To evaluate purified honey bee (
) venom (HBV) biotherapy for the treatment of osteoarthritis (OA) knee pain and physical function.
Five hundred and thirty-eight patients with Kellgren/Lawrence grade ...1-3 radiographic knee OA and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score ≥2 were randomized 1:2 to either control ("histamine") or HBV in this double-blind study.
After a dose escalation period, patients received 12 weekly dermal injections of control ("histamine") or HBV. At each of the 12 weekly visits, a set of 15 dermal injections (each containing 2.75 μg histamine or 100 μg HBV) were administered at prespecified acupuncture points (5 on each knee: knee top, eye-1 medial, eye-2 lateral, ST 34, BL 40 and 5 near the spinous processes: BL 19, 21, 23, 25, and 27).
Assessments included WOMAC pain and physical function subscales, visual analog scale (VAS), patient global assessment (PGA), and physician global assessment (PhGA). Rescue medication use (acetaminophen) and routine safety parameters were monitored.
HBV biotherapy demonstrated a highly significant improvement over control in WOMAC pain score after 12 weeks (1.1 U mean difference; confidence interval 95% CI: 0.3-2.0; analysis of covariance ANCOVA
= 0.0010 with baseline as covariate) that was also sustained 4 weeks post-treatment. Furthermore, WOMAC physical function was significantly improved over control with HBV (3.1 U mean difference; 95% CI: 0.3-5.9; ANCOVA
= 0.0046), and sustained 4 weeks post-treatment. VAS scores were significantly improved with HBV versus control, as well as PGA and PhGA evaluations, which showed that patients responded more favorably ("very good/good") to their overall OA condition (82.0% vs. 62.4%
= 0.0001 and 82.1% vs. 54.9%
= 0.0015, respectively). Use of rescue acetaminophen was similar between the groups (77%-78% of patients). HBV was associated with higher incidence of injection site reactions (<5%); however, the overall safety profiles were comparable between the treatment groups.
This phase 3 trial demonstrated that HBV biotherapy resulted in significant improvements in knee OA pain and physical function.
Due to its great medical and pharmaceutical importance, honey bee venom is considered to be well characterized both chemically and in terms of biomedical activity. However, this study shows that our ...knowledge of the composition and antimicrobial properties of
venom is incomplete. In this work, the composition of volatile and extractive components of dry and fresh bee venom (BV) was determined by GC-MS, as well as antimicrobial activity against seven types of pathogenic microorganisms. One-hundred and forty-nine organic C
-C
compounds of different classes were found in the volatile secretions of the studied BV samples. One-hundred and fifty-two organic C
-C
compounds were registered in ether extracts, and 201 compounds were identified in methanol extracts. More than half of these compounds are new to BV. In microbiological tests involving four species of pathogenic Gram-positive and two species of Gram-negative bacteria, as well as one species of pathogenic fungi, the values of the minimum inhibitory concentration (MIC) and minimum bactericidal/fungicidal concentration (MBC/MFC) were determined for samples of dry BV, as well as ether and methanol extracts from it. Gram-positive bacteria show the greatest sensitivity to the action of all tested drugs. The minimum MIC values for Gram-positive bacteria in the range of 0.12-7.63 ng mL
were recorded for whole BV, while for the methanol extract they were 0.49-125 ng mL
. The ether extracts had a weaker effect on the tested bacteria (MIC values 31.25-500 ng mL
). Interestingly,
was more sensitive (MIC 7.63-500 ng mL
) to the action of bee venom compared to
(MIC ≥ 500 ng mL
). The results of the tests carried out indicate that the antimicrobial effect of BV is associated with the presence of not only peptides, such as melittin, but also low molecular weight metabolites.
Accidents with venomous bees are a serious worldwide health concern. Since the kidney has been reported as the main venom-target organ, the present study was undertaken to investigate the in vivo ...nephrotoxic effect of Algerian bee venom (ABV) (Apis mellifera intermissa) collected in the middle east of Algeria. A preliminary study was performed on ABV to identify the ABV using SDS-PAGE analysis and to determine the in vivo intraperitoneal median lethal dose (LD50) using the Probit analysis test. In vivo nephrotoxic effect was assessed through the determination of physiological and kidney biochemical markers in mice intraperitoneally injected with ABV at doses of 0.76 (D1); 1.14 (D2) and 2.29 mg/kg body weight (bwt) (D3), corresponding respectively to LD50/15, LD50/10, and LD50/5 (i.p. LD50=11.48 mg/kg bwt) for seven consecutive days. Results revealed a marked decrease in body weight gain and food intake, and an increase in absolute and relative kidney weights in ABV D2 and D3 treated mice compared with controls. Furthermore, ABV D2 and D3 resulted in a significant increase in serum creatinine, urea, and uric acid. ABV-induced oxidative stress was evidenced by a significant increase in kidney MDA level, and a significant depletion in kidney GSH level, and catalase activity. Meanwhile, no marked changes in the above-mentioned parameters were noticed in ABV D1. Accordingly, the adverse nephrotoxic effect of ABV was proved by the dose-dependent kidney histological changes. In summary, the results of the present study evidence that ABV at doses of 1.14 (D2) and 2.28 mg/kg body weight (bwt) can cause marked changes in kidney biochemical and major antioxidant markers, and histological architecture.
Allergy to bee and wasp venom can lead to life-threatening systemic reactions. The identification of the culprit species is important for allergen-specific immunotherapy.
To determine a panel of ...recombinant bee and wasp allergens which is suitable for the identification of bee or wasp as culprit allergen sources and to search for molecular surrogates of clinical severity of sting reactions.
Sera from eighty-seven patients with a detailed documentation of their severity of sting reaction (Mueller grade) and who had been subjected to titrated skin testing with bee and wasp venom were analyzed for bee and wasp-specific IgE levels by ImmunoCAPTM. IgE-reactivity testing was performed using a comprehensive panel of recombinant bee and wasp venom allergens (rApi m 1, 2, 3, 4, 5 and 10; rVes v 1 and 5) by ISAC chip technology, ImmunoCAP and ELISA. IgG4 antibodies to rApi m 1 and rVes v 5 were determined by ELISA and IgE/IgG4 ratios were calculated. Results from skin testing, IgE serology and IgE/IgG4 ratios were compared with severity of sting reactions.
The panel of rApi m 1, rApi m 10, rVes v 1 and rVes v 5 allowed identification of the culprit venom in all but two of the 87 patients with good agreement to skin testing. Severities of sting reactions were not associated with results obtained by skin testing, venom-specific IgE levels or molecular diagnosis. Severe sting reactions were observed in patients showing < 1 ISU and < 2kUA/L of IgE to Api m 1 and/or Ves v 5.
We identified a minimal panel of recombinant bee and wasp allergens for molecular diagnosis which may permit identification of bee and/or wasp as culprit insect in venom-sensitized subjects. The severity of sting reactions was not associated with parameters obtained by molecular diagnosis.
Cancer represents the disease of the millennium, a major problem in public health. The proliferation of tumor cells, angiogenesis, and the relationship between the cancer cells and the components of ...the extracellular matrix are important in the events of carcinogenesis, and these pathways are being used as targets for new anticancer treatments. Various venoms and their toxins have shown possible anticancer effects on human cancer cell lines, providing new perspectives in drug development. In this review, we observed the effects of natural toxins from bee and snake venom and the mechanisms through which they can inhibit the growth and proliferation of cancer cells. We also researched how several types of natural molecules from venom can sensitize ovarian cancer cells to conventional chemotherapy, with many toxins being helpful for developing new anticancer drugs. This approach could improve the efficiency of standard therapies and could allow the administration of decreased doses of chemotherapy. Natural toxins from bee and snake venom could become potential candidates for the future treatment of different types of cancer. It is important to continue these studies concerning therapeutic drugs from natural resource and, more importantly, to investigate their mechanism of action on cancer cells.
Bee venom (BV) is a complex natural toxin that contains various pharmaceutical compounds. Bee venom acupuncture (BVA), involving a BV injection into a certain acupuncture point, has been utilized to ...relieve a range of pain conditions. Regardless of whether pain is caused by disease or injury, if not effectively treated, pain can exert a detrimental effect on all aspects of life. In the past decade, many researchers have investigated the anti-nociceptive effects of BVA through clinical use and experimental evaluation. This report reviews the existing knowledge on the analgesic effects of BVA, focusing on musculoskeletal pain, inflammatory pain and neuropathic pain, and its analgesic mechanisms. Although further clinical trials are needed to clinical application of experimental results, this review will contribute to the standardization and generalization of BVA.
Parkinson's disease (PD) is a progressive chronic neurodegenerative condition characterized by the loss of dopaminergic neurons within the substantia nigra. Current PD therapeutic strategies are ...mainly symptomatic and can lead to motor complications overtime. As a result, alternative medicine may provide an effective adjuvant treatment for PD as an addition to or as a replacement of the conventional therapies. The aim of this work was to evaluate the effects of Bee Venom (BV) and dopamine (DA)-loaded nanoparticles in a reserpine-induced animal model of PD. After inducing PD with reserpine injection, different groups of male rats were treated with L-Dopa, BV, DA-nanoparticles. Our findings showed that BV and DA-nanoparticles administration restored monoamines, balanced glutamate/GABA levels, halted DNA fragmentation, decreased pro-inflammatory mediators (IL-1β and TNF-α), and elevated anti-inflammatory mediators (PON1) and neurotropic factor (BDNF) levels in comparison with conventional therapy of PD. Furthermore, in a reserpine-induced PD rat model, the ameliorative effects of BV were significantly superior to that of DA-nanoparticles. These findings imply that BV and DA-nanoparticles could be useful as adjuvant treatments for PD.
Adipose tissue macrophages (ATMs) exist in either the M1 or M2 form. The anti-inflammatory M2 ATMs accumulate in lean individuals, whereas the pro-inflammatory M1 ATMs accumulate in obese ...individuals. Bee venom phospholipase A2 (bvPLA2), a major component in honeybee (Apis mellifera) venom, exerts potent anti-inflammatory effects via interactions with regulatory T cells (Treg) and macrophages. This study investigated the effects of bvPLA2 on a high-fat diet (HFD)-induced obesity in mice.
For in vivo experiments, male C57BL/6, CD206-deficient, and Treg-depleted mice models were fed either a normal diet 41.86 kJ (ND, 10 kcal% fat) or high-fat diet 251.16 kJ (HFD, 60 kcal% fat). Each group was i.p. injected with PBS or bvPLA2 (0.5 mg/kg) every 3 days for 11 weeks. Body weight and food intake were measured weekly. Histological changes in the white adipose tissue (WAT), liver, and kidney as well as the immune phenotypes of the WAT were examined. Immune cells, cytokines, and lipid profiles were also evaluated. The direct effects of bvPLA2 on 3T3-L1 pre-adipocytes and bone marrow-derived macrophages were measured in vitro.
bvPLA2 markedly decreased bodyweight in HFD-fed mice. bvPLA2 treatment also decreased lipid accumulation in the liver and reduced kidney inflammation in the mice. It was confirmed that bvPLA2 exerted immunomodulatory effects through the CD206 receptor. In addition, bvPLA2 decreased M1 ATM and alleviated the M1/M2 imbalance in vivo. However, bvPLA2 did not directly inhibit adipogenesis in the 3T3-L1 adipose cells in vitro.
bvPLA2 is a potential therapeutic strategy for the management of obesity by regulating adipose tissue macrophage homeostasis.
Background
Lung cancer, one of the most common oncological diseases worldwide, continues to be the leading cause of cancer-related deaths. The development of new approaches for lung cancer, which ...still has a low survival rate despite medical advances, is of great importance.
Methods and results
In this study, bee venom (BV), conditioned medium of MSCs isolated from dental follicles (MSC-CM) and cisplatin were applied at different doses and their effects on A549 cell line were evaluated. Dental follicles were used as a source of MSCs source and differentiation kits, and characterization studies (flow cytometry) were performed. Cell viability was measured by the MTT method and apoptosis was measured by an Annexin V-FITC/PI kit on flow cytometer. IC
50
dose values were determined according to the 24th hour and were determined as 15.8 µg/mL for BV, 10.78% for MSC-CM and 5.77 µg/mL for cisplatin. IC
50
values found for BV and MSC-CM were also given in combination and the effects were observed. It was found that the applied substances caused BV to decrease in cell viability and induced apoptosis in cells. In addition to the induction of apoptosis in BV, MSC-CM, and combined use, all three applications led to an increase in Bax protein expression and a decrease in Bcl-2 protein expression. The molecular mechanism of anticancer activity through inhibition of Bax and Bcl-2 proteins and the NF-κB signaling pathway may be suggested.
Conclusion
Isolated MSCs in our study showed anticancer activity and BV and MSC-CM showed synergistic antiproliferative and apoptotic effects.
Bee venom phospholipase A2 is a lipolytic enzyme in bee venom that catalyzes hydrolysis of the sn-2 ester bond of membrane phospholipids to produce free fatty acid and lysophospholipids. Current ...evidence suggests that bee venom phospholipase A2 (bvPLA2) induces regulatory T cell expansion and attenuates several immune system-related diseases, including Alzheimer's disease. The induction of Treg cells is directly mediated by binding to mannose receptors on dendritic cells. This interaction induces the PGE2-EP2 signaling pathway, which promotes Treg induction in CD4
T cells. In this study, we investigated the effects of bvPLA2 treatment on the apoptotic signaling pathway in Treg populations. Flow cytometry was performed to identify early apoptotic cells. As a result, early apoptotic cells were dramatically decreased in bvPLA2-treated splenocytes, whereas rapamycin-treated cells showed levels of apoptotic cells similar to those of PBS-treated cells. Furthermore, bvPLA2 treatment increased expression of anti-apoptotic molecules including CTLA-4 and PD-1. The survival rate increased in bvPLA2-treated Tregs. Our findings indicate that bvPLA2-mediated modulation of apoptotic signaling is strongly associated with the Treg induction, which exhibits protective effects against various immune-related diseases. To our knowledge, this study is the first to demonstrate that bvPLA2 is the major bee venom (BV) compound capable of inducing Treg expansion through altering apoptotic signal.
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