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toxins
Review
Potential Therapeutic Applications of Bee Venom on
Skin Disease and Its Mechanisms: A Literature Review
Haejoong Kim 1, Soo-Yeon Park 2,* and Gihyun Lee 1,*
1College of Korean Medicine, Dongshin University, Naju-si, Jeollanam-do 58245, Korea
2Department of Ophthalmology, Otolaryngology & Dermatology, College of Korean Medicine,
Dongshin University, Naju-si, Jeollanam-do 58245, Korea
*Correspondence: swallow92@dsu.ac.kr (S.-Y.P.); glee@khu.ac.kr (G.L.)
Received: 3 June 2019; Accepted: 25 June 2019; Published: 27 June 2019
Abstract:
Skin is larger than any other organ in humans. Like other organs, various bacterial, viral,
and inflammatory diseases, as well as cancer, affect the skin. Skin diseases like acne, atopic dermatitis,
and psoriasis often reduce the quality of life seriously. Therefore, effective treatment of skin disorders
is important despite them not being life-threatening. Conventional medicines for skin diseases include
corticosteroids and antimicrobial drugs, which are effective in treating many inflammatory and
infectious skin diseases; however, there are growing concerns about the side effects of these therapies,
especially during long-term use in relapsing or intractable diseases. Hence, many researchers are
trying to develop alternative treatments, especially from natural sources, to resolve these limitations.
Bee venom (BV) is an attractive candidate because many experimental and clinical reports show
that BV exhibits anti-inflammatory, anti-apoptotic, anti-fibrotic, antibacterial, antiviral, antifungal,
and anticancer effects. Here, we review the therapeutic applications of BV in skin diseases, including
acne, alopecia, atopic dermatitis, melanoma, morphea, photoaging, psoriasis, wounds, wrinkles,
and vitiligo. Moreover, we explore the therapeutic mechanisms of BV in the treatment of skin diseases
and cytotoxic effects of BV on skin disease-causing pathogens, including bacteria, fungi and viruses.
Keywords: bee venom; alternative treatment; skin; cutaneous disease; mechanism
Key Contribution:
This review summarizes the therapeutic applications of BV in skin diseases,
including acne, alopecia, atopic dermatitis, melanoma, morphea, photoaging, psoriasis, wounds,
wrinkles, and vitiligo. It also deals with the therapeutic mechanisms of BV in the treatment of skin
diseases and cytotoxic effects of BV on skin disease-causing pathogens, including bacteria, fungi
and viruses.
1. Introduction
Bee venom (BV), produced by honeybees (Apis mellifera), is one of the most well-known
natural toxins. BV is a very diverse set of chemicals. It includes peptides such as melittin,
apamine, adolapin, and MCD peptide, enzymes like phospholipase A2 (PLA2), hyaluronidase,
acid phosphomonoesterase, and lysophosphofolipase, and it also contains various amines such as
histamine, dopamine, and norepinephrine [1].
BV has long been used as a therapeutic substance. It generally has been administrated in the form
of piercing directly with bee sting, or injecting extracted and purified BV with a syringe. In oriental
medicine, BV is also injected into specific acupoints related with a disorder [
2
,
3
]. BV has been
broadly used for reducing pain and suppressing inflammation in musculoskeletal disorders, such
as osteoarthritis, rheumatoid arthritis, and lumbar pain [
2
,
4
–
6
], and in recent years, its therapeutic
effects in treating neurological diseases like chronic neuralgia, Parkinson
'
s disease, and amyotrophic
Toxins 2019,11, 374; doi:10.3390/toxins11070374 www.mdpi.com/journal/toxins
Toxins 2019,11, 374 2 of 30
lateral sclerosis have been reported [
7
,
8
]. Another recent study also showed that BV has a therapeutic
effect on periodontal disease [
9
]. Accumulated evidence shows that BV has anti-inflammatory,
anti-apoptotic, antifibrotic, and anti-atherosclerotic properties which support these therapeutic
applications [
10
]. In addition, a number of recent studies have demonstrated antibacterial, antiviral,
antifungal, and anticancer effects of BV [1,11–17].
Many reviews have highlighted the therapeutic value of BV, but none have focused on the effect
of BV on skin diseases. To the best of our knowledge, this is the first review that summarizes the
potential therapeutic mechanisms and applications of BV in skin diseases. They are shown at the end
of the article in order of clinical study,
in vivo
study, and
in vitro
study (Tables 1–3). To date, skin
diseases where therapeutic application of BV has been studied include acne, alopecia, atopic dermatitis,
melanoma, morphea, photoaging, psoriasis, wound, wrinkle, and vitiligo (Figure 1). The purpose of
this review is to provide the present knowledge from a various experimental and clinical reports and to
help researchers design a follow-up study from previous studies and diseases that are yet to be studied.
Toxins 2018, 10, x FOR PEER REVIEW 2 of 31
osteoarthritis, rheumatoid arthritis, and lumbar pain [2,4–6], and in recent years, its therapeutic
effects in treating neurological diseases like chronic neuralgia, Parkinson's disease, and amyotrophic
lateral sclerosis have been reported [7,8]. Another recent study also showed that BV has a therapeutic
effect on periodontal disease [9]. Accumulated evidence shows that BV has anti-inflammatory, anti-
apoptotic, antifibrotic, and anti-atherosclerotic properties which support these therapeutic
applications [10]. In addition, a number of recent studies have demonstrated antibacterial, antiviral,
antifungal, and anticancer effects of BV [1,11–17].
Many reviews have highlighted the therapeutic value of BV, but none have focused on the effect
of BV on skin diseases. To the best of our knowledge, this is the first review that summarizes the
potential therapeutic mechanisms and applications of BV in skin diseases. They are shown at the end
of the article in order of clinical study, in vivo study, and in vitro study (Table 1–3). To date, skin
diseases where therapeutic application of BV has been studied include acne, alopecia, atopic
dermatitis, melanoma, morphea, photoaging, psoriasis, wound, wrinkle, and vitiligo (figure 1). The
purpose of this review is to provide the present knowledge from a various experimental and clinical
reports and to help researchers design a follow-up study from previous studies and diseases that are
yet to be studied.
Figure 1. Skin diseases where the therapeutic application of bee venom (BV) has been studied.
2. Therapeutic Effects of BV in Skin Diseases
2.1. Acne
Acne, marked by the development of papules, pustules, and nodules, is an inflammatory
disorder which occurred on the sebaceous unit. Acne is generally observed on the skin of the face,
breast, and back. Pathological features of acne include increased sebum secretion, inflammation,
keratinization of sebaceous ducts, and bacterial colonization of sebaceous ducts [18,19]. Antibiotics,
one of the various treatment options for acne, have been utilized to suppress inflammation by killing
the causative bacteria [20]. However, frequent use of antibiotics poses the risk of side effects, like the
appearance of resistant bacterial strains [21,22]. Therefore, there is a growing interest in acne
treatments which have a higher therapeutic effect and fewer side effects [22,23]. There are currently
many studies demonstrating that BV might be effective for acne vulgaris.
2.1.1. Clinical Studies
Figure 1. Skin diseases where the therapeutic application of bee venom (BV) has been studied.
2. Therapeutic Effects of BV in Skin Diseases
2.1. Acne
Acne, marked by the development of papules, pustules, and nodules, is an inflammatory disorder
which occurred on the sebaceous unit. Acne is generally observed on the skin of the face, breast,
and back. Pathological features of acne include increased sebum secretion, inflammation, keratinization
of sebaceous ducts, and bacterial colonization of sebaceous ducts [
18
,
19
]. Antibiotics, one of the
various treatment options for acne, have been utilized to suppress inflammation by killing the causative
bacteria [
20
]. However, frequent use of antibiotics poses the risk of side effects, like the appearance of
resistant bacterial strains [
21
,
22
]. Therefore, there is a growing interest in acne treatments which have a
higher therapeutic effect and fewer side effects [
22
,
23
]. There are currently many studies demonstrating
that BV might be effective for acne vulgaris.
2.1.1. Clinical Studies
In a randomized double-blind control trial of Han et al., to examine the therapeutic effects of BV
on acne, a total of 12 subjects received either skincare products containing BV or products without
BV for 2 weeks. The BV group showed a notable advancement in the grading levels based upon the
Toxins 2019,11, 374 3 of 30
count of inflammatory and non-inflammatory lesions compared to the control. In the study, patients
applying cosmetics containing BV showed a reduction by 57.5% in ATP levels, measured to assess a
decrease in the count of skin microbes. These results show that cosmetics containing BV may be good
candidates for therapeutic agents for acne [24].
In a prospective, non-comparative study of Han et al., 30 subjects with mild to moderate acne
were recruited and managed with cosmetics containing BV twice daily for 6 weeks. All the volunteers
showed significant improvement in the average visual acne grade compared to the start. The mean
extent of improvement in acne grade after 6-weeks was 52.3%, and 77% of the subjects showed
advancement in terms of whiteheads and blackheads, papules, pustules, and nodules 6 weeks later
compared with the start of the treatment. There was no skin trouble noticed during the progress of the
study. These results demonstrated that cosmetics containing BV showed a marked therapeutic effect
on acne [25].
2.1.2. In Vivo Studies
Propionibacterium acnes (P. acnes) is the main factor that induces inflammation in acne [
26
]. As a
member of normal bacterial flora, P. acnes coexists in our skin, but its excessive proliferation plays a key
role in the development of inflammatory acne. It contributes to the inflammatory response of acne by
stimulating the production of inflammatory cytokines like IL-8, IL-1
β
and TNF-
α
from keratinocytes,
sebocytes, and inflammatory cells [27].
An et al. intradermally injected P.acnes into the ears of mice, and then BV was applied to the right
ear only to examine the therapeutic effects of BV on inflammatory skin disease induced by P. acnes. BV
treatment significantly decreased the inflammatory cells infiltration, and the expression of TNF-
α
and
IL-1
β
decreased significantly in the BV-treated ear as compared to the untreated ear. The expression of
CD14 and TLR2 was also significantly inhibited by BV treatment in P. acnes-treated tissue. In addition,
the transcriptional activity of NF-
κ
B and AP-1 was noticeably inhibited after BV injection. These results
indicate that BV may be beneficial in treating acne [28].
Melitin, the main component of BV, is cationic and is also a toxic peptide that causes hemolysis [
29
].
Interestingly, recent
in vitro
and
in vivo
studies have shown that these cytotoxic melittins can be used
to treat inflammatory diseases by reducing excessive immune responses [
30
]. Lee et al. investigated
the therapeutic efficacy of melitin as an alternative treatment for inflammatory skin diseases caused by
P. acnes. In this study, melittin significantly decreased the swelling and granulomatous inflammation
response, which were induced by intradermal injection of P. acnes, in the ear when compared to the ear
that only P. acnes was injected into. The thickness of the ear injected with melittin showed a 1.3-fold
decrease in comparison to the ears that only P. acnes was injected into. Moreover, melittin evidently
downregulated the expression of TNF-
α
and IL-1
β
, which further led to remarkable suppression of
CD14 and TLR2 expression. These outcomes indicate that the application of melittin has potential for
the treatment of P. acnes-induced inflammatory skin disorder [31].
2.1.3. In Vitro Studies
In vitro
studies of Hari et al. using human keratinocytes and monocyte cells stimulated by
heat-killed P. acne showed that BV reduced the production of IL-8, TNF-
α
, and IFN-
γ
in HaCaT and
THP-1 cells. BV also suppressed TLR2 expression, which was induced by heat-killed P. acnes-induced,
in HaCaT and THP-1 cells in a dose-dependent manner. The activation of TLR encourages the secretion
of chemokines, pro-inflammatory cytokines, leukotrienes, and prostaglandins [32].
In the study of Han et al., BV decreased the production of IL-8 and TNF-
α
, which was caused by
P. acnes, in THP-1 cell in a similar manner. In this study, BV showed low cytotoxicity against human
keratinocytes and monocyte below 10
µ
g/mL [
33
]. These results indicate that BV might alternate
antibiotic treatment for acne.
Lee et al. tested melittin as a therapeutic agent in heat-killed P. acnes–treated keratinocytes. In this
study, the injection of melittin considerably reduced the expression of diverse inflammatory cytokines,
Toxins 2019,11, 374 4 of 30
such as TNF-
α
, IL-8, IL-1
β
, and IFN-
γ
. Melittin treatment suppressed the expression of TNF-
α
and
IL-1
β
via regulating NF-
κ
B and MAPK pathways in keratinocytes. In this study, melittin did not
influence the cell viability of HaCaT cells during 8 hours of treatment. [31]
2.2. Alopecia
Hair is regarded as one of the most crucial parts of a person’s look. Therefore, loss of hair could
negatively affect self-worth and impair life quality. Genetic predisposition is the most common reason
of hair loss, but stress is also believed to play a crucial role, specifically in the younger generation.
Inflammation of the scalp is also associated with hair loss. According to a recent study, 74.1% of
patients diagnosed with alopecia have inflammatory disorders, such as atopic and contact dermatitis.
Mental illnesses account for 25.5% of the cases [34].
2.2.1. In Vivo Studies
Park et al. investigated the preventive effect of BV on alopecia by application of BV or minoxidil
(2%) to the dorsal surface of mice for 19 days. Dexamethasone (DEX) was used to induce catagen in
mice. In this study, BV promoted hair growth in mice by decreasing the levels of 5
α
-reductase and
increasing keratinocyte growth factor (KGF), which stimulates follicular proliferation [
35
]. 5
α
-reductase
enzymatically catalyzed the conversion of testosterone into DHT that has a higher affinity against
androgen receptors than testosterone, which led to stimulating hair loss by the expression of genes
associated with hair follicle minimization [
36
]. Finasteride and dutasteride, which are currently
used as hair loss treatment agents based on inhibiting 5
α
-reductase, can cause severe side effects,
including sexual dysfunction, depression, and gynecomastia, which generally lead to treatment
discontinuation [
37
,
38
]. In this study, no edema, erythema, irritation, and cytotoxicity were observed
after BV treatment. These results suggest that BV may be used as a hair growth-promoting agent [
35
].
2.2.2. In Vitro Studies
The length of hair relies on the duration of the anagen phase [
39
]. At any given time, hair, which is
in anagen, catagen, and telogen phase, accounts for 90%, 1%, and 9% respectively [
40
].
In vitro
studies
using DEX-stimulated human dermal papilla cells (hDPCs) showed that BV elevates the proliferation
of hDPCs and upregulates growth factors, including FGF7, FGF2, VEGF, and IGF-1 that keep hair in
the anagen stage, and hence encourage hair growth in hDPCs [
35
]. BV presents the potential to be
used as a treatment for hair loss, since it can stimulate hair growth by increasing hair growth factors
and suppressing the progression to catagen phase.
2.3. Atopic Dermatitis (AD)
Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disorder that is marked by a
defective skin barrier, eczema, pruritus, dry skin, and an abnormal IgE-mediated allergic response to
diverse external antigens [41].
The incidence of AD has increased considerably in recent years. About 1 to 3% of adults
and a maximum of 20% of children have at some point suffered from AD [
42
]. Antihistamines,
steroids, NSAIDs and immunosuppressants have been utilized to treat AD [
43
–
45
]. Regrettably, these
medications have serious adverse effects, like nephrotoxicity and neurotoxicity [
43
,
46
]. Thus, natural
substances have emerged as alternative therapeutic agents for immune disorders, such as AD because
they are considered to have strong immunomodulatory effects and fewer side effects [
47
]. Emerging
evidence indicates that BV alleviates AD via its anti-inflammatory mechanisms in clinical trials
in vivo
and in vitro studies.
Toxins 2019,11, 374 5 of 30
2.3.1. Clinical Studies
The disease management for AD is on the basis of hydrating the skin and restoring the collapsed
epidermal barrier. Regular use of suitable moisturizer is an important part of therapy for AD because
xerosis and barrier malfunction are the major symptoms of AD [
48
]. In the study of You et al.,
136 subjects with diagnosed AD were randomly distributed in different groups and were made to
apply either a moisturizer containing BV and silk protein or a moisturizer just without BV for 4 weeks.
Subjects who applied emollient with BV showed significantly lower Eczema Area and Severity Index
(EASI) and visual analogue scale (VAS) value compared to patients who applied emollient without
BV. There were no outstanding differences in the incidence of side effects induced by BV on patients’
skin [49].
2.3.2. In Vivo Studies
Gu et al. investigated the advancement of AD-like lesions caused by ovalbumin (OVA), which are
major egg white proteins, and the mechanism of therapeutic action of BV simultaneously. Histological
analysis of dorsal skin thickness indicated that intraperitoneal administration of BV reduced the
symptoms of AD. BV inhibited inflammatory cytokines by decreasing IgE secretion, TNF-
α
, and thymic
stromal lymphopoetin (TSLP). It also suppressed the infiltration of eosinophils and mast cells into
the lesion. These outcomes indicate BV has a possibility to be developed as an alternative for AD
treatment due to the effective inhibition of allergic skin inflammation in AD [50].
Kim et al. noted the relationship between hyperactivity of the complement system and
the inflammatory response of AD. In a mouse model in which atopic lesions were induced by
1-chloro-2,4-dinitrobenzene (DNCB), subcutaneous injection of BV almost completely resolved the
symptoms of AD. In this study, BV significantly increased the secretion of CD55, a complement
formation inhibitor, from THP-1 cells, resulting in a significant reduction in serum C3C and MAC
levels, which were evaluated as an indicator of complement system activation. These results suggest
that BV may be able to manage AD by inducing CD55 production that inhibits activity of complement
system [51].
Itching, a sensation that causes the desire to scratch, is the most outstanding symptom of AD,
and continuous scratching further worsens AD symptoms [
52
]. In the compound 48/80-induced mouse
skin scratching model used in study of Kim et al, intraperitoneal administration of BV mitigated
scratching behavior in mice. This anti-scratching effect correlated with vascular permeability effects
of BV. In this study, BV also significantly suppressed mast cell degranulation and the production
of pro-inflammatory cytokines including TNF-
α
and IL-1
β
by downregulating the activation of the
NF-
κ
B pathway in compound 48/80-treated epidermal tissues. These outcome indicate that BV
might be used to ameliorate compound 48/80-induced AD symptoms [
47
]. In traditional Oriental
medicine, BV acupuncture (BVA), which involves injecting BV into acupoints, has been utilized to treat
various chronic inflammatory disorder of humans. In a mouse model of thrombotic micro-angiopathy
(TMA)-induced AD used in study of Sur et al., BVA treatment at BL40 acupoint in the ear significantly
inhibited the expression of both Th1 and Th2 cytokines in lymph nodes and ear skin. The severity of
ear skin infection symptoms as AD-like symptoms, including thickness, inflammation, and increased
lymph node weight, were considerably soothed by BVA treatment. The proliferation and infiltration of
T cells and the synthesis of IL-4 and IgE, which are typical Th2 allergic responses, were also suppressed
by BVA treatment. Interestingly, BVA at BL40 acupoint showed a more pronounced inhibitory effect
compared to the non-acupoint placed on the base of the tail. These outcomes suggest that injecting BV
at specific acupoints successfully relieves AD-like lesions by suppressing allergic and inflammatory
responses in a mouse with TMA-induced AD. [53]
Several studies have investigated the pharmacological effects of melittin, the main component
of BV. In the study of An et al. using mouse with DNCB-induced AD, topical application of melittin
significantly alleviated AD-like symptoms, such as dorsal skin thickness by decreasing the number
of mast cell infiltration, CD4+T cells and the serum level of IgE, IL-4, IFN-
γ
, and TSLP. In addition,
Toxins 2019,11, 374 6 of 30
whole BV and melittin restored the abnormal differentiation of epidermis by recovering the expression
of filaggrin. These results indicate that melittin could be a suitable agent for the therapy of AD [54].
In the study of Kim et al., intraperitoneally-injected BV also improved OVA-induced AD-like
symptoms, such as an increase in skin thickness, edema, erythema, and excoriation in mice by
inhibiting mast cell infiltration, by decreasing filaggrin levels, and secretion of AD-related inflammatory
chemokines and cytokines, including CD14, CD11b, IL-1
β
, TNF-
α
, TSLP, and an excessive IgE response.
Taken together, these results confirm that melittin has therapeutic effects on AD-like symptoms. [55]
PLA2, another major component of BV, plays a central role in various cellular responses, such as
signal transduction, and the regulation of inflammatory and immune responses and phospholipid
metabolism [
56
,
57
]. In Dermatophagoides farinae extract (DFE)-induced AD mouse model used in
the study of Jung et al., topical application of PLA2 significantly decreased the serum IgE, Th1,
and Th2 cytokines. AD-induced histological changes and mast cells infiltration were alleviated by
PLA2 application. Meanwhile, the depletion of regulatory T cells eliminated the anti-atopic effects
of PLA2, which suggests that anti-atopic effects of PLA2 rely on the functions of regulatory T cells.
Overall, the results demonstrated that topical application of PLA2 might ameliorate atopic skin
inflammation [58].
2.3.3. In Vitro Studies
The in-vitro study of An et al. using TNF-
α
/IFN-
γ
-treated human keratinocytes, melittin
suppressed the production of chemokines, including CCL22 and CCL17, and pro-inflammatory
cytokines such as IL-6, IL-1
β
, and IFN-
γ
by inhibiting the activation of NF-
κ
B, STAT1, and STAT3
pathways. Modulating AD-associated cytokines and chemokines may therefore, offer therapeutic
efficacy in patients with AD [54].
Filaggrin plays an important role in epidermal barrier function. The activation of STAT3
downregulates filaggrin and Th2-induced cytokines, including IL-4 and IL-13, which are known as
activators of STAT3 signaling [59].
Kim et al. investigated anti-atopic effect of melittin using IL-4 and IL-13-stimulated human
keratinocytes. In the study, melittin prevented filaggrin deficiency caused by IL-4/IL-13 and activation
of STAT3 in keratinocytes. The report proposes that melittin may have a beneficial effect on the skin
barrier function via inhibiting filaggrin deficiency by a reduction of IL-4, IL-13, pSTAT3, and TSLP
expression [55].
2.4. Melanoma
Melanoma is a skin cancer which begins in melanocytes, which are cell types generally found
in skin, eye and the bowel. The treatment for melanoma involves surgical removal, and adjuvant
immuno-, chemo- and radiation therapy, which mainly destroy cancer cells by triggering apoptotic
pathways [60].
2.4.1. In Vivo Studies
Soman et al. investigated the anticancer effect of melittin on B16F10 mouse melanoma [
61
]. Melittin
is a cytolytic peptide that inserts itself into lipid bilayer membranes followed by oligomerization
to make pores on membrane [
62
]. Although this action can be used to destroy harmful cells,
the nonspecific cytotoxicity, genotoxicity and hemolytic action of melittin have restricted its therapeutic
usage [
30
]. To overcome this limitation, investigators used perfluorocarbon nanoparticles, synthetic
nanoscale vehicles, which can deliver melittin to both, targeted tumors and premalignant lesions.
After intravenous injection of melittin-loaded nanoparticles, tumor weight decreased significantly
(~87% reduction). Melittin loaded on targeted nanoparticles induced cancer cell apoptosis via liberation
of cytochrome c from mitochondria. In addition, histological analysis revealed a reduction in the
number of proliferating cells, blood vessels and significant areas of necrosis. There were no apparent
toxic effects in terms of changes in organ weight or serum chemical profile, and the levels of liver
Toxins 2019,11, 374 7 of 30
enzyme aspartate aminotransferase were significantly lower in the melittin group than the normal
control [61].
2.4.2. In Vitro Studies
BV caused the shift of intracellular Ca
2+
concentrations in human melanoma A2058 cells. Changes
in intracellular Ca
2+
concentration generated reactive oxygen species (ROS) and collapsed mitochondrial
membrane potential. As a result, apoptosis-inducing factor (AIF) and endonuclease G (EndoG) were
noted to be translocated from mitochondria into the nucleus to carry out apoptosis. The inactivation of
AKT and the activation of JNK were also observed in this process. Taken together, these experimental
results supply a probable description for the potential mechanisms of BV in melanoma [60].
2.5. Morphea
Morphea is known as a local scleroderma and is a unique inflammatory disease that affects the
skin and subcutaneous tissue, resulting in excessive accumulation of collagen, which eventually leads
to fibrosis. Morphea is sometimes itchy but painless. It typically begins in red or purple skin areas and
becomes thick and white [63].
The exact pathogenesis of morphea is unknown and the causes of morphea are generally
considered as immune activation and inflammatory reaction, vascular endocardial damage, fibrosis,
and nodularization. At the present time, there is no recommended medicinal treatment for morphea.
Hwang et al, showed the successful outcome of BVA treatment in circumscribed morphea in a patient
with systemic sclerosis [64].
Clinical Studies (Case Report)
A 64-year-old female presented with circular white areas (1 and 3 cm in diameter) and a heavy
itch in the right lateral iliac crest. Subcutaneously, BVA was administered two times for the 1st week
and once a week for the following 3 weeks along the edge of the superficial circumscribed lesions.
After the first treatment, scores of sleep disturbance and itchiness dropped from 6 to 2 and from 8 to 4,
respectively, on an 11 points numeric scale. At the 3rd visit, the patient reported that her itchiness
had almost gone after two treatments, but it appeared intermittently. On the 5th visit, she reported
that she did not feel the itchiness any more, and that she could sleep well. Her skin also improved.
With a follow-up evaluation for 3 months, it was confirmed that her skin condition had improved
drastically to resemble normal skin. Though there was a light itch at the site of BVA for around half
a day following treatment, there were no other significant side effects during treatments. The result
demonstrates the potential of BVA to be used as a local treatment for morphea [64].
2.6. Photoaging
Human skin is usually damaged by the exposure to ultraviolet (UV) ray of sunlight. Atmospheric
ozone layer absorbs UVC, but both UVA and UVB arrive at the ground and have physiological
effects [
65
]. In particular, UVB is regarded as one of the most hazardous environmental carcinogen
because UVB irradiation can lead to the production of MMP-1 and MMP-3 in fibroblasts, inducing
photoaging of the skin and progression of skin tumor [66].
In Vitro Studies
The in-vitro study of Han et al. using human dermal fibroblasts (HDF) irradiated by UVB,
BV significantly decreased UV-induced MMP-1 and MMP-3 by 50–80% and 50–85%, respectively,
compared to controls. It also reduced the expression of MMP-1 and MMP-3 mRNA. Moreover, BV
promoted the recovery of the damage caused by UVB irradiation in HDF. One microgram/milliliter
of BV exerted no remarkable effect on both cell viability and morphology. However, at the higher
concentration of 10
µ
g/mL, BV treatment declined cell viability up to 90% [
67
]. These results hint that
Toxins 2019,11, 374 8 of 30
BV might be utilized as a potential protective agent for inhibiting photoaging. It is considered that BV
allergy is mainly due to its allergic components, such as PLA2. Hyunkyoung et al. investigated the
efficacy of PLA2-free bee venom (PBV) in preventing photoaging by comparing it with original BV.
In this study, both BV and PBV decreased the levels of MMP-1and MMP-13 in HaCaT cells and MMP-1,
-2 and -3 in HDF cells, which are induced by UVB, and restored the cell damage and production of
collagen. In addition, both BV and PBV downregulated UVB-induced activation of ERK1/2 and p38 in
HaCaT and HDF cells. However, the difference between the two is that BV shows a cytotoxic effect,
whereas PBV showed some advantages in preventing skin wrinkle formation without significant
cytotoxicity [68].
Activities of MMPs induced by UVB caused the degradation of collagen, which led to the loss of
elasticity of skin ultimately forming wrinkles [
69
]. These results suggest that the application of PBV
appears to be an effective method in preventing skin wrinkles and protecting the skin from exposure
to UVB.
2.7. Psoriasis
Psoriasis is a chronic inflammatory skin disorder marked by well-circumscribed erythematous
plaques covered with silvery white scales. The exact pathology is unknown and is believed to be
related to the production of inflammatory cytokines and kemokinesis following the activation of T-cells
and several types of white blood cells that rule cellular immunity [
70
]. Unfortunately, current therapies
can only suppress psoriasis but not cure it. Studies are being planned to evaluate the efficacy of BV as
a new therapy in patients with psoriasis.
Clinical Studies
In the study of Hegazi et al., patients received an intradermal injection of BV. Before treatment
and after 3 months of therapy, Psoriasis Area and Severity Index (PASI) score and serum IL-1
β
were
measured to evaluate the outcome of treatment. Both PASI score and serum levels of IL-1
β
showed a
significant decrease upon BV treatment [
71
]. These results were in accordance with a study which
reported a decrease in levels of IL-1
β
from 289.5 to 29.2 in patients with guttate psoriasis followed by
improvement in psoriasis after tonsillectomy [72].
In this study, intradermal injection of BV showed a superior outcome to oral or topical propolis,
which were used as positive controls. Interestingly, unlike most treatments used in psoriasis, no systemic
adverse effects were observed in all subjects. This indicates that BV might be a safe new treatment
option and could be utilized in patients who have renal or liver dysfunctions [71].
Recalcitrant localized plaque psoriasis (RLPP) is characterized by lesions counting under 10% of
body surface area which does not respond to any topical and systemic treatment [
73
]. Eltaher et al.
used BV as alternative curative agent for RLPP, and their results exhibited full recovery in 23 out of
25 (92%) of patients, whereas only one patient out of 25 (4%) showed a recovery in symptoms in the
placebo group. PGA score and TNF-
α
levels were remarkably decreased in patients treated with BV
compared to the group with placebo. The activity of inflammatory cytokines, including TNF-
α
, IL-6
and IL-1
β
, is considered to take responsibility for the development of psoriasis [
74
]; hence, decreasing
their levels might contribute to improvement of the disease. In this study, no adverse effects were
observed excluding erythema, mild swelling and slight pain at the spot of BV injection and these
troubles eventually got better. Psoriatic lesions did not relapse following 6 months of observation.
These results suggested that BV could be safe and effective management for RLPP [75].
2.8. Skin Wounds
Wound healing is the result of a complex and dynamic course of tissue repair that includes
various cellular and molecular events [
76
]. Wound healing is achieved through five interrelated phases;
hemostasis and formation of clot, fibroplasias and neovascularization, granulation tissue formation,
re-epithelialization, and creation of new ECM and tissue remodeling [77,78]
Toxins 2019,11, 374 9 of 30
In Vivo Studies
Han et al. examined the efficacy of BV on healing wound in mice. For research, full-thickness
wounds were induced on the dorsal surface of mice, and mice were divided into BV control and
Vaseline groups. All the treatments were applied on the gauze covering the wound. The expression of
type 1 collagen showed an increase upon BV treatment compared to the other two groups. The speed
of wound closure in the BV group was notably faster than in the other two groups. Histology also
showed that BV induced remarkable progression of wound healing. In this study, BV reduced the
level of fibronectin, TGF-
β
1, and VEGF but elevated type 1 collagen. The results demonstrated that BV
promoted wound healing by inhibiting cytokines related with fibrosis, which led to a reduction of
wound size and an increase in propagation of epithelium in mice with full-thickness excision. These
results suggest that the topical application of BV could be highly useful in decreasing the sizes of
wounds [79].
In diabetic patients, skin wound healing disorders are often the cause of morbidity and
mortality. Insufficient recruitment of macrophages and neutrophils at the wound and damage
to neovascularization are responsible for impaired diabetic wound healing [80,81].
Hozzein et al. examined the therapeutic effect and mechanism of BV on impaired wound healing
caused by diabetes in a mouse model with type I diabetes mellitus. In this study, the rate of wound
closure and recovery were increased in the BV-treated group in comparison to the control. Type I
collagen showed significant restoration in diabetic mice treated with BV. In addition, the percentage of
apoptotic macrophages decreased markedly in BV-treated groups compared to controls, which led to a
significant increase of the phagocytic index. Furthermore, BV promoted angiogenesis via recovering
Ang-1/Tie-2 signaling and increasing the expression of Nrf2, ERK, Akt/eNOS, and
β
-defensin-2, which
shows a reduction in wound tissues in diabetic mice. These results indicate that BV could be applied
as a new potential treatment for encouraging angiogenesis and repairing the impaired wound healing
in diabetes [82].
2.9. Skin Wrinkling
Wrinkles are a change in appearance induced by ultraviolet rays, and the intrinsic aging process
over a prolonged time. Both these factors induce collagen alteration, leading to skin aging. The desire
to improve aging skin has led to the development of numerous cosmetics that slow down wrinkle
formation. Currently, various ingredients have been added to theses cosmetics and BV is one of the
added ingredients.
Clinical Studies
Han et al. assessed the beneficial effects of serum containing BV on facial wrinkles. The results of
the application of BV-containing serum decreased average wrinkle depth, the total wrinkle area and
count. Topical application of BV is considered to be safe for human skin since it showed no dermal
irritation in animal researches [
83
]. Therefore, BV serum might be effective in improvement of skin
wrinkles [84].
Toxins 2019,11, 374 10 of 30
Table 1. Clinical study on therapeutic application of bee venom for skin disease.
Disease Model Venom/Compound/(Bee
Species)
Dose (Administration
Method) Results Mechanism/Molecular
Response Reference
Acne Human DB, RCT
(n =12)
Cosmetic containing
BV (Apis melifera)
0.06 mg/mL, Cosmetic 4 mL
twice daily for 2 weeks
(Applied to whole face)
Significant improvement of KAGS
score (p<0.01),
57.5% decrease of ATP level which
indicate MO level (p<0.01)
Not reported [24]
Acne Human (n =30) Serum containing BV
(Apis melifera)
Not reported, Serum
0.7–0.9 g twice daily for
6 weeks (Applied to
whole face)
Significant improvement (52.3%) of
MCAGS score after 6 weeks
(p<0.001)
Open and closed comedones were
significantly decreased (p<0.001).
Significant decrease in papules
(p<0.05)
Not reported [25]
Atopic dermatitis Human DB, RCT
(n =114)
Emollient containing
BV (Apis melifera)
Not reported, twice daily
for 4 weeks (Applied to
entire body)
Remarkable reduction of EASI score
in comparison to control (p<0.05).
VAS score for pruritus was notably
declined compared with control
(p<0.05).
TEWL value were not notably
different between two groups.
Not reported [49]
Psoriasis
Human RLPP
patients DB, RCT
(n =50)
BV (Apis melifera)
0.05 mL/cm2(intradermal
injection around
psoriatic lesion)
BV treatment group showed
significant lower PGA scores against
placebo group (p<0.001).
During the follow-up period of 6
months, psoriasis did not recur.
TNF-αwas notably
decreased compared to
control (p<0.05).
[75]
Psoriasis
Human patients with
localized plaque
psoriasis (n =48)
BV (Apis melifera)
Starting with 0.01 µL,
increasing 0.01 µL every
injection untill arriving 1
µL (Intradermal,
twice weekly)
TP: topical propolis
twice daily
OP: oral propolis 1 g/day
by capsule
PASI score was significantly
decreased decreased after treatment
(p<0.01).
Much more reduction than TP
and OP.
The highest reduction in
(TP +OP +BV) group.
Serum IL-1βwas
significantly decreased
after treatment (p<0.05).
Much more decrease than
TP and OP.The highest
decrease in
(TP +OP +BV) group.
[71]
Toxins 2019,11, 374 11 of 30
Table 1. Cont.
Disease Model Venom/Compound/(Bee
Species)
Dose (Administration
Method) Results Mechanism/Molecular
Response Reference
Scleroderma
A case report:
64-year-old Korean
woman, White
circular lesion on the
right lateral iliac crest
BV (Apis melifera)
Dried BV 1 g dissolved in
10000cc water. Total
volume under 0.2 mL.
twice weekly
(subcutaneous, along the
margins of the lesion)
On a 11-point numeric scale (NRS
11), average score of itch declined
from 8 to 4 and sleep disturbance
from 6 to 2, respectively.
On the fifth visit, patient stated that
she no longer felt an itch and had no
sleep disturbance due to itching.
Three months later, the follow-up
evaluation showed that the condition
of the skin was close to normal skin.
Not reported [64]
Wrinkle
Human, Double blind
(n =22)
Serum containing BV
(Apis melifera)
BV 0.006% serum 4 mL
twice daily for 12 weeks
(Applied to whole face)
The average visual grade (SKWGS)
of all patients with BV serum
significantly improved (11.83%
decrement) (p<0.001).
Total area, count and average depth
of wrinkle were significantly
decreased (p<0.05).
Not reported [84]
Abbreviations: ATP: Adenosine triphosphate, DB: double-blind, EASI: eczema area and severity index, KAGS: Korean Acne Grading System, MCAGS: Modified Cook’s Acne Grading
Scale, MO: micro-organism, PASI: psoriasis area and severity index, PASI: psoriasis area and severity index, PGA: physician global Assessment, RCT: randomized controlled trial, RLPP:
recalcitrant localized plaque psoriasis, SKWGS: south Korean wrinkle-grading system, TEWL: transepidermal water loss, TNF-α: tumor necrosis factor-α, VAS: visual analog scale.
Table 2. In vivo studies on therapeutic application of bee venom for skin disease.
Disease Model Venom/Compound/
(Bee Species)/
Dose (Administration
Method)/Control Results Mechanism/Molecular Response Reference
Acne
8-week ICR mice,
P. acnes
intradermally
injected into both
ears. (n =30)
BV (Apis melifera)
1µg blended with 0.05 g
Vaseline (topical, on the
right ear)
NC: P.acnes only
PC: vaseline applied to
left ear
Ear thickness was reduced
three-fold after 24 h compared
to NC (p<0.05).
Swelling, erythema and
inflammatory reactions were
reduced.
TLR2 and CD14 expression is
significantly inhibited.
DNA-binding activity of NF-κB and
AP-1 is remarkably inhibited compared
to NC and PC (p<0.05).
Inhibiting the NF- κB
signaling pathways.
[28]
Toxins 2019,11, 374 12 of 30
Table 2. Cont.
Disease Model Venom/Compound/
(Bee Species)/
Dose (Administration
Method)/Control Results Mechanism/Molecular Response Reference
Acne
8-week ICR mice,
P. acnes
intradermally
injected into both
ear. (n =30)
Melittin (Apis melifera)
100 µg blended with 0.05
g Vaseline (topical, on the
right ear)
NC: P.acnes only
PC: vaseline applied to
left ear
Ear thickness was reduced
1.3-fold after 24 h compared
with NC (p<0.05).
Swelling and granulomatous
response were markedly
reduced.
Significant reduction of TNF-α, IL-1β,
IL-8, IFN-γcompared with NC and PC
(p<0.05).
DNA-binding activity of NF-κB and
AP-1 is remarkably inhibited compared
to NC and PC (p<0.05).
Melittin significantly reduced the
phosphorylation of IKK, I
κ
B and NF-
κ
B.
Inhibiting the NF- κB and MAPK
signaling pathways.
[31]
Alopecia
6-week female
C57BL/6 mice,
catagen phase
induced on dorsal
skin by
dexamethasone.
BV (Apis melifera)
Three CONC:
0.001% 0.005% 0.01% 100
µ
L each Once daily for 19
day (Applied to
dorsal skin)
NC:dexamethasone only
PC: minoxidil 2% 100 µL
Hair growth promoted notably
in a dose-dependent manner at
all doses.
0.01% BV resulted in the
greatest increase in hair growth
compared to PC (p<0.05).
KGF expression is significantly
increased compared with NC (p<0.05).
5α-reductase significantly decreased
compared with NC (p<0.05).
[35]
Atopic dermatitis
DNCB induced
atopic dermatitis
in 7-week male
Balb/c mice (n =8)
BV (Apis melifera)0.3 mg/kg
(subcutaneous) PBS
Dryness, hemorrhage,
excoriation, edema and redness
were almost
completely restored.
Serum C3C and MAC were significantly
decreased after BV injection compared
to PBS injection (p<0.001).
Serum-secreted CD55 were significantly
elevated compared with PBS injection
(p<0.001).
BV increased CD55 production in
THP-1 cells
[51]
Atopic dermatitis
OVA-induced
atopic dermatitis
in 6-week female
Balb/c mice
(n =25)
BV (Apis melifera)
Three doses:
1µg/Kg,
10 µg/Kg, 100 µg/Kg
twice a week for 2 weeks
(intraperitoneal)
NC: untreated PC:
OVA only
Bleeding, erythema, eczema,
and dryness were
significantly reduced.
Dorsal skin thickness was
remarkably reduced in a
dose-dependent manner
compared to PC (p<0.05), the
greatest decrease in BV
100 group.
Significant reduction of mast cell
infiltration in BV 10 and 100 group
compared with PC (p<0.05).
Serum IgE levels were reduced, the
greatest decrease in BV 100 group.
Significant reduction of TNF-αin BV 10
and 100 and TSLP in BV 100 group
compared with PC (p<0.05).
[50]
Toxins 2019,11, 374 13 of 30
Table 2. Cont.
Disease Model Venom/Compound/
(Bee Species)/
Dose (Administration
Method)/Control Results Mechanism/Molecular Response Reference
Atopic dermatitis
DNCB induced
atopic dermatitis
in 6-week female
Balb/c mice
(n =45)
Melittin (Apis melifera)
Three doses:
100 µg,
200 µg,
500 µg blended with
placebo (topical, to
dorsal skin)
Placebo only
Dorsal skin thickness was
notably decreased in
comparison to placebo group
(p<0.05)
Mast cell infiltration was significantly
decreased compared with control
(p<0.05).
Serum IFN-γ, IL-4, IgE and TSLP were
markedly decreased in melittin 200 and
500 group compared to placebo group
(p<0.05).
CD4+and CD3+were significantly
decreased in melittin 500 (p<0.05).
[54]
Atopic dermatitis
Chicken
OVA-induced
atopic dermatitis
in 6-week female
Balb/c mice
(n =25)
Melittin (Apis melifera)
Three CONC:
1µg/Kg,
10 µg/Kg,
100 µg/Kg
(intraperitoneal)
NC: untreated PC:
OVA only
Dorsal skin thickness was
significantly reduced in
comparison to PC (p<0.05),
the greatest decrease in BV
100 group.
Edema, erythema and
excoriation were improved in
melittin group.
Melittin significantly improved
OVA-induced filaggrin deficiency
(p<0.05).
CD14 and CD11b were significantly
decreased in melittin 100 group
compared to PC (p<0.05).
Mast cell infiltration was remarkably
decreased in melittin 10 and 100 group
compared to PC (p<0.05).
Serum IL-1β, TNF-αwas notably
decreased in all dose compared to PC
(p<0.05).
Serum TSLP was remarkably decreased
in melittin 100 compared to PC (p<0.05).
Skin IL-13 mRNA was significantly
declined in melittin 100 compared with
PC (p<0.05).
[55]
Atopic dermatitis
DFE/DNCB-induced
atopic dermatitis
in 7–8-week
female Balb/c
mice (n =25)
PLA2 (Apis melifera)
Two doses:
16 ng/ear,
80 ng/ear
(Applied to ear skin)
NC: DFE/DNCB only PC
:dexamethasone
50 µg/ear
Ear thickness was notably
decreased in all doses
compared to NC (p<0.001),
not more than PC.
AD-like skin lesions were
significantly suppressed
by PLA2.
Th1 cytokines (TNF- α, IL-6 and IFN-)
and Th2 cytokines (IL-4 and IL-13) were
remarkably decreased in comparison to
NC (p<0.05), no more effective than PC.
Epidermal hyperplasia and lymphocyte
infiltration were significantly attenuated
by PLA2 in a dose-dependent manner
compared with control
(p<0.01–p<0.05), no more effective
than PC.
PLA2 has the potential to counteract
AD-like skin lesion-associated
inflammation responses via the
induction of Tregs.
[58]
Toxins 2019,11, 374 14 of 30
Table 2. Cont.
Disease Model Venom/Compound/
(Bee Species)/
Dose (Administration
Method)/Control Results Mechanism/Molecular Response Reference
Atopic dermatitis
Compound
48/80-induced
atopic dermatitis
in 6-week Balb/c
mice (n =32).
BV (Apis melifera)
Two doses:
0.01 mg/Kg
0.1 mg/Kg
(intraperitoneal)
PC: Compound
48/80 only
Scratching behavior caused by
compound 48/80 was
decreased by 75% and 87%
compared with PC in BV 0.01
and 0.1 respectively. (p<0.05)
Vascular permeability of the
skin was decreased by 33.3%
and 70.7% compared with PC
in BV 0.01 and 0.1 respectively.
(p<0.05)
Mast cell degranulation was remarkably
decreased in a dose-dependent manner
compared to PC (p<0.05).
TNF-αand IL-1βwere significantly
suppressed in skin tissue by
BV treatment.
BV inhibited activation of NF-
κ
B, which
was induced by compound 48/80.
[47]
Atopic dermatitis
Trimellitic
anhydride
-induced atopic
dermatitis on ear
skin in 10-week
male Balb/c mice
(n =50).
BV (Apis melifera)
0.3 mg/Kg,
Once daily for 14 day
(subcutaneous,
acupuncture bilateral
point BL40)
NC: TMA treated
PC: prednisone
BVNA: BV at non
acupoint; base of tail
BV at BL40 acupoint
significantly relieved the
AD symptoms.
Thickness of ear and weight of
lymph node were remarkably
decreased compared to NC
(p<0.001).
All results not better than PC
but similar to BVNA indicated
no healing effect on AD-like
symptoms.
Serum IL-4 and IgE was notably
declined compared to NC (p<0.001).
Number of CD4 and CD8 positive cells
was notably declined in comparison to
NC (p<0.01).
TNF-
α
, IFN-
γ
, IL-2, IL-4, IL-10 and IL-12
concentration in auricular lymph node
were remarkably decreased compared to
NC (p<0.001–p<0.05).
[53]
Melanoma
B16F10 murine
melanoma was
implanted
subcutaneously in
C57BL/6 mice
(n =15)
Melittin (Apis melifera)
8.5 mg/Kg, 4 injections
every other day starting
at day 5 (intravenous,
Melittin is loaded on
molecularly targeted
nanoparticles.)
S: saline only
N: nanoparticle only
Tumor weight was significantly
decreased on day 14 compared
with S (~88% reduction) and N
(~87% reduction) (p<0.01).
Decrease in the number of
blood vessels in proliferating
cells, and significant areas of
necrosis in
melittin-treated-tumor.
Melittin-loaded nanoparticles cause
apoptosis of cancer cell via release of
cytochrome c from mitochondria.
[61]
Wound (Diabetic
wound)
Diabetic 12-week
male Balb/c mice
wounded on back
(n =45)
BV (Apis melifera)
200 µg/kg for 15 day
(subcutaneous, on
wound area)
NC: wound on
non-diabetic mice
PC: diabetic mice without
BV treatment
Degree of wound closure was
similar to NC, markedly higher
than PC (p<0.05).
Type I collagen expression was
significantly recovered in BV-treated
diabetic mice compared with PC
(p<0.05), lower than NC.
Ang-1, Nrf2, p-Tyr, p-eNOS, p-AKT,
p-ERK, CD31, CCL2, CCL3, CXCL2 and
β-Defensin-2 expression were
significantly recovered in BV-treated
diabetic mice compared with PC
(p<0.05).
[82]
Toxins 2019,11, 374 15 of 30
Table 2. Cont.
Disease Model Venom/Compound/
(Bee Species)/
Dose (Administration
Method)/Control Results Mechanism/Molecular Response Reference
Wound
7-week male HR-1
mice wounded on
back (n =30)
BV (Apis melifera)
1µg/gauze (Wound was
covered with an equal
size of gauze treated with
BV for 7 day)
NC: untreatedPC: treated
with Vaseline
Dramatic decrease of wound
size was observed in BV group
compared to NC and PC
(p<0.05).
Type 1 collagen was remarkably
elevated in BV group in comparison to
NC and Vaseline.
TGF-b1 and fibronectin were
significantly decreased in BV group in
comparison to control and Vaseline.
VEGF was remarkably declined in BV
and PC compared to NC (p<0.05).
[79]
Abbreviations: AP-1: activator protein-1, CONC: concentration, DEX: dexamethasone, DFE: Dermatophagoides farinae extract, DNCB: 1-chloro-2,4-dinitrobenzene, i.p.: intraperitoneally, i.v.:
intravenous, KGF: keratinocyte growth factor, MAPKs: mitogen-activated protein kinases, NC: normal control, OVA: ovalbumin, P. acnes: Propionibacterium acnes, PC: positive control,
PLA2: phospholipase A2, s.c:. subcutaneous, TGF-b1: transforming growth factor-b1, TNF-
α
: tumor necrosis factor-
α
, Tregs: regulatory T cell, TSLP: thymic stromal lymphopoietin,
VEGF: vascular endothelial growth factor.
Toxins 2019,11, 374 16 of 30
2.10. Vitiligo
Vitiligo is characterized by depigmentation of skin and hair. It is related to abnormal pigmentation
resulting from melanocyte proliferation, melanogenesis, and migration or increases in dendricity
[85,86]
.
Recently, phospholipase A2 of BV has been reported to stimulate melanocyte dendricity and
pigmentation [
86
–
88
]. According to the authors, pigmentation which occurred around the injection
sites and lasted a few months, had been observed after treatment with BV. One study investigated
the effect of BV on the proliferation, melanogenesis, migration, dendricity, and signal transduction of
human melanocytes.
In Vitro Studies
In the study of Jeon et al., BV treatment elevated the melanocyte proliferation around twice
compared to the control in 1 week. By BV treatment, the expression of MITF-M protein increased to the
maximum levels on day 3 and slowly decreased till day 5. BV also activated PKA, ERK, and PI3K/Akt
signaling. Moreover, BV treatment increased the ratio of cells with more than two dendrites by 23%
in a time-dependent manner. The results also showed that BV treatment led to a two-fold increase
in the number of migrated cells as compared to the controls. BV-induced melanocyte dendricity
and melanocyte migration showed complete inhibition upon pre-treatment with PLA2 inhibitor and
aristolochic acid, and this suggests that BV-induced melanocyte dendricity and melanocyte migration
occur via the activation of PLA2.
The results of the in-vitro study indicated that BV has a positive effect on melanocyte proliferation,
melanogenesis, dendricity, and migration. The result suggest that BV has a potential for treatment of
vitiligo by repigmentation in skin [89].
3. Inhibitory Effects of BV against Pathogenic Agent which is Related to Skin Disease
3.1. Bacteria
3.1.1. Propionibacterium Acnes, Clindamycin-Resistant P. acnes,Staphylococcus epidermidis, and
Streptococcus pyogenes
Propionibacterium acnes,Staphylococcus epidermidis,Streptococcus pyrogenes, and Staphylococcus aureus
are microorganisms that originally exist on normal skin. During puberty, they proliferate rapidly and
often contribute to the development of acne [
90
,
91
]. P. acnes infections mainly occur in the pilosebaceous
unit. In contrast, aerobic organisms like S. epidermidis,S. pyrogenes, and S. aureus generally infect the
sebaceous unit [
92
,
93
]. In the study of Han et al., BV shows bacteriostatic as well as bactericidal effects
against P. acnes, clindamycin-resistant P. acnes,S. epidermidis, and S. pyrogenes. In this study, minimum
inhibitory concentrations (MIC) of BV against P. acnes, clindamycin-resistant P. acnes,S. epidermidis,
and S. pyrogenes were 0.086 µg/mL, 0.067 µg/mL, 0.104 µg/mL, and 0.121 µg/mL, respectively [33].
3.1.2. Staphylococcus aureus and Methicillin-Resistant Staphylococcus aureus (MRSA)
Staphylococcus aureus is the main causative pathogen of Impetigo [
94
], Paronychia [
95
],
and Staphylococcal-scalded skin syndrome [
96
]. BV exhibited a significant antibacterial effect against
S. aureus in an in-vitro study using the disc diffusion method [
11
]. Although antibiotics effectively deal
with S. aureus infections these days, the appearance of methicillin-resistant S. aureus (MRSA) is posing
a challenge to global health systems at present [97].
In the study of Han et al. that investigated the antimicrobial effect of BV on MRSA strain in
terms of minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC),
the MIC values of BV against MRSA CCARM 3366 and MRSA CCARM 3708 were 0.085
µ
g/mL and
0.11
µ
g/mL separately. Its MBC against MRSA 3366 and MRSA 3708 were 0.106
µ
g/mL and 0.14
µ
g/mL
respectively. Interestingly, MRSA strains were more sensitive to the mix of BV and vancomycin
Toxins 2019,11, 374 17 of 30
or gentamicin than either ampicillin or penicillin alone. These outcomes showed that BV exhibits
antimicrobial and enhancing antibacterial effects versus MRSA strains [13].
Choi et al. examined whether BV and melittin could suppress MRSA infections
in vitro
and
in vivo
.
Surprisingly, BV showed outstanding antimicrobial effect
in vitro
, but strengthened the proliferation
and infection of MRSA
in vivo
. All the mice, injected with MRSA USA300 and BV, died 18 h after
infection, while only five died in the control 24 hours after infection. In addition, no outstanding
difference was noticed in terms of the diameter of abscesses formed by MRSA USA300 even after
BV treatment.
Unlike BV, melittin showed remarkably better protection in the mice models of bacteremia and
skin infection. Half of the mice survived over 24 h when 5mg/kg of melittin was injected 1 hour after
bacterial infection and the abscess diameters were notably lower than the control [98].
3.1.3. Dermatophytes, Trichophyton mentagrophytes, and Trichophyton rubrum
Trichophyton mentagrophytes and Trichophyton rubrum, common dermatophytes, are known to cause
various skin infections in humans and animals. Dermatophytes infect keratinized epithelium, the hair
and nails. Tinea pedis is described as a dermatophyte infection on the soles of the feet and interdigital
spaces; tinea cruris as an infection of the groin; tinea faciei as the facial infection; and tinea corporis as
a fungal infection of the rest of the skin [99].
Yu et al. reported that BV showed significant antifungal effects against the two dermatophytes.
In this study, 0.63 ppm of BV inhibited the growing of T. menatgrophytes by roughly 92% and T. rubrum
by 26% after 1 h of incubation. Furthermore, BV exhibited much stronger antifungal activities than
that of fluconazole, a standard antifungal agent utilized for the prevention and management of fungal
infections. The results of this study suggest that BV could be developed as a natural antifungal
drug [100].
Onychomycosis or tinea unguium which accounts for about half of all nail abnormalities is also
caused due to dermatophytes, with the most common agent being Trichophyton rubrum. In the study
of Park et al. that investigated the antifungal effects of BV, mellitin, apamin, and BV-based mists
on T. rubrum indicated that BV and BV-based mist exhibited strong antifungal effect on T. rubrum.
However, the isolated BV components, such as mellitin and apamin, showed no significant effect in
hindering the growth of the fungal colonies [101].
3.2. Fungi
3.2.1. Candida Albicans
Cutaneous candidiasis is typically caused by Candida albicans, which exists as normal flora of
human skin as well as in the gastrointestinal and genitourinary systems [
102
]. In the study of Lee et al.,
Sweet BV (SBV), which is made by removing enzymes and histamine known as allergens from BV,
and BV exhibited an antifungal effect against 10 clinical isolates of C. albicans that were incubated from
blood and the vagina.
In this study, SBV was noted to have much stronger antifungal activity than that of BV. The MIC
values measured by the broth microdilution method diverge from 62.5
µ
g/mL to 125
µ
g/mL for BV,
and in the case of SBV, from 15.63
µ
g/mL to 62.5
µ
g/mL. on the kill-curve assay, SBV acted similar to
amphotericin B that was utilized as a positive control [103].
Park et al. demonstrated that melittin exerts its antifungal effect by inducing apoptosis. C. albicans
treated with melittin exhibited an increase of ROS. In addition, markers that are indicators of apoptosis
in yeast, involving externalization of phosphatidylserine, and fragmentation of DNA and nucleus
fragmentation were observed. This study suggests that melittin exerts an antifungal effect by promoting
apoptosis [104].
Toxins 2019,11, 374 18 of 30
3.2.2. Malassezia furfur
Malassezia furfur, a lipophilic yeast-like fungus exists as an opportunistic pathogen in human skin
and causes disorders such as dandruffand pityriasis versicolor.
In the study of Prakash et al., wherein 5 mg/mL BV was loaded onto the disc spread with M. furfur,
a large zone of inhibition with an area of 86.9 mm
2
was observed. Ketoconazole (200 mg/mL) was used
as a standard reference and it showed an area of inhibition of 156.1 mm
2
. Since the doses of BV were in
the range of 1–5 mg/mL, ketoconazole was applied at 5 mg/mL and it exhibited a suppression zone of
38.8 mm2.
In this study, BV showed good inhibition against M. furfur. Shampoos that can be bought in the
commercial market are mostly made of chemicals and have many side effects. Therefore, supplements
with natural compounds such as BV can be a better treatment for skin diseases caused by M. furfur. [
105
].
3.3. Viruses
Herpes Simplex Virus
Herpes simplex virus (HSV) invades skin and mucous membranes, harming keratinocytes and
causing severe inflammation which is accompanied by small blister on the Erythema. Genital infections
are mainly caused by HSV-2, while infections of other areas and the mouth are mostly caused by
HSV-1 [106].
In the study of Uddin et al., a non-cytotoxic quantity of BV significantly suppressed the replication
of HSV. These antiviral properties are mainly based on the virucidal activity of BV. Apart from antiviral
activity, BV stimulated IFN-1, which could subsequently initiate antiviral signaling in the host cell and
additionally suppress the replication of the virus.
Uddin et al. also examined the antiviral effect of several components of BV to know which
compounds in BV played a critical role in the virucidal effect of BV. Among those, only melittin in
non-cytotoxic amounts exhibited similar effects to BV. Melittin directly destabilized the structure of
virus particle, thereby suppressing viral infectivity. However, melittin was unable to interrupt the
cell attachment and entry of the virus into the cells, and hence, once the cells were infected, it could
not suppress viral infection and replication [
12
]. These results indicate that BV or melittin has the
possibility to be a prophylactic or therapeutic agent in viral skin diseases.
Toxins 2019,11, 374 19 of 30
Table 3. In vitro studies on the therapeutic application of bee venom for skin disease.
Disease Model Venom/Compound/
(Bee Species) Dose Results Mechanism/Molecular Response Reference
Acne THP-1 cell dealt with
heat-killed P. acnes BV (Apis melifera)
Three CONC:
0.1 µg/mL,
1µg/mL,
5µg/mL for 48 h
Significant reduction of TNF-α, IL-8
in a concentration-dependent
manner (p<0.05).
Lowest TNF-αat 5 µg/mL
Lowest IL-8 at 1 µg/mL
Not reported [32]
Acne THP-1 cell dealt with
heat-killed P. acnes BV (Apis melifera)
Three CONC:
1 ng/mL,
10 ng/mL,
100 ng/mL for 8 h
Significant reduction of TNF-α, IL-8,
IFN-γat all doses compared to
control (p<0.05).
Reduced in dose dependent manner.
TLR2 expression
significantly suppressed [107]
Acne
THP-1 cell treated
with heat-killed
P. acnes
Melittin (Apis melifera)
Three CONC:
0.1 ng/mL, 0.5 ng/mL,
1 ng/mL. for 8 h
Significant reduction of TNF-α, IL-8
at all doses compared to control
(p<0.05).
Reduced in dose-dependent manner.
Melittin significantly reduced the
phosphorylation of IKK, I
κ
B and NF-
κ
B.
Inhibiting the NF- κB
signaling pathways.
[107]
Acne
HaCat cell treated
with heat-killed
P. acnes
BV (Apis melifera)
Three CONC:
1 ng/mL, 10 ng/mL,
100 ng/mL for 8 h
Significant reduction of TNF-α, IL-8,
IFN-γat 10, 100 ng/mL in
comparison to control (p<0.05).
Reduced in dose-dependent manner.
TLR2 expression
significantly suppressed [107]
Acne HaCat cell dealt with
heat-killed P. acnes
Melittin (Apis melifera)
1µg/mL
Significant reduction of TNF-α,
IL-1β, IL-8, IFN-γcompared with
control (p<0.05).
TLR2 and 4 expression
significantly decreased.
Melittin significantly reduced the
phosphorylation of IKK, IκB, NF- κB
and p-38.
Inhibiting the NF-κB and MAPK
signaling pathways.
[31]
Alopecia hDPC treated with
0.1% dexamethasone BV (Apis melifera)
Three CONC:
100 ng/mL, 200 ng/mL,
500 ng/mL for 24 h
Significant increase of FGF-2, FGF-7,
IGF-1R and VEGF compared with
DEX only.
(p<0.001–p<0.05).
Protein-level of VEGF is increased
1.95-, 2.95-, 2.08 and 1.47-fold with
100, 200, 500 ng/mL BV and 2%
minoxidil respectively.
Not reported [35]
Toxins 2019,11, 374 20 of 30
Table 3. Cont.
Disease Model Venom/Compound/
(Bee Species) Dose Results Mechanism/Molecular Response Reference
Atopic
dermatitis
Hacat cell treated
with TNF-αand
IFN-γ
Melittin (Apis melifera)
Three CONC:
0.1 µg/mL, 0.5 µg/mL,
1µg/mL.
IL-1β, IL-6 and IFN-γwere
decreased in a
dose-dependent manner.
mRNA of CCL17 and CCL22 were
significantly decreased in a
dose-dependent manner in melitin
0.5 and 1 in comparison to control
(p<0.05).
pJAK2, pSTAT1 and pSTAT3
expression was decreased in melittin
1µg/mL
NF- κB DNA-binding activity was
markedly reduced. [54]
Atopic
dermatitis
Hacat cell treated by
50 ng/mL of IL-4
and IL-13
Melittin (Apis melifera)
Three CONC:
0.1 µg/mL, 0.5 µg/mL,
1µg/mL. for 24 h
Filaggrin expression was remarkably
elevated in a dose-dependent
manner in all doses compared to
control (p<0.05)
pSTAT3 expression was significantly
decreased in melittin 1 µg/mL
Not reported [55]
Melanoma Human melanoma
A2058 cells BV (Apis melifera) 4 µg/mL
Application of 4 mg/mL BV for 2 h
resulted in the death of
approximately 80% of A2058 cells.
BV generated reactive oxygen species
(ROS) and altered mitochondrial
membrane potential transition.
BV causes apoptosis in
AIF/EndoG-dependent but
caspase-independent manner.
BV interfered with AKT and MAPK
family kinase activation.
BV treatment significantly reduced
phosphorylated AKT and p38 BV made
ER and extracellular Ca2+drift to
the cytosol.
[60]
Photoaging HDF cell irradiated
by UVB (312 nm)
PLA2-free BV(PBV)
and BV (Apis melifera)
PBV:
1.5 µg/mL, 3.0 µg/mL,
BV 1.5 µg/mL,
3.0 µg/mL
Both PBV and BV significantly
restored Type 1 procollagen
synthesis in UVB-irradiated HDF
cells except for BV 3
µ
g/mL (p<0.05).
Type 1 collagen significantly
increased in both BV, PBV compared
with control (p<0.05).
(Degree: 3.0 BV >1.5 BV >3.0 PBV >
1.5 PBV)
PBV and BV treatments significantly
attenuated the MMP-1, 2 and 3
expressions (p<0.05).
Both PBV and BV significantly inhibited
the UVB-stimulated phosphorylations of
ERK1/2 and p38 (p<0.05).
[68]
Toxins 2019,11, 374 21 of 30
Table 3. Cont.
Disease Model Venom/Compound/
(Bee Species) Dose Results Mechanism/Molecular Response Reference
Photoaging Hacat cell irradiated
by UVB (312 nm)
PLA2-free BV(PBV)
and BV (Apis melifera)
PBV:
1.5 µg/mL, 3.0 µg/mL,
BV:
1.5 µg/mL, 3.0 µg/mL.
PBV and BV treatments significantly
attenuated the MMP-1, 13
expressions (p<0.05).
Both PBV and BV significantly
inhibited the UVB-stimulated
phosphorylations of ERK1/2 and p38
(p<0.05).
[68]
Photoaging HDF cell irradiated
by UVB (280–350 nm) BV (Apis melifera)
Three CONC:
0.01 µg/mL, 0.1
µg/mL, 1 µg/mL for
24 h
BV significantly decreased MMP-1
expressions by 50–80% while MMP-3
expression by 50–85% compared to
controls (p<0.05).
The biggest MMP-1 and MMP-3
inhibitions were observed at a
0.1 µg/mL.
Not reported [67]
Vitiligo Human epidermal
melanocyte BV (Apis melifera) 10 µg/mL
Melanocyte proliferation and
melanin content were remarkably
increased compared to control
(p<0.05), similar to melanocyte
treated with 10 µM forskolin but no
more than.
Forskolin increased the cAMP level
40-fold, but BV only tripled. Based on
this, the cAMP level does not appear to
be the deciding factor
[89]
Abbreviations: AIF: apoptosis-inducing factor, AKT: protein kinase B, cAMP: cyclic adenosine monophosphate, CONC: concentration, DEX: dexamethasone, EndoG: endonuclease G,
ER: endoplasmic reticulum, ERK1/2: extracellular signal-regulated kinase 1 and 2, FGF: fibroblast growth factor, HaCat: human keratocyte, HDF: human dermal fibroblasts, hDPC:
human dermal papilla cell, HEK: human epidermal keratinocyte, IGF-1R: insulin-like growth factor 1 receptor, MAPK: mitogen-activated protein kinase, P. acnes:Propionibacterium acnes,
pJAK: phosphorylated janus kinases, pSTAT3: phosphorylated signal transducer and activator of transcription, TLR2: Toll-like receptor 2, UVB: ultraviolet, VEGF: vascular endothelial
growth factor.
Toxins 2019,11, 374 22 of 30
4. Therapeutic Mechanisms of BV on Skin Diseases
Collective evidence from in-vitro experiments, in-vivo studies and clinical trials showed that BV
has a potential therapeutic effect on skin diseases. The therapeutic mechanisms of BV mentioned above
are as follows:
(1) In acne, TNF-
α
, IL-1
β
, TLR2, and CD14 expressions were remarkably decreased by BV
treatment in P. acnes-injected tissues. In addition, the DNA-binding activity of NF-
κ
B and AP-1 was
noticeably inhibited by BV treatment [
28
]. BV reduced the expression of IL-8, TNF-
α
, and IFN-
γ
in
HaCaT (keratinocyte) and THP-1 (monocytes) cells. It also suppressed TLR2 expression induced by
heat-killed P. acnes in HaCaT and THP-1 cells [
107
]. Melittin significantly decreased TNF-
α
and IL-1
β
expression, leading to a noticeable suppression of TLR2 and CD14 expression in keratinocytes [31].
(2) In alopecia, BV promotes hair growth by reducing 5
α
-reductase expression and increasing
KGF which stimulates follicular proliferation. BV increases the proliferation of hDPCs and upregulates
growth factors, such as FGF7, FGF2, IGF-1, and VEGF, which maintain hair follicles in the anagen
phase [35].
(3) In AD, BV suppressed the inflammatory cytokines by decreasing IgE, TNF-
α
, and TSLP levels.
It also suppressed the infiltration of mast cells and eosinophils [
50
]. BV significantly increased the
secretion of CD55, a complement formation inhibitor, from THP-1 cells, resulting in a significant
reduction in serum C3C and MAC levels, which were evaluated as an indicator of complement system
activation [51]. BV significantly inhibited mast cell degranulation and synthesis of pro-inflammatory
cytokines, like TNF-
α
and IL-1
β
, by downregulating NF-
κ
B activation [
47
]. The propagation and
infiltration of T lymphocyte and the production of IL-4 and IgE, which are induced by Th2 type allergic
responses, were suppressed by BV treatment [53].
Melittin decreased CD4+T lymphocytes, mast cell infiltration and serum levels of IgE, IFN-
γ
,
IL-4, and TSLP. Melittin also suppressed the production of chemokines, like CCL17 and CCL22,
and pro-inflammatory cytokines involving IL-6, IL-1
β
, and IFN-
γ
by inhibiting the activation of
NF-
κ
B, STAT1, and STAT3 signaling pathways in keratinocytes [
54
]. Moreover, melittin inhibited
filaggrin deficiency induced by IL-4 and IL-13 in keratinocytes. In addition, it suppressed mast cell
infiltration and AD-related inflammatory molecules, such as CD14, CD11b, IL-1
β
, TNF-
α
, and TSLP
and exaggerated IgE response [
55
]. The application of PLA2 significantly suppressed the increase in
serum IgE and Th1 and Th2 cytokines. It also attenuated the infiltration of mast cells and histological
changes [58].
(4) In melanoma, BV induced fluctuation in intracellular Ca
2+
concentrations which increased the
levels of ROS and collapse of membrane potential of mitochondria. As a result, AIF and EndoG are
translocated from mitochondria into the nucleus to initiate apoptosis [
60
]. Melittin, loaded on targeted
nanoparticles, induced apoptosis of cancer cell via release of cytochrome c from mitochondria [61].
(5) In morphea, the therapeutic mechanism of BV has not been studied yet.
(6) In photoaging, BV significantly decreased UVB-induced MMP-1 and MMP-3 expression in
HDFs [
67
]. BV also decreased the levels of MMP-1 and MMP-13 in HaCaT cells, and MMP-1, -2, and -3
in HDF cells, which are induced by UVB. Moreover, cell damage and production of collagen were
restored by BV treatment. Furthermore, BV treatment downregulated UVB0-induced activation of p38
and ERK1/2 in HaCaT and HDF cells [68].
(7) In psoriasis, a notable reduction in the serum level of IL-1
β
was observed upon BV treatment [
71
].
(8) In skin wound healing, BV treatment elevated type 1 collagen expression and decreased the
levels of TGF-
β
1, VEGF, and fibronectin, which are cytokines associated with fibrosis [
79
]. In diabetic
wound healing, BV treatment markedly restored type 1 collagen expression. BV significantly decreased
the percentage of apoptotic macrophages. In addition, BV promotes angiogenesis via recovering
Ang-1/Tie-2 signaling and increasing the expression of Nrf2, ERK, Akt/eNOS and
β
-defensin-2, which
are normally downregulated in wounded tissues [82].
(9) In wrinkled skin, the therapeutic mechanism of BV action is yet to be explored.
Toxins 2019,11, 374 23 of 30
(10) In vitiligo, BV significantly increased melanocyte proliferation, melanogenesis, dendricity,
and migration. Hence, BV activated PKA, ERK, and PI3K/Akt signaling and increased MITF-M protein
expression [89].
5. Discussion
Although no severe adverse effects were accounted from the studies reviewed here (Table 4),
it cannot be ruled out that BV might cause fatal adverse reactions such as anaphylaxis [
108
]. Thus,
physicians who use BV should be careful when administering BV to patients. In clinics, a skin test
is used to determine whether BV treatment is suitable for individual patients, however, negative
results of a skin test do not always guarantee safety [
109
]. Furthermore, one case report showed that
anaphylaxis may occur in patients who have had no adverse reaction after former BV therapy [
110
].
Since anaphylaxis can occur under any circumstances, an emergency kit in accordance with the
guidelines for management of anaphylaxis should always be kept ready. Meanwhile, one retrospective
case study reported that the mean time to onset of anaphylaxis after BV therapy was 21.75 min [
111
],
therefore, it is necessary to monitor the patient for at least 30 min after BV treatment. One recent study
reported that high levels of basal serum tryptase increased the risk of severe anaxphylaxis [
110
]. As per
this information, even if an injection of BV did not cause anaphylaxis in the past, if the basal serum
tryptase is elevated at a certain time for some reason, anaphylaxis may occur when BV is injected.
If this hypothesis is correct, the specific physiological state of the body at the point of BV injection may
be a strong risk factor for the development of anaphylaxis. The analysis of safety of BV treatment will
be a crucial factor in determining the value of BV as a therapeutic agent. We hope that further studies
on prediction factors to prevent anaphylaxis upon BV administration will be conducted.
Table 4. Adverse effects reported in clinical studies and in in vivo studies.
Disease Type of Study Venom/Compound/(Bee
Species)
Adverse Effect
(Severity) Reference
Atopic
dermatitis Clinical Emollient containing BV
(Apis melifera)
Irritation, pruritus,
erythema, urticaria
and disease
exacerbation (mild).
No significant
differences in the
incidence compared
with control.
[49]
Psoriasis Clinical BV (Apis melifera)
Mild pain, redness and
swelling at the site of
apitheraphy injection
[75]
Psoriasis Clinical BV (Apis melifera)
4patients experienced
itching but not
significant.
No systemic
adverse effect.
[71]
Scleroderma Clinical BV (Apis melifera)
Slight itchiness at the
location of inoculation
for 1 half-day.
[64]
In this review, we surveyed the reports that showed the cytocidal effect of BV on pathogenic
microorganisms that cause skin diseases as well as have a therapeutic effect on skin diseases. BV showed
a significant inhibitory effect against various bacteria, fungi and viruses, and these results show potential
applications of BV for diseases wherein the microbial agent is the main therapeutic agent. We expect
further studies that examine the effect of BV on the treatment of various skin infections.
Toxins 2019,11, 374 24 of 30
Treatment of warts by subcutaneous injection of BV is already being practiced in oriental medicine
clinics in Korea. So, we believe that there would be a study that shows the therapeutic effects of BV
on warts, but there have been no documented reports were warts were treated by using BV. Warts is
known to be caused by skin infection with human papilloma virus (HPV). BV may also have a virucidal
effect on the HPV virus that causes warts, as it is reported to have antiviral properties [
12
]. We look
forward to further research about using BV in the management of warts. Furthermore, we hope that
clinicians who use BV for the treatment of skin disorder actively report their cases.
Treatment with natural substances is expected to have fewer side effects than with conventional
medicine, but this comparison should ensure sufficient therapeutic effects. Many studies reviewed
here have shown the ability of BV to reduce inflammatory cytokines and the disease-causing microbes;
however, the status of BV among the current treatments is not very clear. Using current commercial
drugs as positive controls in the future studies will help assess the precise therapeutic effect of BV.
However, it may not be accurate to conclude that BV is meaningless as an alternative treatment because
conventional medicine shows a greater magnitude of change
in vitro
studies. Because life has a very
complex and organic structure, reactions to certain substances can be different between at the cell
level and at the living level. Therefore, in order to ultimately determine whether BV has a therapeutic
effect or not, it is necessary to evaluate how much change is made by BV in the lesion in the animal or
human, not just in the cell. In addition, even if the efficacy of BV is lower than conventional therapy,
it can be valuable as a therapeutic agent if it can make enough improvement of disease.Of course,
in-vitro study can easily help in the analysis of molecular mechanisms and it plays an important role
in providing hypotheses for follow-up research at a low cost; however, clinical trial and in-vivo study
are necessary to decide the dosage and appropriate use of BV. Meanwhile, such studies are also very
important in identifying the side effects of BV. Choi et al. conducted
in vitro
and
in vivo
studies to
examine whether BV and melittin are able to suppress MRSA infections. Surprisingly, BV showed
outstanding antimicrobial activity
in vitro
, but strengthened the proliferation and infection of MRSA
in vivo
[
98
]. Among 25 studies on 10 diseases surveyed this time, 15 studies were on acne and AD. The
number of studies on the other eight diseases was not sufficient to conclusively assert the therapeutic
role of BV. Especially, for vitiligo and photoaging, only
in vitro
studies have been carried out. We look
forward to additional studies in the form of a clinical trials and more
in vivo
studies for the remaining
eight diseases.
In this review, we have tried to investigate not only the therapeutic effects of BV, but also its acting
mechanism. In the case of much studied acne and AD, there is considerable information about the
mechanism of BV action. However, despite a limited number of studies, therapeutic mechanisms of
BV action in alopecia, melanoma, photoaging, wound healing, and vitiligo were also found. However,
no studies have been carried out for morphea, psoriasis and skin wrinkles. Despite many studies,
the precise use of BV in treatment has not been accurately identified. We look forward to further
studies that examine the molecular mechanism of BV treatment.
This review only dealt with melanoma in relation to skin cancer, but there was also a study that
tested the efficacy of melittin in relation to the treatment of squamous cell carcinoma (SCC). SCC has
the second highest prevalence of skin cancer after melanoma [112], with 700,000 new cases occurring
each year [
113
]. The major risk factors of SCC are ultraviolet light and ultraviolet light absorbed
by skin cells
'
DNA, including keratinocyte, causing genetic and epigenetic changes in these cells.
In particular, studies have shown that p53 and the RAS pathway are responsible for this malignant
transformation [
114
]. Do et al. demonstrated that the combination of melittin and 5-FU, which is used
as topical treatment for SCC, increased the cancer-killing effect and reduced the cytotoxicity on normal
keratinocyte [
115
]. Despite delicate data collection, there were studies that were missed. In the data
collection process for preparing a review paper, a search method that can scan not only the title of the
paper but also the contents of the paper should be considered.
It is not necessary to use only one method to treat diseases nor is it needed to replace the
conventional drugs completely with natural substances. We expect that there is potential that a
Toxins 2019,11, 374 25 of 30
combination of BV and conventional medicine could prove to be a valuable therapeutic asset and could
minimize adverse effects. We look forward to various types of follow-up research using BV.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
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