Fphar 13 900439

TYPE Systematic Review
PUBLISHED 22 July 2022

DOI 10.3389/fphar.2022.900439
The potential application of

OPEN ACCESS natural products in cutaneous
EDITED BY
Ralf J Ludwig,
University of Lübeck, Germany
wound healing: A review of
REVIEWED BY
Igor Prudovsky,
preclinical evidence
Maine Medical Center, United States
Shiqi Hu,
North Carolina State University,
E Liu 1, Hongjin Gao 1, YiJia Zhao 1, Yaobing Pang 1, Yejing Yao 2,
United States Zhengru Yang 1, Xueer Zhang 1, YanJin Wang 1, Siming Yang 1,
*CORRESPONDENCE Xiao Ma 3*, Jinhao Zeng 4* and Jing Guo 1*
Xiao Ma,
[email protected] 1
Dermatological Department, Affiliated Hospital of Chengdu University of Traditional Chinese
Jinhao Zeng, Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China, 2Neijiang Hospital of
[email protected] Traditional Chinese Medicine, Neijiang, China, 3State Key Laboratory of Southwestern Chinese
Jing Guo, Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine,
[email protected] Chengdu, China, 4TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of
Chengdu University of Traditional Chinese Medicine, Chengdu, China
SPECIALTY SECTION
This article was submitted to
Experimental Pharmacology and Drug
Discovery, Under normal circumstances, wound healing can be summarized as three
a section of the journal processes. These include inflammation, proliferation, and remodeling. The
Frontiers in Pharmacology
vast majority of wounds heal rapidly; however, a large percentage of
RECEIVED 20 March 2022
nonhealing wounds have still not been studied significantly. The factors
ACCEPTED 28 June 2022
PUBLISHED 22 July 2022 affecting wound nonhealing are complex and diverse, and identifying an
CITATION
effective solution from nature becomes a key goal of research. This study
Liu E, Gao H, Zhao Y, Pang Y, Yao Y, aimed to highlight and review the mechanisms and targets of natural products
Yang Z, Zhang X, Wang Y, Yang S, Ma X,
(NPs) for treating nonhealing wounds. The results of relevant studies have
Zeng J and Guo J (2022), The potential
application of natural products in shown that the effects of NPs are associated with PI3K-AKT, P38MAPK,
cutaneous wound healing: A review of fibroblast growth factor, MAPK, and ERK signaling pathways and involve
preclinical evidence.
Front. Pharmacol. 13:900439.
tumor growth factor (TNF), vascular endothelial growth factor, TNF-α,
doi: 10.3389/fphar.2022.900439 interleukin-1β, and expression of other cytokines and proteins. The 25 NPs
COPYRIGHT that contribute to wound healing were systematically summarized by an
© 2022 Liu, Gao, Zhao, Pang, Yao, Yang, inductive collation of the six major classes of compounds, including
Zhang, Wang, Yang, Ma, Zeng and Guo.
This is an open-access article
saponins, polyphenols, flavonoids, anthraquinones, polysaccharides, and
distributed under the terms of the others, which will further direct the attention to the active components of
Creative Commons Attribution License NPs and provide research ideas for further development of new products for
(CC BY). The use, distribution or
reproduction in other forums is wound healing.
permitted, provided the original
author(s) and the copyright owner(s) are
KEYWORDS
credited and that the original
publication in this journal is cited, in natural products, wound healing, skin, inflammation, proliferation, remodeling
accordance with accepted academic
practice. No use, distribution or
reproduction is permitted which does
not comply with these terms. Abbreviations: AS, asiaticoside; ASEE, angelica sinensis ethanol extract; AS-IV, astragaloside IV; APS,
astragalus polysaccharides; BSP, bletilla striata polysaccharide; col1, type I collagen; col3, type III
collagen; COX, cyclooxygenase; ECM, extracellular matrix; EGF, epidermal growth factor; EGFR,
epidermal growth factor receptor; FGF, fibroblast growth factor; FVP, flammulina velutipes; GA, gallic
acid; GL-PS, ganoderma lucidum polysaccharide; IL-1, interleukin-1; LOX, lipoxygenase; NF-κB,
nuclear factor; NPS, natural products; OLE, oleuropein; PDGF, platelet-derived growth factor;
PPAR, peroxisome proliferator-activated receptor; RD, resina draconis; SOD, superoxide
dismutase; SSF, snail secretory filtrate; TNF, tumor growth factor; UV, ultraviolet; VEGF, endothelial
growth factor.
Frontiers in Pharmacology 01 frontiersin.org

Liu et al. 10.3389/fphar.2022.900439
Introduction smoking, and hypoxia (Burns et al., 2003). Wound healing can be
accelerated based on the understanding of normal tissue repair
For ages, human beings relied on nature to meet their basic needs, and the factors affecting the process. In addition to this, cell
The most critical of these are herbal medicines capable of treating a migration, proliferation as well as extracellular matrix (ECM)
variety of diseases. Natural products(NPs) have been regarded as the deposition is also considered important activities in wound
active ingredients of traditional medicines and herbal medicines. The healing. (Falanga, 2005). The normal wound healing process is
use of approximately 1,000 plant-derived substances in Mesopotamia a complex interplay between immune cells, signaling molecules,
was recorded around 2600 BC(Cragg and Newman, 2013). Natural growth factors, and the vascular system (Ahmed and Antonsen,
products remain a valuable source of inspiration for the development 2016). The normal healing of wounds includes the following
of modern small molecule drugs. Approximately two-thirds of all eight processes: initial injury, complement, and cytokine
small-molecule drugs approved between 1981 and 2019 are associated response, neutrophil recruitment and response, macrophage
with NPs to some extent (Newman and Cragg, 2020). Natural recruitment and response, fibroblast activity, initiation of
products have long been a source of traditional Chinese medicine angiogenesis, T lymphocyte response while regulating wound
for the treatment of diseases in multiple fields, including immune and closure, and proper granulation of tissue remodeling.
inflammatory diseases, cardiovascular and metabolic diseases, Wound healing mainly includes the following three stages
tumors, neurological diseases, as well as infectious diseases, among (Figure 1): “Inflammation, proliferation, and remodeling” (Han
others (Melander et al., 2020). NPs treat not only diseases but also and Ceilley, 2017). Although these stages are separated for
have great economic benefits. In 2000, 2001, and 2002, NP-derived simplicity, they overlap several times, and even different
drugs ranked among the 35 best-selling drugs worldwide (Butler, wound areas may be in different healing stages. Any
2004). In environmental terms, as a renewable resource, natural interruption in the healing process will disrupt the subsequent
products are able to play a greater value in the circulatory stage and may lead to wound collapse for a long time
economy (Drasar and Khripach, 2019). (Gantwerker and Hom, 2011).
According to statistical data from the United States, approximately Coagulation is a necessary process to stop bleeding and
more than 6.5 million people are living with chronic wounds in the protect wounds (Baron et al., 2020). Bleeding from the wound
United States, and this trend is increasing. Considering the current exposes platelets to the subendothelial layer of thrombosis.
situation, it is estimated that the medical cost may exceed $14 billion Platelets provide initial hemostasis and also release various
(Niu et al, 2019). The causes of wound non-healing are often because of cytokines (insulin-like growth factor-1, tumor growth factor
local tissue hypoxia, repetitive trauma, and proliferation of bacteria, [TGF] -α, TGF-β, and platelet-derived growth factor [PDGF]),
which, coupled with impaired cellular and host responses to stress, and hormones and chemokines allow macrophages and
perpetuate injury and impede progression to the proliferative fibroblasts to enter the wound (Sorg et al., 2017). Even more,
remodeling phase (Stojadinovic et al., 2008). Currently developed at 5–10 min of injury, the injured vessels undergo
targeted agents are unable to meet clinical needs despite their well- vasoconstriction to reduce blood loss, and the tissue gap is
defined therapeutic effects. And because the pathogenicity of multiple filled with thrombus. They are composed of cytokines and
factors prompts current drugs in achieving wound healing less than growth factors (Buganza-Tepole and Kuhl, 2013). At this
envisioned (Zhao et al., 2016). Therefore, the development of natural time, fibronectin can be found in the blood clot. Coagulation
products is highly necessary for addressing non-healing wounds. and platelet degranulation activate the inflammatory phase, and
Studies have shown that some NPs can act on the skin, promote the chemokines released by these platelets are important in the
wound healing, and repair the barrier because of their anti- recruitment of leukocytes (mainly neutrophils) and stem cells or
inflammatory and antioxidant properties (Lin et al., 2017a). fibroblasts in wounds (Pazyar et al., 2014). Neutrophils produce
Moreover, the systematic induction and sorting of the modern elastase, collagenase, TNF-α, and interleukin-1 (IL-1), which will
effects of NPs of plants, animals, and algae on wound healing recruit fibroblasts and epithelial cells (Lee et al., 2012).
and their related molecular mechanisms can provide an additional Monocytes transform into macrophages, engulf necrotic tissue,
therapeutic approach to nonhealing wounds. disintegrate neutrophil fragments and bacterial products, and
release platelet-derived growth factor (PDGF) and TGF-β. β-
Fibroblast growth factor (FGF), TNF-α, IL-1, and IL-6 help heal
Pathogenesis of wound formation the proliferative stage, promote collagen synthesis, secrete
and healing epidermal growth factor (EGF), promote vascular endothelial
cell proliferation and angiogenesis, and play a crucial role in the
At the physiopathological level, wound healing is a proliferation of wound tissue (Khanna et al., 2002; Buganza-
continuous and complex process, which involves many Tepole and Kuhl, 2013; Martin and Nunan, 2015).
interconnected influencing factors. (Fereydouni et al., 2019). Four to five days after injury is approximately the time at
However, several factors play an adverse role in the process of which the proliferative phase appears, even lasting several weeks.
wound healing, such as malnutrition, various drugs, radiation, It includes angiogenesis, granulation tissue, and ECM formation

Liu et al. 10.3389/fphar.2022.900439
FIGURE 1
Diagram of the mechanisms of wound formation and healing. Inflammatory phase: after platelets perform initial hemostasis and release
chemokines recruiting neutrophils, fibroblasts. Conversion of monocytes into macrophages engulfs necrotic tissue, decomposes bacterial products,
and helps the wound to enter the proliferative phase. Proliferative phase: angiogenesis, granulation tissue regeneration, attachment of fibroblasts
onto the wound. Remodeling phase: fibroblasts and myofibroblasts continuously differentiate to form tight cross links.

Liu et al. 10.3389/fphar.2022.900439
and re-epithelialization (Yip, 2015). At the same time, the tissue and attenuate the inflammatory process, which is beneficial
recruits fibroblasts from the surrounding intact tissue. for wound healing (Havsteen, 2002; Silva et al., 2021).
Endothelial cells undergo migration under the stimulation of Anthraquinones, which have hemostatic antibacterial
vascular endothelial growth factor (VEGF) to promote the effects, and their beneficial components will contribute to
formation of new blood vessels (Yun et al., 2010). The newly the hemostatic phase of wound healing and the inflammatory
formed capillaries are connected with adjacent capillaries phase (Masi and Evidente, 2020). Polysaccharides are essential
migrating in the same direction and forming granulation components of higher plants, animal cell membranes, and
tissue. Fibroblasts are attracted to the wound and produce microbial cell walls (Yu et al., 2018). At present,
ECM and contain high levels of immature type III collagen polysaccharide-based scaffolds have been developed and
(col3), which is completely different from type I collagen used in wound healing, and they have high moisturizing
(col1) seen in normal skin and mature scars (Zielins et al., ability and are nontoxic, thus ideal for humans (Nosrati
2015). The highest concentration of collagen in the wound is et al., 2021). The newly developed hydrogels of
found approximately 3 weeks after the initial injury. Moreover, polysaccharides can provide suitable moisture to wounds
3–5 days after injury, fibrin embolus is replaced by granulation and also act as a barrier against bacteria. Although the
tissue, and the wound begins to shrink. At this stage, growth effectiveness of NPs varies, they play a role in the different
factors and other peptides are crucial in the supplement and phases of wound healing (Figures 2, 3, 4).
direction of cells. VEGF, (PDGF and FGF protein family
(particularly FGF-2) are all associated with angiogenesis and
tissue repair (Yun et al., 2010; Hu et al., 2014). Finally, it enters Saponins
the last stage of wound healing, which is called the remodeling
stage. Ginsenoside Rb1
Reconstruction is a dynamic process, starting from the end
of granulation tissue development (Landén et al., 2016). A Ginsenoside Rb1 (Figure5A) belongs to one class of saponin
series of key events in the process of wound healing and tissue compounds. Saponins are a diverse group of compounds widely
repair is the effective differentiation of fibroblasts and distributed in the plant kingdom (Güçlü-Ustündağ and Mazza,
myofibroblasts, including mechanical tension and cytokines 2007). As a traditional medicine, ginseng is known as the king of
(TGF-β, PDGF, and FGF). Drive fibroblasts to differentiate herbal medicine. It has been used as a treatment for diseases in
into myofibroblasts, and myofibroblasts express α-smooth Asian countries for thousands of years (Ratan et al., 2021).
muscle actin, allowing the wound to form a close cross- Ginsenoside Rb1 is the main active component of ginseng and
linking and increasing the tensile strength of mature scars belongs to sterols (Lee et al., 2018). Ginsenoside Rb1 can accelerate
up to 80% of uninjured skin, In addition, with the wound epithelialization and intervene to accelerate PDGF-BB and
transformation of immature col3 into mature col1, the ratio PDGF receptor-β and the peak expression of FGF-2 protein and
of skin stretching col3 and col1 decreases (Sgonc and Gruber, mRNA, promote wound healing and reduce wound healing time.
2013; Landén et al., 2016; Opneja et al., 2019), and this process It can be inferred that ginsenoside Rb1 can regulate PDGF-BB/
can last up to 2 years. PDGF receptor-beta signal pathway to regulate the expression of
FGF-2to have a therapeutic effect on wound healing (Zhang et al.,
2021). In a vivo and vitro model, ginsenoside Rb1 was able to
NPs treatment for wound healing promote neovascularization around the wound and increased
VEGF, IL-1β in the regenerated skin area and expression by
NPs have diverse biological activities (Melander et al., macrophages. Besides, Ginsenoside Rb1 at concentrations from
2020), and a large proportion of newly developed drugs are 100 fg ml−1 to 1 ng ml−1 enhanced the VEGF production and HIF-
produced from NPs (secondary metabolites) and compounds 1α expression induced by IL-1β in HaCaT cells. (Kimura et al.,
derived from them (Li and Vederas, 2009). Like saponins, 2006). Ancient Chinese have always spoken ginseng as a
polyphenols, flavonoids, anthraquinones, and supplement. And subsequent studies have found that several
polysaccharides, NPs play crucial roles in wound healing. ginsenosides isolated from P. ginseng have beneficial effects on
Saponins can promote vascular regeneration and shorten multisystem diseases in the body, which is enough to illustrate the
wound healing time. Moreover, studies have revealed that safety of ginsenosides (Ahmed et al., 2016).
polyphenols, widely present in the human diet, can improve
wound healing because of their beneficial factors such as
antioxidant, immunomodulatory, and bacteriostatic Astragaloside IV
activities (Paszkiewicz et al., 2012). Flavonoids occur in a
wide range in nature, such as food, vegetables, and fruits, and Astragaloside IV (AS-IV, Figure 5B) is an organic
their compound inhibitors can kill several bacterial strains substance and a drug extracted from Astragalus

Liu et al. 10.3389/fphar.2022.900439
FIGURE 2
Diagram of natural product antimicrobial mechanisms. Five natural products of oleuropein, aloin, chamomile, honey, Resina Draconis promote
wound healing by antibacterial, antiviral mechanisms.
membranaceus. To date, many cellular and animal studies which would further explain how as-iv promotes the
have shown that the neuroprotective, hepatoprotective, proliferation and migration of vascular endothelial cells,
anticancer, as well as antidiabetic effects of as-iv, can be antagonizes the poor microenvironment of hypoxia and
attributed to its antioxidant, anti-inflammatory as well as high glucose, and improves angiogenesis and wound
anti-apoptotic properties (Zhang et al., 2020). AS-IV could healing in vitro and in vivo (Shen et al., 2021). In
stimulate wound healing, improve the strength of repairing addition, AS-IV hydrogel is effective in repairing skin
skin, promote angiogenesis and collagen synthesis, and wounds and significantly Promotes wound healing,
reduce collagen I/III and TGF-β 1 secreted by fibroblasts increases collagen synthesis as well as restores skin
level. In vivo studies showed that (Chen et al., 2012) AS-IV tensile strength. At the same time, AS-IV hydrogel
was able to stimulate the wound to recover faster after activates skin appendages and increases TGF-β1 in serum
topical injection in a rat model of full-thickness (Peng et al., 2012). AS-IV loaded with solid lipid
cutaneous excisional wounds. Angiogenesis occurred at nanoparticles-enriched hydrogel gel proved to be
the wound site after 30 days of treatment. Wang et al. excellent local preparation for wound healing and scar
demonstrated that as-iv could increase the protein resistance (Chen et al., 2013). Interestingly, AS-IV not
expression in HUVECs by activating the sumo pathway, only has the effect of Astragalus polysaccharide, but its

Liu et al. 10.3389/fphar.2022.900439
FIGURE 3
Diagram of the mechanisms of action of natural products to promote angiogenesis. Astragaloside IV, asiaticoside, gallic acid, apigenin,
quercetin, hesperdin, bleilia striata polysaccharide, astragalus polysaccharide, snail mucins, angular sinensis ethanol extract, Simmondsia chinensis,
the above 11 natural products play a positive role in wound healing by promoting angiogenesis.
drug efficacy is also more than 30 times that of Astragalus inflammatory and antibacterial efficacy (Gohil et al., 2010;
polysaccharide, so it can be used as a skin-healing agent. Antognoni et al., 2011). Maquart and colleagues believe that
asiaticoside can promote wound healing through fibroblast
proliferation, and this mechanism may be associated with the
Asiaticoside migration of tissue cells around the wound or the expression and
activation of certain growth factors (Maquart et al., 1999). Asiaticoside
Asiaticoside (AS, Figure 5C) is extracted from the medicinal plant induces the synthesis of col1 in human dermal fibroblasts through the
Centella asiatica. It grows in Asia, where it is abundant in India, phosphorylation of Smad 2 and Smad 3 and further binding Smad
Pakistan, as well as Madagascar (Brinkhaus et al., 2000). In skin 3 and Smad 4 (Lee et al., 2006). In vivo and in vitro studies showed
diseases, Centella Asiatica can improve the healing of small wounds, that asiaticoside exhibited remarkable healing ability in both the
scratches, burns, and hypertrophic wounds, and exert anti- normally healed wound model and the long-standing unhealed

Liu et al. 10.3389/fphar.2022.900439
FIGURE 4
Diagram of the mechanisms by which natural products promote wound re epithelialization. Ginscnoside Rb1, lupeol, curcumin, ferulic acid,
Flammulina velutipes, Ganoderma lucidum polysaccharides, the above six natural products release IL-1, TNF - α and EGF by keratinocytes to
promotes wound re epithelialization.
wound model (Shukla et al., 1999a). In excised rat skin wounds, The of fibroblasts embedded in a collagen matrix (Wardecki et al.,
enzymatic and nonenzymatic antioxidants were able to be increased 2016). Studies have shown more significant wound healing
by topical application of 0.2 concentration of Asiaticoside twice a day activity with topical lupeol ointment than control, increased
for 7 days. (Shukla et al., 1999b). granulation tissue, and more efficient wound healing in a
dead space wound model (Harish et al., 2008). In vitro studies
showed that to reduce keratinocyte and fibroblast proliferation,
Lupeol the dose of lupeol was about 20 µg/ml. Lupeol may activate PI3K/
Akt and p38 MAPK, NF- κ B signaling, inhibition of keratins as
Lupeol (Figure 5D) is a pentacyclic triterpenoid saponin, well as MMP-2 and Tie-2 to promote wound healing. (Pereira
present in the epidermis of lupeol seeds and the latex of fig trees Beserra et al., 2018). In terms of experimental indicators, in vivo,
and rubber plants, and in strawberries, mangoes, grapes, olives, experimental studies show that in the lupeol treatment group, the
and other fruits. It can be used to treat various types of diseases expression of NF-κβ and IL-6 decreased significantly and the
such as arthritis, diabetes, as well as skin wounds (Barros et al., level of IL-10 increased. Lupeol also increased FGF-2, TGF-β1,
2010). Lupeol participates in the closure of skin wounds by HIF-1α, and the expression of HO-1 and superoxide dismutase
stimulating the migration of keratinocytes and the contraction (SOD)-2 (Beserra et al., 2019). Besides that, on one hand, lupeol

Liu et al. 10.3389/fphar.2022.900439
FIGURE 5
Diagram of the chemical formula structure of natural products.
cream was able to modulate NF- κ B expression to exert anti- col1, keratinocyte growth factor-1, and epidermal growth
inflammatory effects and promote granulation tissue growth, factor receptor (EGFR) in human gingival fibroblasts in vitro
vascular regeneration as well as re epithelialization. On the other wound healing model. ERK signaling pathway is essential for
hand, it can regulate Ki-67, VEGF, EGF, and TGF- β 1 as well as curcumin-induced col1 and EGFR mRNA expression. Gong and
stimulating the synthesis of collagen fibers to promote tissue colleagues (Gong et al., 2013) tested a dressing made of curcumin
remodeling (Pereira Beserra et al., 2020). thermosensitive gel in vitro experiments. Compared with other
groups, animal wound healing with curcumin heat-sensitive
dressing was significant, with a higher degree of re-
Polyphenolic compounds epithelialization, well-arranged granulation tissue, and
fibroblast deposition. In addition, as a skin wound healing
Curcumin agent, curcumin has been identified to produce TGFβ1 in the
promotion of wound healing. TGFβ1 can stimulate fibroblasts of
Curcumin (Figure 5E) is a polyphenol compound. As a the tissue surrounding the wound to proliferate and express
yellow dye, the main active ingredient of curcumin widely appropriate integrin receptors, thereby moving to the wound site
exists in the medicinal plant turmeric (Trigo-Gutierrez et al., to favor wound healing (Hong et al., 2008; Thi et al., 2020).
2021). Modern research shows that curcumin has a wide range of Interestingly, the fad also identified curcumin as a safe
pharmacological effects, including anti-inflammatory compound. Clinical data studies revealed that topical
antioxidation, and antibacterial effects (Witika et al., 2021). curcumin showed good bioactivity, which will provide a useful
Curcumin may play a crucial role in wound healing due to its aid for the further development of effective composite
antioxidant and anti-inflammatory functions. Four processes formulations (Vollono et al., 2019).
such as the formation of granulation tissue, collagen
deposition, tissue remodeling as well as wound contraction
may all receive the influence of curcumin, thereby promoting Oleuropein
the healing of wounds. (Zhao et al., 2019). One study found that
(Rujirachotiwat and Suttamanatwong, 2021) found that Oleuropein (OLE, Figure 5F) is a phenolic compound found
curcumin significantly upregulated the mRNA expression of in the olive plant. It has crucial anti-inflammatory and

Liu et al. 10.3389/fphar.2022.900439
antioxidant effects. Some studies proved that ole exerted anti- Flavonoids
inflammatory activity may be related to the production of
lipoxygenase activity, leukotriene B4 (Motawea et al., 2020). In Apigenin
addition, the biosynthesis of pro-inflammatory cytokines or
inflammatory parameters is also associated with its inhibitory Apigenin (Figure 5I) is a common flavonoid compound that
effects (de la Puerta et al., 1999). Results indicated that ole could widely exists in fruits and vegetables (such as onion, orange, and
exert obvious favorable effects in the cutaneous wound healing of parsley) (H u et al., 2021). Overall, the exertion of its
aged male Balb/c mice (Mehraein et al., 2014). In vivo study pharmacological effects is mainly related to anti-inflammation,
showed that the wound closure time was shortened when the antioxidation, andante-cancer. Studies have shown that topical
diabetic rats and non-diabetic rats were treated with ole wound application of apigenin gel resulted in faster wound re-
dressing topically. The above findings indicate that ole wound epithelialization and improved inflammation (Lopez-Jornet
dressing is a suitable choice for the treatment of diabetic wounds et al., 2012). The findings revealed that apigenin combined
(Samancio et al., 2016). The acute toxicity test results found that with LysGH15 acts as a topical antibacterial agent against
the mice did not experience any side effects or fatal situations Staphylococcus aureus (Cheng et al., 2018). In plastic surgery,
even when the dose reached 1,000 mg/kg (Zheng et al., 2021). the integrity of wound healing is extremely crucial. Apigenin can
promote angiogenesis in mice, promote the survival rate of the
skin flap area, and reduce tissue edema (Zhu et al., 2021). Up to
Gallic acid now, apigenin is considered safe and, even at high doses, there
have been no reports of toxicity. However, at high doses, it is able
Gallic acid (GA, Figure5G) is a polyphenolic organic to elicit muscle relaxation as well as produce sedation (Ross and
compound widely found in plants such as Rheum palmatum, Kasum, 2002).
EucalyptusGrandiss, and Cornus. GA has antioxidant, anti-
inflammatory, and analgesic effects (Comino-Sanz et al.,
2021). Studies have shown that GA can improve wound Quercetin
healing in diabetic rats, and promote neovascularization, and
collagen deposition during wound healing in diabetic animals Quercetin (Figure 5J) belongs to flavonoids, which are widely
(Singh et al., 2019). In vitro studies have shown that GA distributed in the stems, leaves, flowers, skins, seeds, and fruits of
upregulates the expression of antioxidant genes, stimulates cell plants, such as apples, grapes, onions, tea, tomatoes, and Ginkgo
migration on fibroblasts, and activates healing factors (Yang biloba (Li et al., 2016). Quercetin mainly exerts anti-
et al., 2016). More notably, GA can not only be extracted inflammatory and antioxidant activities and improves
from many plants and can be produced in large quantities by immunity. In vitro experiments, the mechanism by which
biological and chemical synthesis. Taking a step further, GA quercetin exerts anti-inflammation activity is associated with
hardly has any obvious toxicity and toxic side effects in any the inhibition of the cyclooxygenase (COX)and lipoxygenase
animal experiments and clinical experiments (Bai et al., 2021). (LOX) (Kim et al., 1998); Moreover, quercetin can induce
inflammation by increasing peroxisome proliferator-activated
receptor C (PPAR-γ) In activity to indirectly prevent
Ferulic acid inflammation and thereby antagonize NF-κB or
transcriptional activation of activator protein-1 inflammatory
Ferulic acid (Figure 5H) is a polyphenol and the most common genes (Li et al., 2016). Studies have shown that after quercetin
compound in whole grains, spinach, parsley, grapes, rhubarb, and binds to collagen, the hydroxyproline concentration in
cereal seeds. It has low toxicity and several physiological functions. granulation tissue has increased from 0.78 mg/ML in controls
Such as exerting anti-inflammatory, antimicrobial, antioxidant, to 1.84 mg/ML, indicating enhanced collagen production in
anticancer as well as anti-diabetic effects. (Zduńska et al., 2018). granulation tissue (Hatahet et al., 2016). Cytokines, growth
In vivo studies showed that ferulic acid accelerated wound factors, and proteases play critical roles in wound healing. The
regeneration and healing. The granuloma attack and findings suggest that quercetin ointment at a topical 0.3% w/w
epithelization of the ferulic acid group were faster than the concentration can promote better wound outcomes in a rat
control group (Dwivedi et al., 2022). The use of ferulic acid cutaneous diabetic wound model, which may be related to the
ointment during healing can inhibit lipid peroxidation and reasons mentioned above (Kant et al., 2021). As quercetin is
increase catalase, superoxide dismutase, and glutathione (Ghaisas poorly water-soluble, improving the permeation ability to
et al., 2014). Considering the safety of drugs, ferulic acid, as an increase the stability is the main purpose of quercetin nano
important potential therapeutic agent, has the characteristics of low dosage forms (Brüll et al., 2015). therefore, the current
cost, easy availability, low toxicity, and few side effects (Kaur et al., nanoformulation with quercetin as the main raw material
2022). comes with an age limit.

Liu et al. 10.3389/fphar.2022.900439
Hesperidin Aloe-Emodin
Hesperidin (Figure 5K) is a flavonoid found in the peel of Aloe-emodin (Figure 5M) is an anthraquinone compound in
citrus fruits and is an antioxidant found in plants, that is, essential aloe. It can be used in the development of pharmaceutical raw
for human health. It has recently been shown to exert several materials, intermediates, and anticancer drugs. It has broad
functions on the skin (Man et al., 2019), including wound application prospects in the field of medicine. In vitro studies
healing, UV protective, anti-inflammatory, antimicrobial, show that aloe-emodin can protect against burn wounds (Lin
antioxidant, and whitening effects. The study revealed a et al., 2017b). The activity of forex-isolated compounds (aloe-
significant increase in the wound closure process at 24 h after emodin, chrysophanol, and aloin) was investigated by Kambiz
the addition of hesperidin containing 0.05% to the culture et al. (Kambizi et al., 2005). They found that aloe-emodin and
medium. and administration of hesperidin significantly along A exhibit inhibitory activities against a variety of bacteria a.
upregulated TGF-β in wound tissues and Smad-2/3 mRNA Existing evidence suggests that the use of multiple dosages of aloe
expression (Li et al., 2018). In addition, topical or oral may effectively enhance the wound healing process compared
hesperidin can shorten the wound healing time of irradiated with traditional treatment methods (Maenthaisong et al., 2007).
mice, which was 3 days,s and may be associated with the This study confirmed that increased wound healing occurs
inhibition of NF-lB. COX-II and LOX have been associated following treatment with aloe-emodin, thus supporting the use
with their transcriptional activation (Jagetia and Rao, 2022). of aloe vera plants to improve burn wound healing (Lin et al.,
Moreover, The results demonstrated that topical hesperidin 2016). However, adverse effects of aloe-emodin have been
enhanced epidermal skin permeability and barrier homeostasis reported, including phototoxicity, hepatotoxicity, and
in mice and further stimulated epidermal proliferation and nephrotoxicity (Dong et al., 2020). Therefore, we should look
differentiation (Hou et al., 2012). In general, hesperidin at this problem dialectically.
appears to be very safe with no adverse effects even during
pregnancy. In animal experiments (Garg et al., 2001),
phosphorylated hesperidin is nontoxic to organisms and Polysaccharides
tissues, readily absorbed, and does not cause allergic reactions.
Bletilla striata polysaccharide
Anthraquinone compounds Bletilla striata polysaccharide (BSP) is typically

considered the main active component of Bletilla striata. It
1Aloin is an orchid, mainly distributed in southern China. More and
more shreds of evidence show that BSP has various activities,
Aloe Vera (Figure 5L) is one of the major active components including immune regulation, anti-inflammatory, wound
of the plant aloe vera, belonging to anthraquinone compounds. healing, and antioxidant. Studies have shown that Bletilla
Aloe protects the skin mainly through anti-inflammatory and polysaccharides can promote the growth of endothelial cells
antioxidant mechanisms (Sánchez et al., 2020). A study suggested and enhance the self-secretion of endothelial growth factors r
that the mechanism by which aloe glycoside exerts partial anti- (Wang et al., 2006). The root whiskers of Bletilla striata are
inflammatory activity may be related to the inhibition of the extremely valuable and able to unite with pseudoscalar, both
reactive oxygen species (ROS) - mediated JAK1-STAT1/ of which share similar chemical compositions (Jiang et al.,
3 signaling pathway in RAW264 macrophages (Ma et al., 2013). BSP could promote endothelial cell proliferation and
2018). Moreover, aloe glycoside was able to produce skin VEGF expression and enhance NO synthase, TNF- α, And IL-
protective effects. This may be related to decreased IL-8, DNA 1 β Levels of mRNA (Diao et al., 2008; Hung and Wu, 2016).
damage, lipid peroxidation, and reactive oxygen species BSP shows good healing function and can regulate
production (Liu et al., 2015). In mouse skin samples, macrophages during inflammation and proliferation, which
macrophages and neutrophils were increased at the site of will further exert its good potential to promote wound
injury after Aloesin treatment, which illustrates that aloesin healing. (Chen et al., 2018). In the in vivo study, BSP
exerts a positive effect on inflammation at an early stage. In hydrogel was applied on the mouse wound skin with a
addition, aloesin can promote neoangiogenesis, which may be good wound healing effect, infiltrating inflammatory cells
related to an increase in TGF- β1 is associated (Wahedi et al., and TNF- α attenuated, But the secretion level of EGF
2017). In recent years, one of the reasons for the increasing increased (Luo et al., 2010). At present, BSP-based
number of aloe external preparations may be that it plays a role in derivatives are also constantly being developed, which
promoting skin healing. paves the way for promoting wound healing.

Liu et al. 10.3389/fphar.2022.900439
Flammulina velutipes cause IκBα and cyclin D1 to reduce mRNA and protein
expression levels, This may be related to wound healing (Zhao
In recent years, edible bacteria have become a type of food et al., 2017). In vivo study, Astragalus polysaccharide-loaded
with a high nutritional value because of the umami taste and fibrous mats promoted the recovery of microcirculation in
rich nutrition. Flammulina Velutipes (FVP) is one of the most and around the skin wound, and mouth, which may be
common economic food bacteria (Yuan et al., 2019). FVP associated in a dose-dependent manner to promote blood flow
polysaccharide is one of the active components derived from in the surrounding skin and increase the endocrine and
FVP. TG05 is a major monomer composed of extracted microvessel density in the regenerated skin tissue (Yang et al.,
components of a wide range of sugars. Such as xylose, and 2015). In addition, Astragalus gum extracted from Astragalus
glucose. It is the residue of the culture process of FVP. But also polysaccharide for back wounds in mice has beneficial effects in
has the ability to induce the proliferation and migration of accelerating wound reduction as well as skin healing (Fayazzadeh
human keratinocytes. This depends mainly on the timing of the et al., 2014). Interestingly, Astragalus extracts (APS and
experimental design and the doses used (Xu et al., 2019). astragaloside saponins) are safe without significant toxicity
Interestingly, the novel seeded scaffold, prepared from FVP and side effects. Its safe dose is 5.7–39.9 g/kg in rats and
by cryosection “processing”, can promote the regeneration of 2.85–19.95 g/kg in dogs (Yu et al., 2007). Therefore, there is a
hair follicles and injured tissues (Chen et al., 2021). This novel certain basis for applying Astragalus polysaccharides to wound
technique will further facilitate the study of nonhealing healing.
wounds.
Others
Ganoderma lucidum polysaccharides
Honey extract
Ganoderma lucidum Polysaccharide (GL-PS; Figure 5N) is
a substance extracted from the spore meal or Ganoderma Honey is available as both a food and a natural product. It
lucidum and is one of the most effective components of contains various phenolic compounds, enzymes, and sugars
Ganoderma lucidum. Research has found that it could help and is known for its antioxidant, anticancer, anti-
in avoiding the delayed wound healing and improve wound inflammatory, and antibacterial properties. (Scepankova
angiogenesis in STZ-induced type 1 diabetic mice models by et al., 2021). Honey has been used in wound dressings for
inhibiting cutaneous MnSOD nitration, p66Shc, and thousands of years. A survey showed that compared with
mitochondrial oxidative stress (Tie et al., 2012). In vitro nonantibacterial drugs, the average time of wound healing
studies revealed that 10, 20, and 40 µg/mL GL-PS after intervention with honey was reduced by 5.32 days
significantly increased the viability, promoted the (Norman et al., 2017). The findings suggest that honey
migration, and upregulated the cell-in-cell phenomenon can reduce the level of inflammation, edema, and pain by
and TGF-β in fibroblasts. The expression of Wnt/β, which reducing the activities of COX1 and COX2 (Nooh and Nour-
may be related to the activation of Wnt/β and TGF-β1, was Eldien, 2016; Yadav et al., 2018). In vitro, honey can promote
associated with the upregulation (Hu et al., 2019). Previous angiogenesis, which may be associated with peroxidation,
studies have shown that Wnt/β-catenin signaling may be and induce macrophages to release VEGF for stimulating
involved in wound healing (Liu et al., 2012), and GL-PS angiogenesis (Rossiter et al., 2010). In recent years, honey
may also be implicated in this signaling pathway for wound products have had great potential in wound healing.
healing. Notably, in vitro studies, GL extracts exhibit toxic Whether directly applied or mixed with fiber or hydrogel
effects when present at higher concentrations in cells than membrane, it has achieved a good curative effect (Molan and
required for a stimulatory effect (Bishop et al., 2015). Rhodes, 2015; Sen et al., 2021). It is worth noting that the
poisoning symptoms caused by honey may differ depending
on the source of the toxin (Islam et al., 2014). Honey should
Astragalus polysaccharide not be considered a completely safe food.
Astragalus Polysaccharides (APS, Figure 5O) can be

produced from the main active components extracted from Comfrey extract
the traditional Chinese medicine Astragalus membranaceus.
Modern pharmacological studies believe that most of the Comfrey is a perennial herb in the genus Shikonin of the
active components that Astragalus plays a role in the process family purpura, belonging to the family Boraginaceae
of wound healing are polysaccharides and saponins. In vitro (Staiger, 2012), and extracts from its leaves and roots have
experiments, aps2-1 purified from Astragalus membranaceus can been used in the treatment of wounds. In a clinical trial, the

Liu et al. 10.3389/fphar.2022.900439
wound healing time was significantly shorter after the topical of the wound, and acts as a physical barrier, thus shortening
application of an ointment of a comfrey extract preparation the inflammatory process (Chen et al., 1994).
(Staiger, 2012). In addition, in children, a 10% concentration
of Shikonin extract formulation was applied topically to
wounds, and its healing rate was higher than that of a 1% Simmondsia chinensis
concentration (Barna et al., 2012). In addition to that, some
extracts with comfrey as raw materials are widely used in Simmondsia Chinensis is a plant with a tenacious life span and
clinical practice, such as comfrey cream, comfrey oil, etc. drought tolerance ability. The oil produced from it is the main
Unfortunately, Comfrey is recognized as hepatotoxic as well biological source of wax fat, which can be used for various skin
as has carcinogenic potential for human health (Mei et al., injuries, including skin infections and wounds (Pazyar et al., 2013).
2010). In vitro, jojoba liquid wax significantly enhances the wound closure
of keratinocytes and fibroblasts. Its mechanism of action is strictly
dependent on the flow of calcium ions. Besides that, the involvement
Chamomile extract of multiple signal pathways including PI3K Akt mTOR, p38, and
ERK1/2 MAPK was involved (Ranzato et al., 2011). In addition,
Chamomile is one of the flavonoids, mainly from the jojoba is often used as a food additive, showing high safety and no
flowers and leaves of the plant chamomile (Hussain et al., significant toxicity and side effects (Ibrahim et al., 2011).
2017). Studies have shown that chamomile extract has
antioxidant (Singh et al., 2011) effects. In vitro studies
have shown that chamomile extract can produce anti- Snail mucins
inflammatory effects by interfering with the COX-2
pathway (Srivastava et al., 2009). In the in vivo study, Recently, snail mucins have also been viewed as a profitable
chamomile extract was applied to a rat skin burn model, resource and used as skin care products, wound healing agents,
applied twice a day, and after 61 days a clear wound healing surgical gels, and anti-gastric ulcer agents (McDermott et al., 2021).
was visible (Jarrahi, 2008). Some findings showed that topical In addition, studies have shown mucus secretions to be more
application of 0.04 ml/day of chamomile ointment treated resistant to infection than some antibiotics (e.g., amoxicillin and
wounds on the rat tongue over 10 days, re-epithelialization streptomycin) (Gugu et al., 2020). Snail mucus can promote wound
of the wound as well as collagen fiber formation (Duarte healing and has emerged as a base substance for various biomaterials
et al., 2011). The results of this study show that tribo oil from (Park, 2011). In mouse models, snail secretory filtrate (SSF)
chamomile extract is able to additively accelerate wound significantly increased the rate and percentage of wound area
healing in rats. As technology continues to update, materials closure and COL3A1 level and decreased MPO expression in the
such as hydrogels are also able to be combined with wound and IL-1β. Moreover, TNF-α expression levels of the
chamomile extracts, These results suggest that starch/ restorative growth factor TGF-β in wounds level up, suggesting an
extract/4 wt% nZ dressing significantly promoted wound enhancement of the adaptive wound healing process (Gugliandolo
healing (Salehi et al., 2017). et al., 2021). This illustrates that snail extract is a safe and effective
alternative therapy for wound healing (Tsoutsos et al., 2009).
Resina draconis
Angelica sinensis ethanol extract
Resina Draconis (RD) is a red resin, which extracts from
the trunk of calcaneal cochinensis, which mainly grows in The ethanol extract of Angelica Sinensis comes from Angelica
Yunnan and Guangxi provinces (Vaníčková et al., 2020). It has Sinensis. Studies have shown that (Zhang et al., 2017) both in vivo
antithrombotic, antioxidant, antiseptic, and other effects and in vitro studies, Angelica Sinensis ethanol extract (ASEE) can
(Choy et al., 2008). In the animal model, after using Resina produce obvious effects on angiogenesis. It has been shown to
Draconis extract and burn ointment, the time of wound re- improve wound healing in diabetic rats in vivo studies, a mechanism
epithelization was significantly shortened, which could restore that may also derive from effects exerted by angiogenesis. In vitro
the integrity and protect from infection (Liu et al., 2013). The study found that (Bai et al., 2012a) the concentration was 5 × 10(−4)
expression of TGF-β1 and VEGF increased significantly in ~5 × 10(−2) g/L of ASEE can significantly promote the proliferation of
wound tissue of the skin, which are the main genes for wound human normal fibroblasts, accelerate the cell cycle of fibroblasts,
healing (Santos et al., 2007). In clinical studies, the use of upregulate the expression of collagen I and collagen III, and enhance
Longxue cream can significantly improve the wound healing wound healing. Interestingly, ASEE could accelerate the cell cycle of
time (Namjoyan et al., 2015), which may be because of the KC, and inhibit cell apoptosis. This may be associated with the
formation of a protective layer of polyphenols on the surface downregulation of cyclin D1 mRNA and caspase-3 mRNA. Such

Liu et al. 10.3389/fphar.2022.900439
findings suggested that the pathway by which ASEE promoted et al., 2011), Snail mucins (Gugliandolo et al., 2021), Angelica
wound healing was associated with accelerated wound re- Sinensis ethanol extract (Bai et al., 2012b), Apigenin (Choi et al.,
epithelialization. (Bai et al., 2012b). 2016)have important potential to promote wound healing, and the
molecular mechanism should be further studied. This conclusion is
supported by desirable results, both in animal and cell experiments.
Conclusions and perspective Regrettably, both the mechanisms and targets through which the
above natural products act warrant further exploration.
Perfect wound healing includes not only integrity in appearance Taking a step further, besides focusing on natural product active
but also restoration of local tissue function. In the process of wound ingredients, toxic side effects of drugs should also be paid attention to.
healing, bacteria as well as the reduction of inflammation, the Such as Aloe Emodin is phototoxic, hepatotoxic, and nephrotoxic
regeneration of blood vessels, and the repair of re-epithelialization (Dong et al., 2020). Toxicity also occurs when GL-PS exceeds the
all play important roles. Through a systematic summary, The results stimulatory concentration (Bishop et al., 2015). Honey extract is also
show that NPs have bacteriostatic and anti-inflammatory activities partially toxic (Islam et al., 2014). Comfrey Extract has hepatotoxic
(such as OLE, aloin, chamomile, aloe-emodin, etc.) and promote and carcinogenic properties (Mei et al., 2010). How to maximize the
angiogenesis (such as AS-IV, asiaticoside, GA, apigenin, quercetin, extraction of active ingredients of drugs instead of toxicity is also a
etc.) and re-epithelialization (such as ginsenoside Rb1, lupeol, question that should be addressed in natural product extraction.
curcumin, ferulic acid, FVP, etc.). Selection of the corresponding The presently developed derived products such as hydrogels,
pharmacological treatment, based on differences in the local nanoparticles, scaffolds, and dressings have a promising future (Sun
characteristics of the wound, might be able to be more targeted. et al., 2018; Dart et al., 2019; Moeini et al., 2020; Sharma et al., 2020;
In addition, due to the good ability of some drugs to promote Sharma et al., 2022)–(Sun et al., 2018; Dart et al., 2019; Moeini et al.,
wound healing, they have been widely used in the clinic, such as 2020; Sharma et al., 2020; Sharma et al., 2022). Although the active
Centella Asiatica, Curcumin, Resina Draconis, and Quercetin. ingredients of these natural medicines can effectively treat unhealed
Clinical studies have shown that Centella Asiatica extract can wounds, their effects depend on the advanced nature and suitable
promote skin wound healing after laser, improve skin texture dosage of sophisticated technologies and instruments. Although several
and reduce pigmentation (Damkerngsuntorn et al., 2020), experiments have confirmed the significance of the therapeutic effect, it
Besides, Curcumin has been widely used in the clinic. Such as still needs to be further implemented in clinical practice. Regrettably,
capsules, nanofibers, transdermal patches, etc. Clinical studies have only the active ingredients of a single natural product are discussed, and
shown that compared with oral curcumin, local use seems to have a whether the above drugs can be used in combination still deserves
more obvious effect on wound healing [68 (Vollono et al., 2019), As continued exploration. Cosmetically, increased scar proliferation,
a safe and easily available drug, dragon’s blood is an ideal choice for hyperpigmentation, and keratinization of the wound after healing
wound healing. Clinical studies have shown that the phenolic also need to be taken into account.
compounds in Longxue cream can shorten the inflammatory
process and form a physical barrier to prevent microbial
infection (Namjoyan et al., 2015). To improve diabetes foot Data availability statement
ulcers, after using nano hydrogel embedded with quercetin and
oleic acid, the wound healed completely within 1 month without The original contributions presented in the study are included in
adverse drug reactions. This indicates that the preparation can be the article/Supplementary Material, further inquiries can be directed
used for the management of wound healing (Kant et al., 2021). The to the corresponding authors.
clinical effects of the above four natural products on wound healing
have been verified, and further research and development of new
clinical drugs will be the direction of efforts. Author contributions
As research continues to deepen, certain natural products
may be able to work together with matrices such as hydrogels, Concepts: EL; Wrote the paper: EL, MX, HG, and YZ;
dressings, seeded scaffolds, fibrous mats, and so on. Such as AS- Designed the figures: EL, MX, YP, YY, ZY, XZ, YW, and SY;
IV (Peng et al., 2012), FVP (Chen et al., 2021), APS (Yang et al., Reviewed manuscript: MX,JG, and JZ. All authors commented
2015), OLE (Samancio et al., 2016), BSP (Luo et al., 2010), on the manuscript. All authors contributed to the article and
Chamomile extract (Salehi et al., 2017). These novel products approved the submitted version.
hold great promise in improving wound healing and are highly
worth entering clinical research.
In general, Ginsenosides Rb1 (Zhang et al., 2021), Lupeol Funding
(Pereira Beserra et al., 2020), garlic acid (Singh et al., 2019),
Ferulic acid (Dwivedi et al., 2022), Hesperdin (Jagetia and Rao, This work was supported by the National Natural
2022), Aloin (Liu et al., 2015), Simmondsia cheinensis (Ranzato Science Foundation of China (grant nos. 82074443), and

Liu et al. 10.3389/fphar.2022.900439
by Xinglin Scholar ResearchPromotion Project of Publisher’s note

Chengdu University of TCM (grant nos QNXZ2020003),
and the “Hundred Talents Program” of the Hospital of All claims expressed in this article are solely those of the authors
Chengdu University of Traditional Chinese Medicine and do not necessarily represent those of their affiliated organizations,
(grant nos. 20-B01) and by the Program of Science and or those of the publisher, the editors and the reviewers. Any product
Technology Department of Sichuan Province that may be evaluated in this article, or claim that may be made by its
(2021ZYD0089). manufacturer, is not guaranteed or endorsed by the publisher.
Conflict of Interest Supplementary material

The authors declare that the research was conducted in the The Supplementary Material for this article can be found
absence of any commercial or financial relationships that online at: https://www.frontiersin.org/articles/10.3389/fphar.
could be construed as a potential conflict of interest. 2022.900439/full#supplementary-material
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TYPE Systematic Review

PUBLISHED 22 July 2022

The potential application of

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Anthraquinone compounds Bletilla striata polysaccharide (BSP) is typically

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Astragalus Polysaccharides (APS, Figure 5O) can be

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by Xinglin Scholar ResearchPromotion Project of Publisher’s note

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