June 2019
Haejoong Kim, Soo-Yeon Park, and Gihyun Lee
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 killing effects of BV on skin disease-causing pathogens, including bacteria, fungi and viruses.
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 [2,4,5,6], 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 [1,11,12,13,14,15,16,17].
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 ahead of discussion in order of clinical study, in vivo study, and in vitro study (Table 1, Table 2 and Table 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.
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.
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.
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 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.
