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Activities:
Analgesic, antioxidant, anti-inflammatory, antimicrobial, antitumor, antiseptic, antipyretic, antiulcer,1 hepatoprotective, immunomodulatory2
Important Chemical Components:
Honey: Hydrogen peroxide, lysozyme, polyphenols, phenolic acids, flavonoids, methylglyoxal, ascorbic acid, α-tocopherol, carotenoids, glucose oxidase, catalase, and bee peptides3
Propolis: Flavonoids (e.g., galangin, chrysin, pinocembrin, quercetin),4 phenolic acids and their esters (particularly caffeic acid phenethyl ester),5 cinnamic acid derivatives (i.e., drupanin, baccharin, and artepillin C), sesquiterpene quinones, coumarins, amino acids, and steroids1
Royal Jelly: 10-hydroxy-2-decenoic acid (10-HDA), water, proteins, free amino acids, carbohydrates, lipids, minerals, and vitamins
Origin Classification:
All of these ingredients used in skin care are natural products of bees.
Personal Care Category:
Antioxidant, antiaging, photoprotection, antiseptic, wound healing
Recommended for the following Baumann Skin Types:
DRNT, DRNW, DRPT, DRPW, DSNW, DSPW, ORNT, ORNW, ORPT, ORPW, OSNW, and OSPW
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Honeybees, Apis mellifera, play an important but often underappreciated role in our lives (Figure 60-1). Human beings rely on bees for pollinating approximately one-third of our crops, including numerous fruits, vegetables, nuts, and seeds.6,7 Of course, they also play a pivotal role in the propagation of other plants, flower nectar, and flower pollen. A. mellifera, the European honeybee, is the primary pollinator in Europe and North America but other species, including A. cerana, A. dorsata, A. floria, A. andreniformis, A. koschevnikov, and A. laborisa produce honey.8 Further, the honeybee is the only insect that produces food consumed by human beings.3
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Honey is a sweet food product produced by honeybees from flower nectar. It contains over 180 substances and is supersaturated in sugar, though it also contains phenolic acids, flavonoids, ascorbic acid, α-tocopherol, carotenoids, the enzymes glucose oxidase and catalase, organic and amino acids, and proteins.9 In Ayurvedic medicine, honey has been used to treat diabetes since ancient times.8 It has also been used for millennia to treat infected wounds.10 For dermatologic purposes, honey has and continues to be used in Ayurvedic medicine to treat acne, and is also used in cosmetic formulations such as facial washes, skin moisturizers, and hair conditioners.8
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Propolis is a yellowish-green to dark brown resinous material that originates in the buds and barks of various plant sources, mostly poplar trees,1,11,12 and is gathered by honeybees and used in the construction and maintenance of their hives.13,14 The sources of propolis can vary widely by region and even season, however. In all cases, propolis, used to seal holes and trap predators, stabilizes bee hives and honeycombs and protects bees against cold weather and potential intruders.11 Also known as bee glue, this extract from bee hives has been used for hundreds of years in naturopathic medicine and is known to display biologic and pharmacologic properties. In traditional medicine, it has been used for its purported antioxidant, anticancer, anti-inflammatory, and immunomodulatory effects.15 Currently, some radiation therapists use propolis to treat actinic stomatitis and mucositis,11 but this bee product is used more often for wound care and minor cutaneous indications as well as a dietary supplement. It is believed to contain as many as 300 constituents, including resin, wax, essential oils, pollen, and organic substances such as phenolic acids and their esters, particularly caffeic acid phenethyl ester (CAPE), flavonoids, terpenes, β-steroids, aromatic aldehydes and alcohols, sesquiterpenes, and stilbene terpenes.1,9
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Royal jelly, a yellowish, viscous secretion from the hypopharyngeal and mandibular glands of worker bees that nourishes bee larvae of all kinds (i.e., drones, workers, queens) after which it becomes the exclusive nourishment for queens throughout their development, has been used by humans for centuries for its health-promoting characteristics.16–18 Antitumor, antihypercholesterolemic, antibacterial, anti-inflammatory, antioxidant, antiangiogenetic, collagen production-promoting, estrogenic, hypotensive, immunomodulatory, vasodilative, and wound-healing activity have been linked to royal jelly.9,18–22
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Honey, propolis, and royal jelly have all been used for medicinal purposes since ancient times, with honey, the earliest bee product discovered, particularly known for its use in wound healing.3,9,11,12,14,23,24 In fact, the topical application of honey for various conditions has been a common traditional medical practice for at least 2,700 years, which many researchers have retrospectively attributed to its antibacterial properties.3,25 Of course, the antiseptic and antimicrobial properties of honey are recent discoveries,3 with the antibacterial properties of honey reported in 1892 (as cited by Dustmann in 1919).26
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In folk remedies, honey has served as a potent anti-inflammatory and antibacterial agent and its use dates back to ancient Egypt [it was even found in the tomb of King Tutankhamun (better known as King Tut)], Greece, and Rome, with the bee products mentioned in writings in Egypt, India, and China dating back to 5500 BCE.3,11,12,27,28 Honey has been used in Ayurvedic medicine for at least 4,000 years.3 The use of honey to treat wounds was practiced in China during the Xin dynasty (circa 2000 BCE), and ancient physicians (the Greeks Hippocrates and Dioscorides, Romans Celsus and Galen, and Arabs El Mad Joussy and El Basry) are said to have cited the healing qualities of honey.3 Abu Ali bin Sina (Latinized as Avicenna), a leading Persian doctor and scholar circa 11th century CE, wrote of using cooked honey and myrrh to decrease exudates from wounds contributing to partial tissue loss.1,29 More recent uses of honey in medicine hewed to wound treatment, including gunshot wounds in the 17th and 18th centuries (it was an official drug in London pharmacopoeias in the 17th century)5,30 and through World War I usage by the Russians and Germans.29,31,32 Not until the discovery of antibiotics in the 1940s did the traditional medical use of honey begin to wane.29,33
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The word “propolis” is derived from the Greek words pro (before) and polis (city), which reflects the ancient observation that bees built walls of the substance near the entrance of their hives.5,12,14,34,35 It was considered the third natural product of bees (in addition to honey and wax). Ancient Egyptians, making use of the antiputrefactive activity of bee glue, used propolis to embalm their dead.34,35 The Greek philosopher Aristotle wrote about the basic characteristics of propolis in his work Historia Animalium over 2,000 years ago, with recordings of its use dating back to at least 300 BCE; its use in medical applications was covered by Alexander of Tralles in the 6th century CE.11,14,34
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Propolis has been used for centuries in folk medicine in Europe, the Americas, China, and Japan.1 In traditional medicine, propolis was most successful in treating a wide range of wounds because of its antiedematous and anti-infectious properties. Propolis was also used in the ancient world for muscle, tendon, and joint pain. In addition, bee glue was used to treat cutaneous conditions such as lichens and condylomata.11 In more recent times, propolis was used to treat wounds during the Anglo-Boer war between 1899 and 1902 as well as World War II, and was an accepted medical ingredient in the former Soviet Union as recently as 1969.1 Other indications have included burns, sore throat, and stomach ulcers.36 In fact, propolis has continued to be a popular therapeutic choice in the Balkan countries of Southeast Europe for these indications and it is marketed in some European countries for the treatment of prostate hyperplasia.37
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Modern studies of the medicinal benefits of propolis are traced to Stan Scheller in 1960s Poland, where the study of its biological characteristics by way of a novel approach to delivering hydrophobic ethanol extracts of propolis into aqueous solutions led to the identification of antioxidant, antibacterial, immunostimulating, and radioprotective qualities.38
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The “queen substance” 9-oxo-2-decenoic acid (9-ODA), a queen honeybee pheromone, was isolated from queen honeybee mandibular glands by Butler et al. in 1961.39,40 Johnston et al. found in 1965 that this minor component of royal jelly rapidly metabolizes into 9-hydroxy-2-decenoic acid (9-HDA), a precursor to royal jelly that stabilizes swarm activity.39,41,42 Royal jelly is now used in cosmetics, dietary supplements, and beverages. Particularly in Asia, it is deployed as a health tonic.17,43 Royal jelly has also exhibited effectiveness in alleviating chilliness in young women.44.
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The myriad biological functions associated with honey (e.g., antibacterial, antioxidant, antitumor, anti-inflammatory, antibrowning, and antiviral), propolis (e.g., antitumor, antioxidant, antimicrobial, anti-inflammatory, and immunomodulatory), and royal jelly (e.g., antibacterial, anti-inflammatory, vasodilative, hypotensive, disinfectant, antioxidant, antihypercholesterolemic, and antitumor) are chiefly ascribed to the plethora of phenolic compounds, such as flavonoids, found in these bee products (Table 60-1).9 The flavonoid chrysin is present in honey and propolis and is thought to play a key role in conferring anti-inflammatory activity.9
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Honey itself contains carbohydrates, proteins, 18 free amino acids (of which proline is the most abundant), vitamins (trace amounts of B2, B4, B5, B6, B11, and C), minerals (e.g., calcium, chromium, iron, magnesium, manganese, phosphorus, potassium, selenium, and zinc), antioxidants (primarily flavonoids, including pinocembrin, which is found only in honey and propolis), enzymes (e.g., invertase, amylase, glucose oxidase, catalase, and acid phosphorylase), as well as acetic, butanoic, citric, formic, gluconic, lactic, malic, pyroglutamic, and succinic acids.8,45,46 Medical-grade honeys such as manuka honey (a monofloral honey derived from Leptospermum scoparium, a member of the Myrtaceae family, native to New Zealand) and Medihoney® (a standardized mix of Australian and New Zealand honeys mainly originating from Leptospermum species) are rich in flavonoids.45,47–49 Honey exhibits a pH ranging between 3.2 and 4.5, an acidity level that hinders the growth of many microorganisms.29,50–52
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Propolis is a complex mixture of partially digested resins from trees and bees wax, containing approximately anywhere from 50 to 300 constituents including balsams, resins, waxes, essential oils, pollen, cinnamyl alcohol, flavonoids, minerals (e.g., calcium, copper, iodine, iron, magnesium, manganese, potassium, sodium, and zinc), as well as vitamins A, B (B1, B2, B6), C, and E.1,53 Interestingly, Tsai et al. have shown that while propolis acts as an antioxidant, it can also induce oxidative DNA damage by producing hydrogen peroxide (H2O2). But they note that propolis-treated cells display a lower level of DNA damage when challenged with another oxidative compound (e.g., amoxicillin). They concluded that this adaptive response may play a role in the beneficial results associated with propolis.4 Overall, propolis is thought to confer significant antioxidant activity. Phenolic compounds (particularly vanillic, coumaric, rosmarinic, chlorogenic, caffeic, and ferulic acids) and flavonoids such as quercetin are thought to account for these propolis properties, which has been found, according to in vitro and in vivo studies, to protect skin against ultraviolet (UV)-induced damage.1,35,54–58
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Royal jelly, which bees produce from pollen, contains water, proteins (82–90 percent of which are known as the major royal jelly proteins, with five primary members), lipids, sugars, carbohydrates, free amino acids, vitamins, and minerals.8,9,19 Its primary unsaturated fatty acid is 10-hydroxy-2-decenoic acid (10-HDA), which is uniquely found in royal jelly.59 The benefits to human health associated with royal jelly can be partly attributed to the activity of constituent lipids, primarily aliphatic free fatty acids and few esters, which render the royal jelly emulsion highly acidic and therefore able to impart antimicrobial properties.8 These royal jelly components are considered to function in ways that protect against skin aging, modulate the immune system, potentially thwart cancer development, induce neurogenesis, and alleviate symptoms of menopause.16
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Honey is the oldest sweetener and one of the oldest foods consumed by humans, having been in popular usage in the diet throughout the world for thousands of years. It never spoils and was even found in edible condition in King Tut’s tomb.45 The preservative qualities of honey have been attributed to its antioxidant properties.58 Darker honeys (such as buckwheat) are associated with greater antioxidant activity.58
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Propolis is extensively used in food and beverage products to boost human health.1,60 In 1995, the National Food Institute of Argentina recognized propolis as a dietary supplement.1 It is typically available in capsule form.
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In 1990, Fujii et al. found that orally administered royal jelly exhibited anti-inflammatory activity and wound-healing capacity in streptozotocin-diabetic rats,61 a result supported by more recent findings.62 For instance, in 2003, Taniguchi et al. found that the oral administration of royal jelly hinders the development of atopic dermatitis-like skin lesions in mice.63
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In over-the-counter cosmetic formulations, honey is used primarily as a moisturizing agent and in hair conditioning products because it has strong humectant properties. It is also used in home remedies for burns, wounds, eczema, and dermatitis, particularly in Asia.8
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Propolis has been shown to have several potential topical dental applications worthy of investigation. In a study of the histological effects of propolis topically applied to dental sockets and skin wounds in rats, a 10 percent hydroalcoholic solution of propolis or a 10 percent hydroalcoholic solution alone were compared. Examination of cutaneous wound healing and the socket wound after tooth extraction revealed that topical application of the propolis hydroalcoholic solution accelerated epithelial repair but had no effect on socket wound healing.64 Propolis has also been found to be effective in treating aphthous ulceration.65–67
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There are several commercially available products such as lotions, creams, shampoos, lipsticks, toothpastes, and mouthwashes, as well as cough syrups, lozenges, and vitamins that contain propolis as an active ingredient.
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In 2010, Majtan et al. showed that incubation with honey activated human keratinocytes to increase production of mediators including cytokines [tumor necrosis factor-α, interleukin (IL)-1β, and transforming growth factor (TGF)-β1] and matrix metalloproteinase (MMP)-9. In addition, they demonstrated that this increased amount of epidermal MMP-9 facilitated the degradation of collagen type IV in the basement membrane, buttressing the notion that honey has the capacity to accelerate wound healing.24
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A 2013 systematic literature review of honey in contemporary wound care included 55 studies revealing that honey does appear to stimulate healing of burns, ulcers, and other wounds. The authors were hesitant to draw many broad conclusions due to methodological concerns, but found that honey displays antibacterial activity in burn treatment and also exerts deodorizing, debridement, anti-inflammatory, and analgesic activity.29 However, a search of the Cochrane Wounds Group Specialized Register, the Cochrane Central Register, Ovid Medline, Ovid Embase, and EBSCO CINAHL completed earlier that year of 25 randomized and quasi-randomized trials assessing honey in the treatment of acute or chronic wounds found that honey might delay healing in partial- and full-thickness burns compared to early excision and grafting, and it does not significantly enhance healing of chronic venous leg ulcers.68 The authors suggested that while honey may, indeed, prove to be more effective than some conventional dressings, there is insufficient evidence to support this claim.
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Propolis has also been found to exert a wound-healing effect. In 2002, Pachalski et al. assessed the use of propolis in treating the skin of the stumps of 156 patients rehabilitating after lower limb amputation (55 upper leg and 101 lower leg). Patients were treated twice daily with 4 percent propolis ointment for seven days. Treatment was extended to 14 days in cases of unsatisfactory improvement within one week. Patients with upper leg amputations experienced slightly better results, though both groups exhibited the best outcomes with Staphylococcus infections. The investigators noted that topically applied propolis improves circulation, stimulates intracellular metabolism, and alters skin reactivity. They also concluded that propolis ointment is indicated for skin disorders on stumps and local trophic conditions.69
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Like its associated bee products, royal jelly has reportedly contributed to wound healing. In 2008, Abdelatif et al. conducted a pilot study to ascertain the safety and effectiveness of a new ointment combining royal jelly and panthenol (Pedyphar) in 60 patients with limb-threatening diabetic foot infections. By the end of week 9 and through six months of follow-up, 96 percent of the patients with full-thickness skin ulcers (Wagner grades 1 and 2) or deep tissue infection and suspected osteomyelitis (grade 3) responded well, with all grade 1 and 2 ulcers healing and 92 percent of grade 3 ulcers healing. All patients with gangrenous lesions (grades 4 and 5) healed after surgical excision, debridement, and conservative treatment with the royal jelly/panthenol formulation [see Chapter 27, Vitamin B5 (Pantothenic Acid/Dexpanthenol)]. The investigators suggested that more double-blind, randomized controlled studies are required to confirm their promising findings that the royal jelly/panthenol combination is safe and effective.70
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Suemaru et al. compared the effects of topically applied honey, propolis, and royal jelly on 5-fluorouracil (5-FU)-induced experimental oral mucositis in hamsters. The size of the lesions was not diminished by the use of honey (1, 10, and 100 percent) or propolis (0.3, 1, and 3 percent) in comparison to the Vaseline-treated control group. Royal jelly ointments (3, 10, and 30 percent) dose-dependently led to significant improvements and healing, suggesting its possible use in treating chemotherapy-induced moral mucositis in humans.71 More recently, several of the same investigators furthered their study of royal jelly and its effects on 5-FU-induced oral mucositis in hamsters. Chitosan-sodium alginate film containing royal jelly was used to achieve healing. These films (10 and 30 percent) significantly ameliorated the damage caused by 5-FU, decreasing myeloperoxidase activity and proinflammatory cytokine production. In addition to such anti-inflammatory effects, the investigators noted that royal jelly displayed antioxidant activity. They attributed the healing effect from severe oral mucositis to the anti-inflammatory and antioxidant properties of royal jelly.72
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In 2010, Kim et al. treated freshly scratched normal human dermal fibroblasts with different concentrations of royal jelly (0.1, 1, or 5 mg/mL) for up to 48 hours. They found that fibroblast migration peaked at 24 hours after wounding and that royal jelly significantly and dose-dependently accelerated the migration at the eight-hour mark. In addition, various lipids in fibroblasts involved in the wound-healing process were influenced by royal jelly treatment, with the cholesterol level lowered and sphinganines increased.62
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The following year, Siavash et al. conducted a small study of eight patients to assess the efficacy of topically applied royal jelly in the treatment of diabetic foot ulcers. Of the eight ulcers treated, seven healed, with a mean healing duration of 41 days. The eighth ulcer improved, with significant reductions in size. The investigators concluded that a royal jelly dressing appears to be an effective alternative treatment option for diabetic foot ulcers.73 However, in 2013, Siavash et al. assessed the efficacy of topical royal jelly on diabetic foot ulcers in a double-blind placebo-controlled clinical trial of 25 patients (6 females, 19 males). The 60 ulcers considered in the final analysis were treated with either 5 percent sterile topical royal jelly or placebo. They found no significant differences in the regimens.21
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Koya-Miyata et al. have demonstrated that royal jelly fosters collagen production by skin fibroblasts in the presence of ascorbic acid-2-O-α-glucoside (AA-2G) and that its primary fatty acid constituent 10-HDA promotes the synthesis of collagen by AA-2G-treated fibroblasts by initiating the production of TGF-β1 production.20
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Seborrheic Dermatitis/Dandruff
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In 2001, Al-Waili completed a study in 30 patients (20 males, 10 females aged 15 to 60 years) with chronic seborrheic dermatitis of the scalp, face, and chest to evaluate the potential of topically applied crude honey (90 percent honey diluted in warm water). Treatment over a four-week period consisted of gentle rubbing of the ointment for two to three minutes onto lesions every other day, leaving honey on for three hours before gentle warm water rinsing. A six-month prophylactic phase split the group evenly into a once-weekly treatment group and a control group. Honey application yielded further marked improvements, with itching and scaling resolved within the first week. Within two weeks, skin lesions healed completely. Patients also reported subjective improvement in hair loss. Whereas no patients treated with honey experienced relapse, 12 of the 15 patients in the control group experienced relapse within two to four months of initial treatment cessation. The author concluded that weekly use of crude honey delivers significant improvement in seborrheic dermatitis and related hair loss.74
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Subsequently, Al-Waili et al. conducted a review of the antimicrobial activity of honey, finding topical effectiveness in the treatment of adult and neonatal postoperative infection, boils, burns, infected and nonhealing wounds and ulcers, necrotizing fasciitis, pilonidal sinus, diabetic foot ulcers, as well as venous ulcers.76 Internally, honey lowers prostaglandin levels while raising nitric oxide levels, and displays anti-inflammatory and prebiotic activity.75
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Allergic reactions to honey, propolis, and royal jelly have been reported.76,77 Propolis is relatively innocuous, though.34 A no-effect level (NOEL) of 1,400 mg/kg body weight/day was found in a 90-mouse study on propolis.14 Some cases of allergic contact dermatitis as well as allergic contact cheilitis to propolis in humans have been reported.53,78–81
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Royal jelly has been known to provoke an anaphylactic response in some people.17,82 Asthmatic and anaphylactic reactions to the ingestion of royal jelly have been found to be true IgE-mediated hypersensitivity reactions.83 Contact dermatitis has also been reported in reaction to topical royal jelly.84 Indeed, although royal jelly has been linked to broad health benefits, such as promoting growth in children, improving general health, and enhancing longevity, adverse reactions ranging from contact dermatitis, acute asthma, anaphylaxis and even death have been linked to its use.85
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A 1997 cross-sectional survey of 1,472 hospital employees in Hong Kong conducted by Leung et al. revealed that 461 subjects (31.3 percent) had taken royal jelly in the past. Adverse reactions to royal jelly, including urticaria, eczema, rhinitis, and acute asthma, were reported by nine subjects. Skin tests were conducted on 176 questionnaire respondents (13 of whom had a positive skin test to pure royal jelly) and 300 consecutive asthma clinic patients (23 of whom had positive skin tests). Thirty-five of the 36 participants with positive royal jelly skin tests were atopic to other common allergens.86 In a retrospective evaluation of common environmental allergens in adult asthmatic patients completed later that year in Hong Kong, many of the same investigators found that royal jelly was the fifth most common allergen associated with positive skin tests (after Dermatophagoides pteronyssinus, D. farinae, cockroaches, and cat dander).87
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In a 2008 study aimed at characterizing the major allergens of royal jelly, Rosmilah et al. identified major royal jelly protein 1 and major royal jelly protein 2 as the main allergens in royal jelly that affected the 53 human subjects with royal jelly allergy who were evaluated.85
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In 2013, Moriyama et al. assessed the hypoallergenicity of alkaline protease-treated royal jelly in vitro and in vivo. They demonstrated that the immunoglobulin E-binding capacity of the treated royal jelly was substantially diminished via in vitro assays of the blood from patients sensitive to royal jelly. In 75 percent of royal jelly-sensitive patients given a skin-prick test, royal jelly did not elicit an allergic reaction.17
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As stated above, human beings depend on bees to pollinate approximately one-third of our crops, including a large proportion of the produce that we consume. Among global agricultural crops, the European honeybee is the most economically valuable pollinator.88 A. mellifera also plays a significant role in maintaining biodiversity via pollinating several species of plants that need an obligatory pollinator to be fertilized.88 Notably, the antibacterial activities of bee products, especially honey and propolis, place bees at an even more potentially crucial position related to human health given the alarming global increase in antibiotic resistance among several bacterial strains. Indeed, Dr. Margaret Chan, director-general of the World Health Organization, has warned of the dangers of increasingly pervasive antibiotic resistance, referring to this insidious threat as the possible “end of modern medicine as we know it.”89
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Given that honey, in particular, has been exploited since ancient times for its antibacterial properties in treating infected wounds and is currently known to exhibit broad-spectrum effectiveness against antibiotic-resistant strains, this iconic bee product would appear to merit careful consideration and study, as would propolis, along with a concerted effort to stem the overuse, abuse, and misuse of antibiotics. However, the effects of “colony collapse disorder” – the decimation of bee populations – certainly loom as a substantial threat to further exploring a natural alternative to antibiotic resistance within our midst. The etiology of this bee colony disaster has recently become less mysterious, as the use of neonicotinoid pesticides in industrial agriculture appears to account for much of the devastating impact on honeybees, though calls for more larger studies persist.90,91 The European Commission has banned the use of three neonicotinoids based on such concerns.92 Colony collapse disorder is a global phenomenon,93 and poses significant worldwide risk to the produce on which human beings significantly rely. Regardless of the cause or causes, whether it is pesticide use or the parasitic Varroa mite,94 colony collapse disorder presents a significant existential impact on honeybees and, possibly, numerous other species including humans.
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The greater environmental impact related to bee products, then, is not in the harvesting and processing of these products themselves but, rather, from the marked strains that human industry places on the very existence of the honeybee. We quite possibly continue the use of neonicotinoid pesticides, now believed to have a pernicious effect on bees,95 and overuse of antibiotics for livestock96 at our own peril.
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FORMULATION CONSIDERATIONS
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Geographical location, pollen source, climate, environmental conditions, season during collection, genetic factors, and the processing methods it undergoes influence honey composition and quality.9,33 Because honey is readily contaminated through processing, medical grade honey is sterilized through γ-radiation, which destroys various microorganisms without compromising the compound’s antibacterial activity.29,46,97–100
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Like honey, the collection location, time, and plant source affect propolis quality, chemical composition, and biologic activity, thus there is great variability in these products.1,35,101,102 However, because of the unique ecosystems in which different honeybees live and the variety of plant sources from which bees collect ingredients, propolis does not have a specific chemical connotation or formula.35 Given the potential for its use as a topical agent because of its antioxidant capacity, Marquele-Oliveira et al. found in 2007 that propolis formulations prepared with Polawax exhibited functional and physical stability in percutaneous studies in pig ear skin and hairless mouse skin as well as an in vivo study that indicated the viability of the formulation in protecting human skin from UVB photodamage.103
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Dosage and safety are among the greatest challenges of using bee products for medical purposes.23 Honey and royal jelly processed into formulations for wound care first pass through fine filters that remove the majority of pollen and other impurities. Some viable spores, such as clostridia, may be included in honey.23 Bacterial sensitivity to bee products is influenced by the botanical origin of the product and there is significant variability in bacterial sensitivity to bee products.23
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Honey that is not medical grade is liable to contain viable bacterial spores (including clostridia), and may also exhibit less predictable antibacterial properties.10 Several countries have approved of the use of medical-grade honey (e.g., manuka, Medihoney) and numerous brands of sterile, irradiated, antibacterial topical honey preparations are available.10,33,104,105
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Royal jelly is used in cosmetics, dietary supplements, and beverages. Particularly in Asia, it is deployed as a health tonic.43
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SIGNIFICANT BACKGROUND
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Manuka honey and Medihoney are the primary forms of honey used in clinical practice. Propolis is one of the most copious sources of polyphenols, particularly flavonoids and phenolic acids, some of the most potent antioxidants yet discovered.106,107
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In 2005, a study by Marquele et al. of Brazilian propolis extracts alone and in topical pharmaceutical formulations revealed that the antioxidant activity of the extracts was maintained in the topical products. The bee glue was particularly active against the superoxide radical.108
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A 2006 study using New Zealand white rabbits revealed that topical propolis exhibited antioxidant, anti-inflammatory, and antibacterial activity against Staphylococcus aureus keratitis.109
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In 2009, Nakajima et al. compared the antioxidant effects of various bee products, specifically Brazilian green propolis, water-soluble royal jelly, and a bee pollen ethanol extract against H2O2, superoxide anion, and hydroxyl radicals. They found water extracts of propolis to have the greatest potency, followed by ethanol extracts of propolis, and pollen. Royal jelly had no effects. Of the primary constituents of propolis, caffeic acid displayed the greatest antioxidant activity, followed by artepillin C, and drupanin.110 Also that year, Izuta et al. found that Brazilian green propolis and Chinese red propolis and their components (CAPE and caffeoylquinic acid derivatives) acted as potent scavengers of the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical.111
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Recent chemical analyses of Algerian propolis indicated a high content of polyphenols and diterpenes from samples in various north Algerian regions. Using the DPPH assay, Piccinelli et al. found that the polyphenol-rich samples of propolis exhibited potent antioxidant activity.112
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In addition, propolis has been shown to lower oxidative stress, altering catalase, malondialdehyde, and nitric oxide levels, in Nω-nitro-L-arginine methyl ester (1-NAME)-induced hypertension in rats, suggesting a modulatory impact on the antioxidant system.113
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A 2010 study by Cole et al. showed that Sydney propolis significantly and dose-dependently protected mouse skin against edema, immunosuppression, and lipid peroxidation. The investigators concluded that Sydney propolis has the potential to protect human skin against UV-induced skin cancer and other photodamage.114
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In 2011, Fonseca et al. showed that green and brown propolis extracts, with varying composition and properties, both effectively prevented UV-induced glutathione depletion in vivo. Oral administration of extracts in hairless mice yielded a higher recovery of glutathione, after reductions caused by UV exposure, in the green propolis group (30 percent vs. 22.8 percent). Topical propolis pretreatment before UV exposure netted a 14 percent recovery in both groups. The investigators concluded that both green and brown propolis extracts are promising agents for combating oxidative stress in skin.55
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In 2013, Bolfa et al. studied the wide-ranging effects of a Romanian propolis topically applied in two concentrations (3 mg and 1.5 mg polyphenols/cm2) before or after UVB exposure in a Swiss mouse model. Both concentrations significantly decreased malondialdehyde formation and IL-6 levels while restoring the activity of glutathione peroxidase. Epidermal hyperplasia and dermal inflammation were diminished with the smaller concentration, with only dermal inflammation reduced by pretreatment with the larger concentration. Romanian propolis also decreased sunburn cell formation and exhibited an antigenotoxic effect by significantly attenuating cyclobutane pyrimidine dimer formation. In light of the antioxidant, anti-inflammatory, antiapoptotic, and antigenotoxic properties manifested in their study, the investigators concluded that Romanian propolis provides significant photoprotection in the mouse model and warrants consideration as a chemopreventive agent for mitigating several UVB-induced cutaneous signaling pathways.108 Also that year, Moniruzzaman et al. found that two Malaysian honeys, longan and sourwood, are good sources of antioxidants as compared to other rubber tree and manuka honeys.115
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Antimicrobial and Anti-inflammatory Activity
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Potent antibacterial activity is exhibited by honey, propolis, royal jelly, as well as bee venom, with even epidemic strains of methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin-resistant Enterococcus (VRE) showing sensitivity.23 Among the bee products, propolis has shown the greatest antibacterial activity,23 though clinical trials and laboratory data suggest that honey acts as an effective broad-spectrum antimicrobial agent.3,76 These wide-ranging functions are thought to be derived from its acidity; bacteriostatic, bactericidal, and antioxidant constituents (i.e., H2O2, antioxidants, lysozyme, polyphenols, phenolic acids, flavonoids, methylglyoxal, and bee peptides); osmotic effect; high sugar concentration; induction of cytokine release; as well as immunomodulatory and anti-inflammatory activity.3,76
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In a 2008 evaluation of medical grade honey (Revamil), Kwakman et al. found that within 24 hours 10 to 40 percent (vol/vol) honey eradicated antibiotic-susceptible and -resistant isolates of Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecium, Escherichia coli, Pseudomonas aeruginosa, Enterobacter cloacae, and Klebsiella oxytoca. They also noted a 100-fold decline in forearm skin colonization in healthy volunteers after two days of honey application, with the number of positive skin cultures falling by 76 percent. The investigators concluded that the topical antimicrobial honey agent Revamil displays significant potential to prevent or treat infections, including those engendered by multidrug-resistant bacteria.25 It is worth noting that honey is known to suppress 150 bacteria species, including clinical strains of MRSA and VRE, with no reports of microbial resistance.10 In fact, honey has been shown to be clinically effective in treating various kinds of wound infections, reducing skin colonization of several bacteria (including MRSA),25 and accelerating wound healing, without provoking adverse effects.10 A 2009 report by Blair et al. supports the notion that medical-grade honey has the potential to lessen the strain caused by the emergence of antibiotic-resistant bacteria.116
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In 2000, Vynograd et al. evaluated propolis for efficacy in the treatment of recurrent genital herpes simplex virus type 2. Ninety adults, all with local symptoms, participated in a randomized, single-blind, masked investigator, controlled study at seven medical centers in which Canadian propolis ointment containing natural flavonoids was compared with ointments of acyclovir and placebo, with 30 people randomized to each group. Study ointments were applied four times daily. Participants were examined on the 3rd, 7th, and 10th days of treatment for clinical symptoms, including the number and size of herpetic lesions, with lesions classified into four stages: vesicular, ulcerated, crusted, and healed. On Day 3, 15 members of the propolis group had crusted lesions as opposed to eight in the acyclovir group and none on placebo. Local symptoms were noted in three propolis group members, eight acyclovir individuals, and nine on placebo. On Day 7, healing was observed in 10 propolis patients, four acyclovir patients, and three in the placebo group. Investigators reported that 24 propolis patients and 14 acyclovir patients had healed by Day 10. Overall, the propolis ointment was considered more effective in healing lesions and reducing local symptoms.117 In an earlier study of 65 patients, a topical ointment containing propolis, Nivcrisol-D, showed a significant therapeutic effect against recurrent herpes and zona zoster, with patients using the study drug healing from outbreaks in an average of four days while patients using placebo took an average of eight days to heal from outbreaks.118
++
In 2002, Gregory et al. assessed the purported antimicrobial, anti-inflammatory, and scar-healing capacity of a high-grade Brazilian propolis cream. Patients presenting with bilateral superficial second-degree burns over less than 20 percent of their body surface, with wounds of similar depth and quality, were admitted into the study within 48 hours of their injuries and then treated with propolis cream on one wound and silver sulfadiazene applied to a similar one on the other side. Wounds were debrided and dressings changed on the following morning. Patients returned to the clinic at three-day intervals to have their wounds checked and dressings changed, with reapplication of the ointment taking place only at these visits. In addition, investigators cultured the wounds for microbial growth and took photographs to record inflammation and scar formation. No significant differences were noted in microbial colonization, but wounds treated with the propolis cream showed less inflammation and quicker scar formation as compared to the silver sulfadiazene-treated burns. While noting the beneficial effects of propolis on burns, the researchers speculated that more frequent changing of wound dressings would have evinced antimicrobial results also.119
++
Omani propolis has been found to differ from many known propolis types, as it is derived from the resin of Azadiracta indica (neem tree), Acacia spp. (most probably A. nilotica) and Mangifera indica. However, like many other forms of propolis, the Omani variety contains biologically active phenolic compounds (e.g., prenylflavanones, cardols, and anacardic acids) and has exhibited antimicrobial activity.36
+++
Activity Against Pruritus and Xerosis
++
In 2011, Duplan et al. assessed the activity of a synthetic counterpart to 10-HDA in several experiments (in vitro, ex vivo, and in vivo) aimed at characterizing its potential use in treating UV-induced xerosis. Hydroxydecine® induced involucrin, transglutaminase-1, and filaggrin protein production in normal human keratinoctyes and yielded increases in these compounds in topical treatment of skin equivalents. In healthy volunteers with UV-induced xerosis, Hydroxydecine cream use led to an increase of 28.8 percent in the hydration index after seven days and 60.4 percent after 21 days of treatment. In the ex vivo findings in a model of inflammation and barrier impairment involving human skin explants maintained alive, the formulation restored skin barrier function and lessened inflammation. The investigators concluded that the synthetic version of 10-HDA also displayed efficacy in activating keratinocyte differentiation in vitro as well as in vivo in hydrating dry human skin.60
++
In 2013, Yamaura et al. examined an experimental allergic contact dermatitis model in hairless mice to ascertain the antipruritic activity of topical royal jelly on chronic pruritus. They found that five weeks of treatment with topical royal jelly (0.01 or 1 percent) and 0.01 percent β-methasone significantly alleviated chronic pruritus induced by five weeks of repeated application of 2,4,6-trinitro-1-chlorobenzene. The level of nerve growth factor mRNA in back skin was elevated in mice with contact dermatitis, lower in those treated with β-methasone, and unchanged in mice treated with royal jelly. The investigators acknowledged the likely different mechanisms of action between royal jelly and β-methasone in suggesting that royal jelly may be a useful ingredient in cosmetics for easing chronic pruritus.43
+++
Anticarcinogenic Activity
++
Various components of propolis have also been isolated and found to possess anticarcinogenic properties. Flavonoid aglycones are some of the significant constituents of propolis that are believed to contribute to antitumorigenic activity.13 A study with a fractionated methanol extract of a Brazilian propolis resulted in the isolation of a tumoricidal substance characterized as a new clerodane diterpenoid, which reduced the growth and number of skin tumors induced by 7,12-dimethylbenz(a)anthracene (DMBA) application on mouse back skin by inhibition of DNA synthesis.13
++
In a study to determine whether CAPE, a propolis constituent, inhibits the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced processes associated with carcinogenesis, low doses of CAPE were topically applied to SENCAR mice. CAPE was found to strongly inhibit several TPA-mediated oxidative processes considered sine qua non for tumor promotion, including: polymorphonuclear leukocyte infiltration into mouse skin and ears; H2O2 production; and formation of oxidized bases in epidermal DNA. In addition, researchers noted inhibition of edema and ornithine decarboxylase induction in CD-1 and SENCAR mice after CAPE application, as well as the inhibition of TPA-induced H2O2 production in bovine lenses. Researchers concluded that CAPE appears to have potent chemopreventive capacity, particularly in treating disorders associated with strong inflammatory and/or oxidative stress processes, such as cancer and cataracts.27
++
In a different study on skin tumors, CD-1 mice were initiated with DMBA and then treated twice weekly with topically applied TPA, resulting in 18.8 skin papillomas per mouse. Subsequent topical application of CAPE to the backs of the mice together with TPA twice a week for 20 weeks inhibited the number of skin papillomas and reduced tumor size in a dose-dependent manner. The same combination also decreased the level of 5-hydroxymethyl-2′-deoxyuridine (HMdU) in epidermal DNA produced through the previous initiation with DMBA. In addition, in vitro CAPE introduction to cultured HeLa cells inhibited DNA, RNA, and protein synthesis. All of these inhibitory effects conferred by CAPE were deemed by investigators to be potent.120
++
In a 2004 study on polyphenolic compounds and antitumorigenic properties, a water-soluble derivative of propolis, caffeic acid, CAPE, and quercetin administered to mice resulted in a reduction in the number of lung tumor nodules. Researchers related the antitumor properties of the tested substances to their immunomodulatory capacity, cytotoxicity to tumor cells, and ability to induce apoptosis and necrosis, suggesting that propolis, caffeic acid, CAPE, and quercetin show promising potential for combating tumor growth.121
++
In 2011, Watanabe et al. found that propolis appears, in vitro and in vivo, to act against various tumor cells, suggesting its possible role in future anticancer drugs.15
++
In 2011, Park et al. measured the 10-HDA content of royal jelly and investigated its effects on UVB-induced skin photoaging in normal human dermal fibroblasts. The tested royal jelly (0.211 percent 10-HDA) led to increased synthesis of procollagen type I and TGF-β1, without altering MMP-1 levels. The researchers concluded that due to its potential to spur collagen production, royal jelly could be used to protect the skin against UVB-induced photoaging.122 Park et al. followed this work up the following year, finding that the synthesis of type I collagen in the dorsal skin of ovariectomized Sprague-Dawley rats was augmented by the dietary supplementation of 1 percent royal jelly extract. Although MMP-1 levels were again unchanged, the investigators suggest that royal jelly may provide an antiaging benefit by virtue of enhanced collagen production alone.19
++
In 2013, Zheng et al. studied the protective effects of the royal jelly fatty acid component 10-HDA against UVA-induced damage in human dermal fibroblasts and its inhibitory effects on UVA-induced MMP expression. They found that 10-HDA significantly protected the fibroblasts from UVA-induced cytotoxicity, reactive oxygen species, and cellular senescence. In addition, 10-HDA hindered the UVA-generated expression of MMP-1 as well as MMP-3, and stimulated the production of collagen. Activation of the c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) pathways was also diminished due to 10-HDA treatment. The investigators concluded that this royal jelly fatty acid exhibits potential for use in the prevention and treatment of cutaneous photoaging.22
++
In 2013, Angelo et al. demonstrated that the addition of propolis protected L. angustifolia (lavender) essential oil from UV-induced degradation and preserved its antioxidant capacity in cell oxidative damage assessments on B16–F10 melanoma cells as well as in vitro antioxidant assays. The investigators concluded that propolis may act as an efficient UV-protective and antiradical adjuvant to sunscreens, cosmetics, and other products that contain plant extracts (see Chapter 73, Lavandula).123
++
Skin-lightening indications may also be a viable use for royal jelly. Han et al. found that royal jelly dose-dependently suppressed melanin biosynthesis in the B16-F1 mouse melanocyte cell line by lowering tyrosinase activity. Further, royal jelly decreased mRNA levels of tyrosinase. The researchers concluded that royal jelly merits consideration for inclusion as a therapeutic agent in new skin-whitening products.18
++
Honey, propolis, and royal jelly, all bee products with a long history of traditional medicinal use, have been found to exhibit sufficient biologic activity to warrant consideration in modern medicine. The antibacterial activity of these products is legendary, and the wide array of additional biologic activities, particularly their antioxidant capacity, suggest broad potential for these agents, meriting greater attention and study for dermatologic application. Indeed, more research, in the form of randomized, controlled trials, is needed prior to incorporating bee products into the armamentarium as first-line therapies, but the potential seems vast.
++
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