Indonesia International (Bio)Medical Students

Congress 2015
(Neovasculogenesis stimulation and antioxidant
effect on curcumin promotes faster wound closures
in diabetic rats)
Rochelle Vernique Siem*, M. Vico Rizkyta Wisnu L.** and Edvin Prawira Negara***
* First Year Medical Student, Universitas Brawijaya, rochellesiem@gmail.com
** First Year Medical Student, Universitas Brawijaya, vicrizkyta@gmail.com
***First Year Medical Student, Universitas Brawijaya, edvin_syt3ly@yahoo.com

Abstract
Introduction: Prolonged inflammation, increased oxidative stress, and impaired
neovasculogenesis delay wound healing in diabetic patients. Curcumin, a well known
antioxidant and anti-inflammatory agent, also an important stimulatory agent in
neovasculogenesis process could be an important strategy to accelerate diabetic wound
healing. So, present study was aimed to provide and analyze data related to curcumin as
diabetic wound healing agent.
Material and Methods: We conducted a literature search in four health databases for
randomized controlled trials. Success rates of diabetic wound healing were evaluated based
on gross appearance of wounds, histologic appearance, expressions of anti-inflammatory
cytokines, antioxidant enzymes, and expressions of angiogenic factors.
Result and Discussion: From two studies included in our analysis, it was proved that
curcumin could increase angiogenic factors (VEGF, TGF-1) and other factors (HIF-1,
SDF-1, and HO-1), as well as indirectly, by anti-inflammatory and antioxidant action. Antiinflammatory action was marked by decreasing levels of TNF- , IL-1, and matrix
metalloproteinase-9, while antioxidant action marked by increasing levels of antioxidant
enzymes.
Conclusion: Anti-inflammatory and antioxidant potential of curcumin, as well as curcumininduced angiogenesis could enhance wound healing in diabetic rats. It also meant that
curcumin could be a promising diabetic wound healing therapy in humans.
Keywords: Angiogenesis, Anti-inflammation, Antioxidant, Curcumin, Neovasulogenesis

Introduction
The prevalence of diabetes mellitus is
increasing worldwide; by the year 2025, an

estimated 300 million people will have

diabetes1. The 10 countries estimated to
have the highest numbers of people with
diabetes in 2000 and 2030 are India,
1

China, U.S., Indonesia, Japan, Pakistan,

Russian Federation, Brazil, Italy, and
Bangladesh2. Indonesia ranked four after
the U.S. with numbers of people with
diabetes for 2000 and forecasts for 2030 of
8.4
millions
and
21.3
millions,
respectively. Diabetes itself is a
multisystem disorder that induces tissues
and cells changes which finally leads to
abnormal healing process. Diabetic wound
is one of the most problematic
complications found in patients with
diabetes. Studies concluded that diabetic
foot ulcers, the most common diabetic
wound, are associated with high rate of
morbidity and mortality3,4. Patients with
diabetic wound experience prolonged
inflammatory phase in which neutrophils
continue to release cytotoxic enzymes, free
radicals, and inflammatory mediators that
cause tissue damage. These destructive
processes outbalance the healing process
in such wounds and overproduction of free
radicals that induce oxidative stress results
in detrimental cytotoxic effects causing
delayed wound healing5,6. Therefore,
reduction/termination of the persistent
inflammation and elimination of free
radicals by the introduction of an antiinflammatory agent and antioxidant into
the treatment of wounds could be an
important strategy to improve healing of
diabetic wounds6. Other than free radicals,
impaired neovasculogenesis on diabetic
patients is also an important cause of
delayed
wound
healing.
Neovascularization occurs at the wound
site by the processes of angiogenesis and
vasculogenesis7,8. Angiogenesis consists of
several steps, including the stimulation of
endothelial cells (Ecs) by growth factors,
the degradation of the ECM by proteases,
proliferation of Ecs and migration, and the
eventual formation of new capillary tubes 9.
Major angiogenic factors such as, vascular
endothelial growth factor (VEGF) and
transforming growth factor (TGF)-1,
including some minor ones, are involved
in stimulation, promotion, and stabilization
of new blood vessels10,11. These factors

decrease in diabetic wounds. While

vasculogenesis
occurs
within
the
granulation tissue with the mobilization of
endothelial progenitor cells (EPC) from
bone marrow to wound site12. So, different
factors associated with angiogenesis and
vasculogenesis process are thought to be
new therapeutic targets for improving the
impaired wound healing in diabetes 12.
Current treatment options are expensive,
limited and inefficient which led to the
development of new therapeutics to satisfy
the unmet clinical need13. Meanwhile,
there is an upsurge of using herbal
medicine to accelerate diabetic wound
healing.
Curcumin
(C2H20O6)
or
diferuloylmethane is an active ingredient
of turmeric isolated from the roots of
Curcuma Longa L. which has a long
history of medicinal use including wound
healing12. Studies have shown that
topically
applied
curcumin
in
streptozotocin-induced type 1 acute
diabetic rats accelerates wound healing by
stimulating neovascularization, decreasing
inflammation, and increasing the levels of
antioxidant enzymes 12,14. Both studies12,14
also conclude that curcumin is a promising
agent to accelerate diabetic wound healing
in humans and animals. Therefore, given
the rising prevalence of diabetes and the
danger of prolonged diabetic wound
healing, the goal of our study was to
systematically review the literature to
provide and analyze data about curcumin
as diabetic wound healing agent associated
with the process of neovasculogenesis,
oxidative stress, and inflammation.
Material and Methods
Type of Source Used
Sources used in this review included full
text journals.
Search Strategy and Key Words
Key words used to search for relevant
articles included: curcumin, diabetic
2

wound, wound healing, angiogenesis,

neovasculogenesis, antioxidant, and antiinflammatory. Writers searched for
relevant articles published between 2013
to 2015 in Clinical Key, Science Direct,
Google Scholar, and ProQuest. It is
recommended to use angiogenesis,
neovasculogenesis, antioxidant, and antiinflammatory as key words together with
curcumin to exclude other wound healing
properties of curcumin. Thus, this
literature review will only focus on
specific wound healing mechanism done
by curcumin as active ingredient.
Criteria of Inclusion and Exclusion
Studies were limited to randomized
controlled trials on wounded diabetic rats.
Journals that provided data about curcumin
as diabetic wound healing agent were
reviewed. Literatures taken had to focus on
either angiogenesis and neovasculogenesis
or antioxidant and anti-inflammatory
action of curcumin. We included studies
that provided progressive wound healing
data evaluated by gross appearance of
wound, histologic appearance, and
chemical markers. The chemical markers
used in studies may vary as long as it is
relevant with inclusion criteria and the
focus of this review. Studies were
excluded if the journals discussed about
the use of curcumin in wound healing as
general or if the journals only mentioned
diabetic wound not more than five times.
Journals that did not focused solely on
curcumin but discussed variative herbal
medicines to treat diabetic wound were
also excluded. Lastly, we also excluded
studies that did not provide sufficient
information and experiment data related to
angiogenesis,
neovasculogenesis,
antioxidant, or anti-inflammation.
Number of Studies Found and Included
Fig. 1 shows the selection process of this
review.

Initial citation lists from all

databases by key words (n=1558)
(n=1024 excluded: not a
journal, not using random
controlled trials, not fitting
key terms of inclusion
criteria)

Initial screening of citations

(n=534)
(n=529 excluded: not
mentioning diabetic
wound more than five
times, not focused solely
on curcumin)

Secondary screening of
citations from abstracts (n=5)
(n=3 excluded: did not
provide enough
information and
experiment data about
angiogenesis,
neovasculogenesis,
antioxidant, and antiinflammation)

Full text journals that were

analyzed (n=2)
Fig 1. Selection process based on search
strategy and inclusion criteria
Thus, the number of studies reviewed in
this article is two journals12,14. One focused
on curcumin-induced angiogenesis and
neovasculogenesis12, while the other
focused on curcumin as antioxidant and
anti-inflammatory ingredient14.
Results and Discussion
Study on curcumin-induced angiogenesis12
reported that curcumin application caused
markedly fast wound closure with well
formed granulation tissue dominated by
fibroblast
proliferation,
collagen
deposition, and complete early regenerated
epithelial layer. Immunohistochemistry for
CD31 revealed well formed blood vessels
with increased microvessel density on days
3

3, 7, and 14 in the curcumin-treated group.

Expressions of VEGF and TGF-1 on days
3, 7, and 14, hypoxia inducible growth
factor-1alpha, stromal cell-derived growth
factor-1alpha, and hemeoxygenase-1 on
days 3 and 7 were increased in curcumintreated diabetic rats, as compared with
other groups.
Early formation, shedding of scab, and
wound closure were characteristic
observations in curcumin-treated group, as
compared with control and gel-treated
group12. Gross evaluation of wound
revealed that topical curcumin application
decreased the wound size (Fig. 2A) with
significant percent increase in wound
contraction (Fig. 2B), as compared with
control and gel-treated groups. Scoring of
wound sections revealed that overall
persistence of inflammatory cells was
significantly lower and epithelization was
significantly more in curcumin treated
group on days 14 and 19, as compared
with control. Histopathologic scoring for
wound maturity was significantly higher in
curcumin-treated group during the entire
experiment, as compared with other
groups.

Fig. 2(A) Representative photographs of

wounds of control, gel-treated, and
curcumin-treated groups on different days.
(B) Wound contraction (%) in control, geland cum-treated groups on days 3, 7, 11,
14, and 19 after wounding. Data are
expressed as means standard error of the
mean (n [ 5). *P < 0.05 and ***P < 0.001
versus other group(s) on the same
day.12(Vinay K, Anu G, Dhirendra K, et al. 2015;193:978.)
Upregulation of mRNA and VEGF protein
expression in topical application of
curcumin was remarkably presented in 14
days of observation (Fig. 3). Expression of
VEGF mRNA and protein were
significantly increased in the curcumintreated group on days 3, 7, and 14, as
compared with other groups. Curcumin
application also significantly increased the
mRNA and protein expression of TGF-b1
on days 3, 7, and 14.

Fig. 3(A and B) Relative mRNA

expressions of VEGF (A), TGF-b1 (B) in
healing tissue of excision wounds in rats.
The mRNA expressions were normalized
by b-actin at each time point and data are
expressed as means standard error of the
mean fold change (n [ 4). (D and E)
Semiquantitative protein expressions of
VEGF (D) and TGF-b1 (E) in different
groups. Data are expressed as means
standard error of the mean (n [ 4). *P <
0.05, **P < 0.01, and ***P < 0.001
compared with other group(s) on the same
day.12(Vinay K, Anu G, Dhirendra K, et al. 2015;193:978.)
Curcumin
application
significantly
upregulated the mRNAexpressions of HIF1a, SDF-1a, and HO-1 on days 3 and 7, as
compared with other groups. The
expression of eNOS RNA was markedly
increased on days 7 and 14 in the
curcumin-treated group (Fig. 4).

Fig. 4The relative mRNA expressions of

HIF-1a (A), SDF-1a (B), HO-1 (C), and
eNOS (D) in healing tissue of control, gel-

treated, and curcumin-treated rats on days

3, 7, 14, and 19 after wounding. The
mRNA expressions were normalized by bactin at each time point (n [ 4). Data are
expressed as means standard error of the
mean *P < 0.05, **P < 0.01, and ***P <
0.001 compared with other group(s) on the
same day. 12(Vinay K, Anu G, Dhirendra K, et al. 2015;193:978.)
Wound closures require the formation of
granulation tissue and it is unfortunate that
its synthesis and quality formed poorly in
patients with diabetes. Collagen is a major
component of granulation tissue and its
synthesis from fibroblast is TGF-1
dependent, which is important for proper
wound healing15. Earlier studies have
reported that TNF- application decreased
the expression of collagen and reduced the
tensile strength of the wound16 TNF-
inhibits Smad phosphorylation through cJun N-terminal kinase pathway and
reduces the transcription of TGF-1,
collagen 1A, fibronectin, and alphasmooth muscle actin17.
On the other hand, VEGF is an important
factor to induce angiogenesis by
promoting endothelial cell proliferation
and prevent their apoptosis18 and TGF- 1
involved in angiogenesis by several
possible molecular signaling including
enhancing VEGF synthesis through Akt
and ERK pathways19 or by recruiting
VEGF expressing hematopoietic effecter
cells20. Another substantial factor involved
in neovasculogenesis is HO-1 (Heme
Oxygenase-1). The present study shows
marked elevation of mRNA expression of
HO-1 in curcumin-treated rats (Fig. 4C)
HO-1 has shown proangiogenic, antiinflammatory, and cytoprotective potential,
and its induction is necessary for efficient
wound closure21,22. HO-1 shows its role in
angiogenesis by the regulation of synthesis
and/or activity of VEGF and SDF-1a23,24.
Additionally HIF-1a plays important role
in further mediates hypoxia-stimulated
synthesis of VEGF and SDF-125. VEGF
and SDF-1 cause homing of EPCs, which
5

participate in the formation of new

vessels26.
The essential factor to proper the
functioning blood vessels includes a
bioactive product nitric oxide derived from
endothelium called eNOS. The eNOS play
important role to maintenance the proper
vasodilatory nature and regulation of
antiapoptotic state for endothelial cells.
Evidence from eNOS knockout mice states
that functional eNOS is vital for the
maintenance of vascular healthiness27.
Endothelium-dependent
vasodilatation
becomes abnormal in diabetic patients28,29.
In addition, decreased endothelialdependent arterial relaxation has been
observed in diabetic animals and in
humans30. The cutaneous eNOS expression
significantly decreases in streptozotocininduced diabetic animals, which causes
impaired angiogenesis and wound healing
because of reduced eNOS-dependent nitric
oxide production31,32. Based on previously
mentioned scenario, in the present study12,
markedly decreased expression of eNOS in
the control group might be another
important factor to cause impaired
vasodilatation and formation of occluded
vessels. On the contrary, curcumin
significantly
increased
the
eNOS
expression [Fig.4D] and maintained the
vascular structure at the wound site, thus,
improving
healing
by
better
neovasculogenesis12. It has also been
reported that induction of eNOS
expression at the wound site increases the
wounds closure in diabetics33. In addition,
inhibition or genetic disruption of eNOS
has resulted in interrupted wound
healing34.
While study on antioxidant and antiinflammatory potential of curcumin14
proved
that
curcumin
application
decreased the expressions of inflammatory
cytokines/enzymes i.e. tumor necrosis
factor-alpha, interleukin (IL)-1beta and
matrix metalloproteinase-9. Curcumin also
increased the levels of anti-inflammatory

cytokine i.e. IL-10 and antioxidant

enzymes i.e. superoxide dismutase (SOD),
catalase and glutathione peroxidase (GPx)
(Fig 5).

Figure 5 Levels of SOD (A), catalase (B)

and GPx (C) in healing tissue of the
control, geltreated and curcumin-treated
rats on days 3, 7, 14 and 19 postwounding. Data are expressed as means
SEM (n = 4). *P < 0.05, **P < 0.01 and
***P < 0.001 vs. other group(s) on the
same day.14(Kant V, Gopal A, et al.2014;20:322)
The persistence of oxidative stress and
inflammatory state at the wound site is
detrimental for healing process in case of
diabetic patients12. Curcumin possesses
strong antioxidant and anti-inflammatory
properties, which makes it a unique
molecule for wound healing applications
in diabetes35. The anti-inflammatory effect
of curcumin at the diabetic wound site was
due to inhibition of expression of TNF- ,
IL-1, and matrix metalloproteinase-9.
Different studies have also reported that
inhibitory potential of curcumin on protein
kinase C was probably responsible for
inhibition of the upregulation of matrix
metalloproteinases36.
Oxidative stress, due to overproduction of
various reactive oxygen species and
reactive nitrogen species during prolonged
inflammation,
induces
remarkable
6

cytotoxic and pro-degradative effects

within the wound area leading to impaired
healing in diabetes37,38. Furthermore,
prolonged inflammation which is linked to
oxidative stress can cause defective
angiogenesis in response to ischemia,
activate a number of proinflammatory
pathways,
and
cause
long-lasting
epigenetic changes that drive persistent
expression of proinflammatory genes after
glycemia is normalized39,40. Reactive
oxygen species increases in diabetes
because of the auto-oxidation of glucose,
advanced glycation, and abnormal
mitochondrial function41,42 and causes
damage to granulation tissue along with
impaired angiogenesis and migration of
fibroblast and keratinocytes43.
Wounding site also results in the loss of
different enzymatic and non-enzymatic
free radical scavengers, which recover
either partially or completely following
healing44. Enzymes such as SOD, catalase,
and GPx are known to scavenge free
radicals and prevent oxidative damage45.
Moreover, the delayed wound healing has
been restored in diabetic mice by
adenoviral delivery of Mn-SOD to the
wound site46. Therefore, curcumins
antioxidant potential also essentially
involved in enhancing wound closure
activity.
Conclusion
In conclusion, curcumin has various
effects in accelerating wound healing
process. In the present study it has been
shown
that
curcumin
stimulates
neovasculogenesis
by
increasing
expression
of
angiogenic
and
proangiogenic factors such as VEGF,
TGF- 1, HIF- , SDF-1, as well as HO1. The anti-inflammatory and antioxidant
action of curcumin encompass the
persistent decrease of the inflammatory
state (via decreased expression of TNF-,
IL-1 and MMP-9, and increased levels of
IL-10), and also increase the levels of

antioxidant enzymes (via increasing levels

of SOD, catalase and GPx) at the wound
site.
Acknowledgement
The authors are thankful to the dean and
co-deans of Faculty of Medicine
Brawijaya University, for providing
support to join this competition. We are
also thankful to our teachers who share
their knowledge and time for us.
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