. Reviewer Report For: A Review of Wound Healing Mechanisms of Natural Products in Keratinocyte Cells [version 2; peer review: 1 approved with reservations, 2 not approved]. F1000Research 2022, 11:528 (https://doi.org/10.5256/f1000research.140131.r156037)
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Reviewer Report 21 Nov 2022
Kok-Yong Chin, Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia 
Not Approved
VIEWS 15
https://doi.org/10.5256/f1000research.140131.r156036
Overall, the evidence selection process of this review is not transparent and the selection criteria are contradictory to each other. I could not endorse the indexing of this review.

Specific comments: 

Abstract: 
    ... Continue reading
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    HOW TO CITE THIS REPORT
    Chin KY. Reviewer Report For: A Review of Wound Healing Mechanisms of Natural Products in Keratinocyte Cells [version 2; peer review: 1 approved with reservations, 2 not approved]. F1000Research 2022, 11:528 (https://doi.org/10.5256/f1000research.140131.r156036)
    The direct URL for this report is:
    https://f1000research.com/articles/11-528/v2#referee-response-156036
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    Version 1
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    PUBLISHED 16 May 2022
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    Reviewer Report 01 Aug 2022
    Sisir Nandi, Department of Pharmaceutical Chemistry, Global Institute of Pharmaceutical Education and Research, Kashipur, Uttarakhand, India 
    Approved with Reservations
    VIEWS 39
    https://doi.org/10.5256/f1000research.133716.r141492
    Authors have carried out a critical review on the Wound Healing Mechanisms utilizing Natural Products. This is very significant and the article can be accepted after major revision.
    1. The sentence "In general, the wound-healing process is
    ... Continue reading
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    CITE
    HOW TO CITE THIS REPORT
    Nandi S. Reviewer Report For: A Review of Wound Healing Mechanisms of Natural Products in Keratinocyte Cells [version 2; peer review: 1 approved with reservations, 2 not approved]. F1000Research 2022, 11:528 (https://doi.org/10.5256/f1000research.133716.r141492)
    The direct URL for this report is:
    https://f1000research.com/articles/11-528/v1#referee-response-141492
    NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
    Report a concern
    • Reviewer Response 07 Oct 2022
      David Leavesley, Skin Research Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
      07 Oct 2022
      Reviewer Response
      The authors should not be required to cite their reviewers work. I am confident alternative literature is available to substantiate the authors statements.
      Competing Interests: None.
      Report a concern
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    • Reviewer Response 07 Oct 2022
      David Leavesley, Skin Research Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
      07 Oct 2022
      Reviewer Response
      The authors should not be required to cite their reviewers work. I am confident alternative literature is available to substantiate the authors statements.
      Competing Interests: None.
      Report a concern
    Views
    31
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    Reviewer Report 19 Jul 2022
    David Leavesley, Skin Research Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore;  The University of Newcastle, Newcastle, NSW, Australia 
    Not Approved
    VIEWS 31
    https://doi.org/10.5256/f1000research.133716.r141489
    This document claims to be a systematic review of human keratinocyte wound healing in response to exogenously applied products derived from natural materials; specifically, products manufactured from plants. Traditional and Complementary Medicine (T&CM) practices based on natural products provide essential ... Continue reading
    CITE
    CITE
    HOW TO CITE THIS REPORT
    Leavesley D. Reviewer Report For: A Review of Wound Healing Mechanisms of Natural Products in Keratinocyte Cells [version 2; peer review: 1 approved with reservations, 2 not approved]. F1000Research 2022, 11:528 (https://doi.org/10.5256/f1000research.133716.r141489)
    The direct URL for this report is:
    https://f1000research.com/articles/11-528/v1#referee-response-141489
    NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
    Report a concern
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    20
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    Reviewer Report 20 Jun 2022
    Kok-Yong Chin, Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia 
    Not Approved
    VIEWS 20
    https://doi.org/10.5256/f1000research.133716.r139306
    The abstract is not informative. The background should cover the rationale of using plant material in facilitating wound healing. The results should cover the common pathways of different plants in promoting wound healing. 
    • Introduction: the anatomy
    ... Continue reading
    CITE
    CITE
    HOW TO CITE THIS REPORT
    Chin KY. Reviewer Report For: A Review of Wound Healing Mechanisms of Natural Products in Keratinocyte Cells [version 2; peer review: 1 approved with reservations, 2 not approved]. F1000Research 2022, 11:528 (https://doi.org/10.5256/f1000research.133716.r139306)
    The direct URL for this report is:
    https://f1000research.com/articles/11-528/v1#referee-response-139306
    NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
    Report a concern

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    Version 2
    VERSION 2 PUBLISHED 16 May 2022
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    Open Peer Review

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    Alongside their report, reviewers assign a status to the article:

    Approved
    The paper is scientifically sound in its current form and only minor, if any, improvements are suggested
    Approved with reservations
    A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
    Not approved
    Fundamental flaws in the paper seriously undermine the findings and conclusions

    Reviewer Reports

    Invited Reviewers
    1 2 3
    Version 2
    (revision)
     17 Nov 22     		read read
    Version 1
    16 May 22     		read read read
    1. Kok-Yong Chin, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
    2. David Leavesley, Agency for Science, Technology and Research, Singapore, Singapore; The University of Newcastle, Newcastle, Australia
    3. Sisir Nandi, Global Institute of Pharmaceutical Education and Research, Kashipur, India

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      Alongside their report, reviewers assign a status to the article:
      Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
      Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
      Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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