PERSPECTIVE ARTICLE

Effect of medicinal plants on wound healing

Arie Budovsky, PhD1; Ludmila Yarmolinsky, PhD1; Shimon Ben-Shabat, PhD2
1. Judea Regional Research & Development Center, Carmel,
2. Department of Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel

Reprint requests: ABSTRACT

Shimon Ben-Shabat, Ph.D., Associate
Professor, Department of Biochemistry &
Pharmacology, Faculty of Health Sciences,
Ben-Gurion University of The Negev, P.O.
Box 653 Beer-Sheva 84105, Israel. Tel:
972-8-647-9354; 972-8-647-7363; Fax: 972-
8-647-2984; Email: sbs@bgu.ac.il
Manuscript received: January 4, 2015
Revised: February 13, 2015.
Accepted in final form: February 17, 2015
DOI:10.1111/wrr.12274
In the United States alone, chronic wounds affect 6.5 million patients. It is
expected that the number of chronic wounds will increase worldwide due to the
increase in age-related conditions and pathologies such as diabetes, obesity, and
cardiovascular diseases. An estimated excess of US$25 billion is spent annually
on treatment of chronic wounds, and the burden is rapidly growing due to
increasing healthcare costs, an aging population, and a sharp rise in the
incidence of diabetes and obesity worldwide. While current therapeutic agents
have generally inadequate efficacy and number of serious adverse effects, the
medicinal plants have been used in medicine since ancient times and are well
known for their abilities to promote wound healing and prevent infection without
grave side effects. Thus, herbal therapy may be an alternative strategy for
treatment of wounds. The purpose of this review is to provide the verified data
on the medicinal plants of the world flora with wound healing activity including
the biologically active substances belonging to these herbal preparations and
describe in detail the various cellular and molecular mechanisms of their actions.

INTRODUCTION lus. This is particularly relevant for the skin—an organ

that sustains insult and injury throughout life. Wounds are
Out of estimated 250,000 flowering plant species in the physical, chemical, or thermal injuries which result in
world,1 15% have been evaluated phytochemically and breaking of skin integrity.
only 6% have been screened for biological activity.2 While In all organs of mammals, the normal response to injury
a relatively small portion of all plants have been used as occurs in three overlapping but distinct classical stages:
medicinal agents, their importance should not be under- inflammation, new tissue formation, and remodeling 14
mined as almost 65% of the world’s population has incor- Tissue damage leads to immediate activation of the coagu-
porated them into their primary modality of healthcare.3 lation cascade, inflammatory pathways, and immune sys-
Remarkably, about one-third of all traditional herbal medi- tem to prevent blood fluid loss, to remove dead tissues,
cines are intended for treatment of wounds or skin disor- and to neutralize invading pathogens.15 During and after
ders, compared to only 1–3% of modern drugs.4 Of note, formation of the platelet plug and deposition of fibrin
the beneficial effects of plant extracts on skin wound heal- matrix, neutrophils infiltrate the wound site. After 2–3
ing (WH) has also gained support from several experimen- days, monocytes appear in the wound and differentiate
tal studies.5–11 Given that in the United States alone into macrophages which coordinate the next phase of
chronic wounds affect 6.5 million patients, and that that wound repair.16 The second stage of WH occurs 2–10 days
the number of chronic wounds is likely to grow worldwide after injury and is characterized by cellular proliferation
due to the increase in age-related conditions and patholo-
gies such as diabetes, obesity, and cardiovascular dis-
eases,12 any therapeutic intervention aimed at facilitating B.C. Before Christ
the WH processes should not be disregarded. Here, we HIF-1 Hypoxia-inducible factor
present a systematic and comprehensive review of the lit- NADPH Nicotinamide adenine dinucleotide phosphate-
erature on the pro-WH activity of herbal extracts and plant oxidase
derived chemicals from all corners of the World. NF-kB Nuclear factor kappa-light-chain-enhancer of acti-
vated B cells
NOX NADPH oxidase protein family
CELLULAR AND MOLECULAR ROS Reactive oxygen species
MECHANISMS OF WH PROCESS SMAD Intracellular proteins that transduce extracellular
signals from transforming growth factor beta
WH is a complex biological process consisting of a ligands to the nucleus
synchronized chain of molecular events aimed at repairing TGFb1 Transforming growth factor beta
the damaged tissue and restoring its protective barrier TIMP-2 Metallopeptidase inhibitor 2
function.13 In general, the wound repair occurs in almost WH Wound healing
all tissues after exposure to any kind of destructive stimu- Wnt Group of signal transduction pathway

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Effect of medicinal plants
and migration of different cell types, migration of keratino-
cytes over the injured dermis. In parallel to this migration,
angiogenesis starts as newly emerging capillaries replace
the fibrin matrix and the granulation tissue. Angiogenesis is
positively stimulated by various growth factors such as vas-
cular endothelial growth factor A and fibroblast growth fac-
tor 2.17 Along with the keratinocytes, fibroblasts migrate to
the tissue repair zone and on stimulation by macrophages
turn into myofibroblasts.18 In turn, myofibroblasts bring the
edges of the wound closer to one another and in cooperation
with fibroblasts produce extracellular matrix creating the
scar tissue.19 A key pleiotropic cytokine Transforming
growth factor beta (TGFb1) secreted by fibroblasts stimu-
lates proliferation of fibroblasts and their trans-
differentiation to myofibroblasts.20 The final stage of WH
(remodeling) begins 2–3 weeks after injury and may last for
a year or even more. In the framework of the remodeling,
the inflammatory response is down-regulated as most of the
cells involved in the previous stage of wound repair
undergo apoptosis, and the dead cells are replaced by colla-
gen and other extracellular-matrix proteins.21
The complexity of the wound repair process on the
molecular level stems from the fact that modulation of
hundreds of genes (gene deletion, full or partial loss-of-
function mutations or gene overexpression) in mice and
other model organisms result in either delayed or acceler-
ated WH.22 Among these genes are many growth factors,
pro-inflammatory cytokines and chemokines. Expression
of these pro-inflammatory mediators (e.g., Interleukin 6
and Interleukin 8) may stand behind scar formation and
fibrotic processes in adults while their absence in new-
borns may promote perfect scarless WH (reviewed in 23).
These deviations from regular WH could lead to diverse
age-related pathological conditions, from slow or ineffec-
tive tissue repair to fibroproliferative responses (the so
called never healing wounds).24,25 While formation of
scars and fibrotic responses are from complete tissue
regeneration, the incomplete WH in adults may hold some
evolutionary advantage as quick restoration of tissue
homeostasis is vital for the protection of the organism
from pathogen invasion.26 In any case, several growth pro-
moting and survival pathways become activated during
WH in adults. Signal cascade activated by TGFb1 and
mediated by the SMAD and Wnt dependent pathways
enhances scarring (in particular, in case of the cutaneous
WH) while the expression of TGFb1 is transient in the
skin of the neonates (reviewed in 23). In support of this
notion are the studies on the TGFb1 knock-out mouse
which showed that these mice have defects in the prolifer-
ative phase of WH as at 10 days after incisional injury
there was reduced granulation of the tissue and reduced
collagen deposition.27 Conversely, overexpression of
TGFb1 in keratinocytes led to up-regulation in the type I
collagen expression and increased deposition of the scar
tissue.28 Of note, fibroblasts from both hypertrophic scars
and keloids consistently overexpress proteins involved in
TGFb signal transduction.29 Thus, a prolonged and/or
excessive secretion of TGFb1 in the wound area may redi-
rect the regular process of WH toward fibrosis.30–32 The
hyper-activation of the Wnt pathway by TGFb1 stands
behind excessive scarring reminiscent of keloids and
hypertrophic scars in transgenic mice that constitutively
express the b-catenin.33 In contrast, animals with the con-
172
Budovsky et al.
ditional deletion of b-catenin, display much smaller wounds
and have fewer fibroblasts in their granulation tissue.34
Modulation of the TGFb molecules can also bring benefi-
cial effects. Neutralization of the TGFb1 and TGFb2 mole-
cules by administration of antibodies to incisional rat
wounds resulted in a significant reduction of extracellular
matrix deposition and subsequent scarring.35 The same
effect was achieved by applying recombinant TGFb3 to the
wound area.35 Thus, manipulations and interventions aimed
at modifying the activity and level of WH/fibrosis associ-
ated proteins might lessen or even abrogate scar tissue gen-
eration along with creating conditions for successful WH.
Anti-platelet agents, aspirin or nonsteroidal anti-
inflamatory drugs are the most prescribed in the coagula-
tion phase.36 Glucocorticoids are also used in many cases,
they inhibit production of hypoxia-inducible factor-1 (HIF-
1),37 but they may promote wound infection38 and have
side effects on central nervous system,39 so administration
of antibiotics and antiseptics is necessary. Some chemo-
therapeutic drugs are widespread to inhibit cellular metab-
olism, rapid cell division, and angiogenesis, but they
significantly decrease functions of the immune system, and
often cause excessive bleeding at the wound site.38 Current
treatments for delayed WH (old age, diabetes, or radiation
exposure), excessive healing (hypertrophic and keloid
scars) and fibroproliferative diseases include neutralization
of pro-inflammatory mediators,25 silicone and pressure
dressings,40 vitamin E supplementation,41 administration of
corticosteroids,42 5-fluorouracil,43 bleomycin,44 and others,
reviewed by.45 While meeting some success, these treat-
ments and pharmacological interventions still have various
adverse effects. In fact, single-agent therapies, such as
administration of a growth factor, have only a moderate
impact on WH, most probably because of the considerable
complexity of the wound repair process and redundancy in
associated components and pathways. Since no “magic
bullet” has been found so far to treat abnormal WH and
related processes, we should not neglect herbal agents that
might on one hand accelerate wound closures and on the
other one might reduce fibrosis. From this point of view,
the application of whole, fractionated plant extracts, or
even selected compounds of herbal origin could be highly
advantageous as herbaceuticals may have multiple targets,
thus indicating the possibility of pleiotropic beneficial
effects on WH.4
MEDICINAL PLANTS OF THE WORLD
FLORA WITH WH ACTIVITY
Medicinal plants have been widely acknowledged in medi-
cine since ancient times, at least for 60,000 years.46 Many
ancient civilizations used plants for stimulation of WH.
For example, ancient Egyptians used Aloe vera Mill in
treating wounds as early as 1,500 B.C.47 Many experimen-
tal and clinical studies showed WH properties of the Aloe
vera Mill gel and latex which were obtained from a muci-
laginous tissue of its leaves.48 The possible mechanisms
by which the gel helped WH included keeping the wound
moist, increased epithelial cell migration, more rapid matu-
ration of collagen, and reduction in inflammation49;
increased collagen synthesis50,51; increase in synthesis of
hyaluronic acid and dermatan sulfate in the granulation
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tissue of the healing wound,50 and increased blood supply
as a result of improved oxygenation.52 Mannose rich poly-
saccharides of Aloe vera Mill gel enhanced TIMP-2 gene
expression, collagen, n-acetyl galactosamine and n-acetyl
glucosamine synthesis during the skin wound repair of
rats.53 Although Aloe vera Mill is an outstanding example
of well-studied wound-healing plant, many of its active
phytochemicals have not been identified yet. Leaves
extracts of other species of Aloe such as Aloe literalis
Baker,54 Aloe arborescens Mill, Aloe excelsa Berger, and
Aloe ferox Mill have also significant WH properties.55
The WH activity of 13 Verbascum species was assessed
in vivo using two models (linear incision and circular exci-
sion); V. olympicum Boiss, V. stachydifolium Lam, and V.
uschackense Lam had the highest activities on the both
wound models and the methanolic extracts of V. latisepa-
lum Boiss, V. mucronatum Lam, and V. pterocalycinum
var. mutense showed promising pro-WH potential.10
Although mechanisms of pro-WH actions of the Verbas-
cum species remain unknown, some active phytochemicals
were determined in the case of V. mucronatum Lam.56
While it is known that various combinations of extracts
may be highly beneficial, few researches have been
devoted to studying the synergistic interactions between
the active extracts and other phytochemicals. Nevertheless,
it was shown that ethanol-based mixed extract of Curcuma
longa L., Areca catechu L., Oryza sativa L., and Garcinia
mangostana L. had very low toxicity along with good pro-
WH properties in vitro.57 Extract from the mixture of
Radix astragali Schishkin and Radix Rechmanniae Libosch
in the 2:1 ratio promoted keratinocyte proliferation by reg-
ulating expression of growth factor receptors.58 Another
factor regulating the WH potential of botanicals is the
exposure of plants to the stressful conditions. It is known
that plants under stress are able to produce more bioactive
compounds. For example, Phlomis viscosa Poiret grown in
stressful phytogeographic zone in Judea region (Israel)
showed high pro-WH activity.59
Altogether, in the framework of this manuscript, we
have collected data on different kinds of wound-healing
promoting plant extracts (aqueous, ethanolic, methanolic,
and so on) from various plant organs (roots, stems, leaves,
buds, flowers, fruits, and so on). The major findings
related to WH activities of herbal extracts are summarized
in Table 2. Only crude extracts were included in Table 1
as the active compounds which are responsible for the WH
properties of these plants have not been isolated, purified,
and identified yet.
PLANT PHYTOCHEMICALS WITH WH
ACTIVITY
A wide variety of bioactive constituents of different
structures stands behind the therapeutic activity of the
medicinal plants: polyphenols (flavonoids, phenolic acids,
lignans, tannins, stilbenes, and coumarins); terpenes,
sulfur-containing compounds (sulfides and glucosino-
lates), carotenoids, saponins, furils, alkaloids, polyines,
thiophenes, different sugars, fatty oils, resins, phytoster-
ols, proteins, peptides and etc.83 In particular, review of
Ghosh and Gaba84 analyzes WH properties of several
plant compounds including flavonoids, quinones, phenolic
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Effect of medicinal plants
acids, phenyl propanoids, terpenoids, tannins, and sugars
showing that the main effects of these active compounds
of plants were connected to their anti-microbial activity,
antioxidant properties and their abilities to enhance cell
proliferation, collagen production, and DNA synthesis. It
is reasonable to expect that the majority of plant phyto-
chemicals have a great wound-healing potential, however
in many cases their active molecules have not been iden-
tified yet, and little is known about their modes of action.
Among plant phytochemicals, WH promoting activity of
alkaloids, flavonoids, terpenes, and glycosides is better
researched than that of other bioactive plant constituents.
Therefore, we present data on the more studied
phytochemicals.
Alkaloids
Alkaloids are nitrogen-containing phytochemicals isolated
and identified from plants. Some alkaloids have an impor-
tant role in the process of WH. Many alkaloids are consid-
ered as very toxic phytochemicals. For example, nicotine
is found in the nightshade family of plants (Solanaceae).
Nevertheless, it can improve WH and accelerate angiogen-
esis in small doses85 due to stimulating many intracellular
processes. Specifically, nicotine binds to the nAChR and
increases intracellular level of calcium.86
The effects of the Aconitum baikalense Turcz alkaloids
(mesaconitine, hypaconitine, songorine, napelline, and 12-
epinapelline N-oxide; Figure 1) on functional activity of
fibroblast precursors were studied in vitro.87 Exposure to
some of these alkaloids (songorine, napelline, and hypaco-
nitine) led to direct stimulation of the fibroblast precursors
and to higher production of growth factors by the skin
stromal cells.88 Another alkaloid-taspine (Figure 2) found
in various plants including Magnolia, enhanced WH by
increasing the autocrine activity of TGF-beta1 and epider-
mial growth factor on fibroblasts.89
Flavonoids
Flavonoids are oxygen-containing aromatic compounds
which WH properties are well known. These compounds
are able to promote the rapid WH due to their antimicro-
bial, antioxidant, and astringent properties.90 Quercetin,
found in variety of plants, stimulated incorporation of col-
lagen matrices in case of dermal WH.91 Mixture of flavo-
noids (quercetin, isorhamnetin, and kaempferol), obtained
from Hippophae rhamnoides L, improved collagen deposi-
tion and maturation, and decreased COX-2 level.92 Later,
the WH properties of this plant were also attributed to the
gallic acid which stimulated the increase in ascorbic acid
contents which in turn is important for collagen metabo-
lism.93 Additional quercetin-based flavonoid mixture
(quercetin-3-O-[(6-caffeoyl)-b-glucopyranosyl (1 ! 3) a-
rhamnopyranoside]-7-O-a-rhamnopyranoside, kaempferol-
3-O-[(6-caffeoyl)-b-glucopyranosyl (1 ! 3) a-rhamnopyra-
noside]-7-O-a-rhamnopyranoside, and quercetin-3-O-
methyl) isolated from the aerial parts of the fern Ophio-
glossum vulgatum L proved to be active in a scratch-WH
assay on keratinocytes through intracellular calcium-
dependent, ERK1/2 MAP kinase dependent mechanism.94
Furthermore, quercetin 3-O-glucoside isolated from the
leaves of Sambucus ebulus L was determined as one of the
173
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Table 1. WH properties of plant extracts

Plant (scientific name) Plant organs Type of extract Mechanism of action References

Achyranthes aspera L Leaves Methanol Up-regulated expression of 60,61

matrix metalloproteinases
(MMP-2 and 9)
Acorus calamus L Leaves Aqueous Inhibition of the expression of 62,63
inflammatory mediators at the
mRNA level
Allamanda cathartica L Leaves Aqueous Increased collagen turnover 64
Alternanthera brasiliana L Leaves Methanol Collagen deposition, fibroblast 65,66
proliferation, angiogenesis,
and development of basement
membrane
Atropa belladonna L Overground parts Aqueous Induction of fibronectin and 67
galectin-1 rich ECM formation
in vitro and in vivo.
Calendula officinalis L Flowers Ethanol Angiogenesis 68,69
Carissa spinarum L Root Ethanol Increasing collagen level 70
Cedrus deodara Roxb Overground parts Hexane Unknown 71
Citrus tamurana Hort ex Peel Aqueous Transcriptional regulation of 72
fibroblasts
Datura alba L Leaves Ethanol Expression MMP9 73
Hibiscus rosa sinensis L Flowers Ethanol Increase DNA, total protein and 74
total collagen
Inula viscosa L Overground parts? Aqueous Unknown 75
Justicia flava L Leaves Methanol Improving angiogenesis, collage- 76
nation and reepithelialization
Lannea welwitschii (Hiern) Engl. Leaves Methanol Improving angiogenesis, collage- 76
nation and reepithelialization
Parietaria diffusa Mert. & Overground parts? Aqueous Unknown 75
Petiveria alliacea L Overground parts? Ethanol Decrease NF-cB activation, influ- 77
ence on elastase
Punica granatum L Fruit skin Methanol During early WH phase increas- 78
ing TNF-a and IL-6 level
Pyrostegia venusta Miers Flowers Methanol During early WH phase increas- 79
ing TNF-a and IL-6 level
Rubus sanctus Schreber Overground parts n-Hexane, chloroform, Speeding up the proliferation 11
ethyl acetate, and phase
methanol
Schinus molle L Overground parts n-Hexane and ethanol Decrease NF-cB activation, influ- 77
ence on elastase
Tephrosia purpurea L Overground parts Ethanol Increase in fibroblast cells, colla- 80
gen fibres and blood vessels
formation
Typha elephantine Roxb Flowers Methanol Increasing collagen formation 81
Watheria douradinha Saint-Hilaire Overground parts. Ethanol, hexane Decrease NF-kB activation, influ- 77
ence on elastase
Zeyheria tuberculosa Buman Stems Ethanol Unknown 82

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Table 2. Selected targets of pro-WH herbal compounds
Herbal compounds
Curcumin, epicathechin gallate
Gallic acid, isorhamnetin,
kaempferol, nicotine
quercetin, resveratrol
Curcumin, epicathechin gallate
Kaemferol
Quercetin
Asiaticoside, curcumin
Epicathechin gallate,
nicotine, quercetin
Curcumin, epicathechin gallate,
quercetin, resveratrol, silibinin
Curcumin, epicathechin gallate,
quercetin, resveratrol
Curcumin, epicathechin gallate,
quercetin, resveratrol, silibinin
Curcumin, epicatechin,
epicathechin
gallate, kaempferol,
nicotine, quercetin,
resveratrol
Curcumin, epicathechin gallate,
nicotine, resveratrol, silibinin
Curcumin, epicathechin gallate,
gallic acid, nicotine, quercetin,
resveratrol, silibinin
Asiatic acid, curcumin,
epicathechin gallate,
nicotine, quercetin,
resveratrol, silibinin
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Effect of medicinal plants
Target Relevance of the target to WH Reference
AKT1 Akt1 is associated with assembly of collagen in skin 131
wounds and around the blood vessels. Wounds in
Akt1 (-/-) mice, but not in Akt2 (-/-) mice, were char-
acterized by reduced vascular area as well as
impaired vascular maturation as evidenced by
reduced smooth muscle cell recruitment.
CCL2 Associated with wound reepithelialization as the KO 132
mice had impaired wound angiogenesis.
COL1A1 WH was severely delayed in the KO mice, with 133
wounds remaining significantly wider than wild-type
for the first 2 wk after injury. Reepithelialization of
the Col1a1(r/r) wounds took 7 d longer than in the
wild-type. The Col1a1(r/r) wounds had a prolonged
early inflammatory response.
EGFR Modifies both normal and wound-induced epidermal 134
proliferation
GSK3B Gsk3b-conditional-KO mice (Gsk3b-CKO mice) exhib- 135
ited accelerated wound closure, increased fibrogene-
sis, and excessive scarring compared with control
mice. In addition, Gsk3b-CKO mice showed elevated
collagen production, decreased cell apoptosis, ele-
vated levels of profibrotic alpha-SMA, and increased
myofibroblast formation during wound healing.
HIF1A Early wound closure occurred significantly faster in 136
HIF-1alpha KO mice than in WT mice. Wounds of
KO mice contained similar numbers of neutrophils
and macrophages, but more activated keratinocytes,
consistent with accelerated reepithelialization.
IL6 IL-6-deficient transgenic mice (IL-6 KO) displayed sig- 137
nificantly delayed cutaneous wound healing com-
pared with wild-type control animals, requiring up to
threefold longer to heal. This was characterized by
minimal epithelial bridge formation, decreased
inflammation, and granulation tissue formation.
STAT3 KO mice, whose epidermal and follicular keratinocytes 138
lack functional Stat3, were viable and the develop-
ment of epidermis and hair follicles appeared nor-
mal. However, hair cycle and wound healing
processes were severely compromised.
TNF Knockout promotes granulation tissue formation and 139
retards reepithelialization
TRP53 The wound-healing assay showed a significant reduc- 140
tion in wound closure for the pL53 transgenic mice
4 days after induction of a 3-mm punch biopsy in
the dorsal skin
175
Effect of medicinal plants
active components of the WH as determined by animal
experiments. Specifically, this agent enhanced
reepithelization.9
Another flavone 2-(3,4-dihydroxy-phenyl-5; 7-
dihydroxy-chromen-4 is an active constituent of the Indian
pro-WH plant, Pedilanthus tithymaloides L. It promotes
WH by accelerating epithelization, scavenging of free radi-
cals, and inhibiting several mediators of inflammatory
pathways including the NF-jB activity.95 It was also found
that Vicenin-2 flavonoid (isolated from crude methanol
extract of food plant Moringa olifera) was able to enhance
the proliferation and viability of human fibroblast cells in
vitro which led to subsequent faster WH.96
Figure 2. Chemical structure of Taspine—an alkaloid iso-
lated from various plants of the Magnoliaceae family.
176
Budovsky et al.
Figure 1. Chemical structures of
alkaloids isolated from Aconitum
baikalense: (1-mesaconitine, 2-
hypaconitine, 3-songorine, and 4-
napelline).
Various Hypericum species plants are acknowledged as
popular folk remedies for stimulation of WH. Examination
of Hypericum scabrum L and Hypericum perforatum L oil
extracts for the WH activity showed that the latter plant
and its flavonoids (hyperoside, isoquercitrinrutin, and epi-
catechin) indeed are pro-WH.8
Another popular folk remedy is Silybum marianum L, as
investigations into silibinin from Silybum marianum
revealed its ability to promote a faster WH process by reg-
ulation of Stromelysin-1 gene (encodes stromelysin-1
which belongs to the metalloproteinase family and has an
important role in WH) expression, acetyl hexoseamonine,
and collagen production.97
While in case of various flavonoids the mechanism of
action is still obscure, studies of 40 ,6,7-trimethoxyisofla-
vone (Figure 3), isolated from the Euchresta formosana
Ohwi, showed that this flavonoid increased rate of WH by
promoting migration, but not proliferation of keratinocytes
through induction of NADPH oxidases (NOXs; the
Figure 3. Chemical structure of 40 ,6,7-trimethoxyisoflavone.
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Figure 4. Chemical structures of
Gentiopicroside, sweroside, and
swertiamarine isolated from Gen-
tiana lutea.
expression both at the mRNA and protein levels was
examined).98
Terpenes
Terpenes are large classes of organic compounds, produced
by a variety of plants, which to a great extent exist in
form of essential oils. Gentiana lutea L contains several
various terpenes including gentiopicroside, sweroside, and
swertiamarine which synergistically promote WH stimulat-
ing collagen production and the mitotic activity of embry-
onic fibroblasts (Figure 4).99 Many other monoterpenes
also have beneficial effects on skin WH including ajugol,56
borneol,100 catalpol,56,101 thymol,102 genipin,103 lasiantho-
side,56 alpha-bisabolol,103 alpha-terpiniol,104 and aucu-
bin,56,105 but the precise mechanisms of their actions are
mostly not known. Pro-WH properties of borneol might be
associated with its ability to suppress the proinflammatory
cytokines at the mRNA level.106 Thymol pro-WH activity
could be explained by modulatory effect on the fibroblast
metabolism and collagen synthesis.102
With regard to the more complex terpenes, two lupane
triterpenoids from Paullinia pinnata L 6beta-(30 -methoxy-
40 -hydroxybenzoyl)-lup-20(29)-ene-one, and 6beta-(30 -
methoxy-40 -hydroxybenzoyl)-lup-20(29)-ene-ol had a sig-
nificant fibroblast stimulatory activity.107 The triterpene
oleanolic acid (isolated from Viscum album L) influenced
migratory activity of NIH/3T3 Fibroblasts and Hecate
Keratinocytes. This in turn accelerated wound closure.
Nevertheless, mechanisms behind the beneficial effects of
these glycosides remain to be investigated.108 The triterpe-
niod compounds (asiatic acid, asiaticoside, madecassic
acid, and madecassoside) isolated from Centella asiatica L
promoted WH through induction of expression of genes
involved in angiogenesis and the remodeling of extracellu-
lar matrix, as well as diverse growth factors.109 In particu-
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Effect of medicinal plants
lar, madecassoside’s and asiaticoside’s pro-WH activities
could be associated with increased collagen synthesis
mediated via activation of the TGF-b/Smad signaling path-
way.110,111 Other known monoterpene derivatives showing
beneficial effects on intestinal WH are the cannabinoids
from Cannabis sativa L. It was found that tetrahydrocan-
nabinoid enhanced epithelial wound closure.112 Cannabi-
diol the nonpsychoactive compound in Cannabis sativa L
is also well known for its beneficial effects on intestinal
inflammation as well as reducing cytokine release and pro-
moting WH.113,114
Glycosides
Glycosides are conjugates of sugars with small organic
molecules which can be classified by the glycone groups,
types of glycosidic bonds, and by the aglycone groups. A
classification by the aglycone group is the most useful one
as there are several approaches to this classification.115,116
Many WH associated glycosides have already been men-
tioned in previous chapters, in particular the flavonoid
glycosides.
Many plants are renowned for their pro-WH glycosides.
For example, the mixture of the galactoglycerolipids from
the fern Ophioglossum vulgatum L. (dominant compound
1,2-di-O-linolencyl-3-O-B-D-galacto-pyranosyl-glycerol)
had pro-WH activity and mechanism of their action was
similar to that of the flavonoid glycosides.117 Mixture of
11 saponin glycosides from Panax ginseng promoted ree-
pitalization of the skin wounds in animal models, enhanced
collagen synthesis in skin fibroblasts through phosphoryla-
tion of Smad 2 protein, and inhibited inflammatory proc-
esses at the early phases of WH.118 Compounds from
genetically modified flax seeds with high glycoside content
(secoisolariciresinol diglycoside, p-coumaric acid glyco-
sides, ferulic acid glycoside, and caffeic acid glucosides)
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Effect of medicinal plants
Figure 5. Chemical structures of (22R,25R)-spirosol-5-en-
3b-yl-O-a-L-rhamnopyranosyl-(1-2)-b-D-glucopyranosyl-(1-4)-b-
D-glucopyranosides isolated from Lilium longiflorum.
enhanced proliferation and migration of normal human
dermal fibroblasts as determined by the wound scratch
assay.119 Two steroidal glycosides from Lilium longiflorum
Thunmb ((22R,25R)-spirosol-5-en-3b-yl O-a-L-rhamnopyr-
anosyl-(1-2)-b-D-glucopyranosyl-(1-4)-b-D-glucopyranoside,
and (22R,25R)-spirosol-5-en-3b-yl-O-a-L-rhamnopyrano-
syl-(1-2)-[6-O-acetyl-b-D-glucopyranosyl-(1-4)]-b-D-glucopy-
ranoside) which have very similar structures (Figure 5)
could influence the fibroblast migration, NO production and
TGF-b receptor I mRNA expression.120 It is interesting to
note that the analysis of these compounds in different
organs of L. longiflorum showed their highest concentra-
tions in flower buds (acknowledged in folk medicine as
WH-remedy) and lower stems.121
Phenylpropanoid glycosides are widespread phytochemi-
cals of many plants from Asteraceae, Labiateae, Liliceae,
Oleaceae families. For example, Verbascum mucronatum
is rich in various glycosides including pro-WH one called
verbascoside.56 It was shown that this phenylpropanoid
glycoside is able to enhance hepatocyte growth factor pro-
duction in human dermal fibroblasts.122 The WH proper-
ties of this compound are connected to its chemical nature
ensuring stronger affinity for negatively charged mem-
branes composed of phosphatidylglycerol.123 Verbascoside
Table 3. Clinical trials dealing with the effect of medicinal
plant products on WH
Herbal
product Outcome of
tested the study References
Aloe vera Double-blind clinical 142
gel trial showed significant
WH effect of the gel
at 24 hours post cesarean
Aloe vera, One control and two 143
Calendula experimental groups were
ointment investigated. Application of
each product significantly
increased the speed of
episiotomy WH.
178
Budovsky et al.
was also shown to possess pro-WH properties in conjunc-
tion with another phenylpropanoid glycoside teupolioside
(produced biotechnologically from Syringa vulgaris L and
Ajuga reptans L plant cell cultures)124 and with luteolin-7-
O-glucoside (found in methanol extract of Buddleja glo-
bosa Hope).125
HUMAN TARGETS OF HERBAL PRO-WH
COMPOUNDS
It is reasonable to suggest that the biological effects of the
plant chemicals are to a great extent associated with their
protein targets. With this in mind, we have first extracted
the data on reported pro-WH compounds available in sci-
entific literature, and then determined the proteins interact-
ing with these chemicals, using the STITCH database—
http://stitch.embl.de/126–128 which contains a consolidated
set of chemicals assigned with PubChem ID number along
with their interactions with proteins (physical interactions).
Out of more than 30 pro-WH compounds discussed in
this work, almost half targeted genes associated with WH
modulation.129,130 Remarkably, 110 out of 207 of the above
mentioned WH associated genes were targeted in a pleo-
tropic and synergistic manner by the pro-WH herbal com-
pounds including flavonoids such as curcumin, epicathechin
gallate, resveratrol, and quercitin among others. The
selected compounds and their respective targets were organ-
ized in Table 2 which also includes short description of the
targets’ relevance to the WH process. Thus, the pro-WH
effects of the described compounds are mediated by their
direct involvement in the core WH processes. Subsequently,
these interactions and their impact on human proteome/
interactome should be a point of future investigations.
CLINICAL TRIALS
Although the benefit of medicinal plants and their com-
pounds is confirmed by various experimental studies, few
clinical trials are known. In contrast to 62 experimental
studies, only three human clinical studies were mentioned
in literature.141 These studies focused on the effect of
medicinal plants on WH of burns as they investigated
effect of Aloe vera gel. However, the authors could not
reach definite conclusions due to the small number of
patients and low methodological level. Nevertheless, the
positive effects of dressing with Aloe vera gel on cesarean
WH was shown in prospective randomized double-blind
clinical trial.142 Another clinical study showed that using
Aloe vera and Calendula ointment significantly increased
the speed of episiotomy WH.143 Successful clinical trials
are summarized in Table 3.
CONCLUSIONS
This review shows that a wide plethora of medicinal plants
from all over the World and the phytochemicals that they
contain (alkaloids, flavonoids, terpenes, glycosides) have
beneficial pro-WH properties both in in vivo and in vitro
various models. Thus, they seem to be promising candi-
dates for developing new WH drugs targeting the WH
associated human proteins. In case of other phytochemi-
cals, it may be too early to reach such a conclusion since
Wound Rep Reg (2015) 23 171–183 V
C 2015 by the Wound Healing Society
Budovsky et al.
their purification and identification have not yet been com-
pleted, and their modes of actions were not investigated.
For example, aqueous extract from Ananas comosus L
(pineapple) crown leaves showed beneficial pro-WH prop-
erties which were associated with activity of several pro-
teins which structure and modes of action still remain
unknown.144 It is important to stress that the obvious
weakness of current state of research is incomplete under-
standing of mechanisms behind pro-WH activity of many
herbal compounds. Based on the above-mentioned studies,
we conclude that the majority of the investigated plant
extracts contain at least several compounds responsible for
their pro-WH activity, and thus their synergistic and pleio-
tropic activity should be the focus of future investigations.
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