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) | 1 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 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] |
| 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-γ compared 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, IκB and NF- κB. 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 µL 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: 1 µg/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-α in BV 10 and 100 and TSLP in BV 100 group compared with PC (p < 0.05). |
[50] |
| 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: 1 µg/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-α was 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] |
| 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-α and IL-1β were significantly suppressed in skin tissue by BV treatment. BV inhibited activation of NF- κB, 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] |
| Wound | 7-week male HR-1 mice wounded on back (n = 30) | BV (Apis melifera) | 1 µg/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.