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From a taxonomic point of view, Hymenoptera are subclassified into families: Apidae, including honeybees (Apis mellifera) and bumblebees (Bombus), and Vespidae, which, in turn, are divided into the subfamilies of Vespinae (wasps, including hornets, vespules, dolichovespules) and Polistinae (paper wasp). Hypersensitivity to Hymenoptera venom can be linked to immunological (IgE-mediated or non-IgE-mediated) and non-immunological mechanisms. Reactions are classified into local reactions, large local reactions, systemic reactions, toxic reactions, and unusual reactions. In general, children sensitize less frequently and have less severe reactions than adults, probably due to less exposure to repeated stings and fewer comorbidities. There are risk factors for systemic reactions that should be discussed with patients and their parents as appropriate. A correct diagnosis of Hymenoptera venom allergy relies on a careful clinical history and the appropriate use of skin and in vitro tests. The in vitro tests include serum specific IgE toward venom extracts and toward allergenic molecules. In complex diagnoses, CAP-inhibition and the Basophil Activation Test can also be used. In the presence of a systemic reaction, the basal serum tryptase measurement should be performed to rule out mastocytosis. In case of allergic reactions to Hymenoptera stings, in the acute phase, according to the current guidelines, the treatment of signs and symptoms mainly includes the use of adrenaline as first-line treatment in case of anaphylaxis and antihistamines and corticosteroids as subsequent lines of treatment. Given the impossibility of avoiding a new sting with certainty, the treatment of choice in subjects with hypersensitivity to Hymenoptera venom who have experienced systemic reactions is based on venom immunotherapy (VIT), with the venom of the responsible stinging insect identified after an adequate allergological work-up. VIT is performed in a suitable environment and has proved to be safe and effective with various administration protocols, both accelerated and conventional. The prevention of Hymenoptera venom anaphylaxis in patients who have already developed a previous episode is crucial and must be supported by environmental protection interventions and early therapy. Places where one is more likely to encounter insects and risky behaviors should be avoided. [ABSTRACT FROM AUTHOR]

The Nuclear factor erythroid 2–related factor (Nrf2)/ Heme oxygenase-1 (HO-1) pathway, known for its significant role in regulating innate antioxidant defense mechanisms, is increasingly being recognized for its potential in neuroprotection studies. Derived from bee venom, melittin's neuroprotective effects have raised interest. This study confirmed that melittin specificity upregulated the weakened Nrf2/HO-1 signaling in mice brain. Interestingly, we also revealed melittin's efficient tactic, as it was suggested to first restore redox balance and then gradually stabilized other regulations of the mouse hippocampus. Using a neuro-stress-induced scopolamine model, chromatography and mass spectrometry analysis revealed that melittin crossed the compromised blood–brain barrier and accumulated in the hippocampus, which provided the chance to interact directly to weakened neurons. A wide range of improvements of melittin action were observed from various tests from behavior Morris water maze, Y maze test to immune florescent staining, western blots. As we need to find out what is the focus of melittin action, we conducted a careful observation in mice which showed that: the first signs of changes, in the hippocampus, within 5 h after melittin administration were the restoration of the Nrf2/HO-1 system and suppression of oxidative stress. After this event, from 7 to 12.5 h after administration, a diversity of conditions was all ameliorated: inflammation, apoptosis, neurotrophic factors, cholinergic function, and tissue ATP level. This chain reaction underscores that melittin focus was on redox balance's role, which revived multiple neuronal functions. Evidence of enhancement in the mouse hippocampus led to further exploration with hippocampal cell line HT22 model. Immunofluorescence analysis showed melittin-induced Nrf2 translocation to the nucleus, which would initiating the translation of antioxidant genes like HO-1. Pathway inhibitors pinpointed melittin's direct influence on the Nrf2/HO-1 pathway. 3D docking models and pull-down assays suggested melittin's direct interaction with Keap1, the regulator of the Nrf2/HO-1 pathway. Overall, this study not only highlighted melittin specifically effect on Nrf2/HO-1, thus rebalancing cellular redox, and also showed that this is an effective multi-faceted therapeutic strategy against neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: Maintenance of immune system integrity is a vital requirement to protect human body against pathogens/cancers. Natural compounds have long been used due to their benefits for the immune system. One of which is bee venom that contains a peptide called melittin having antimicrobial and anticancer effects. Since a limited number of studies regarding the effects of melittin on the immune system have been carried out, we aimed to evaluate the effects of melittin on BALB/c mice immune system parameters. Methods: Female BALB /c mice were treated intraperitoneally (i.p) with 0.75 and 1.5 mg/kg doses of melittin for 14 days (5 doses per week). The negative control group received i.p normal saline whereas the positive controls received i.p 20 mg/kg cyclophosphamide (CYP). Immunological parameters such as hematological parameters, delayed-type hypersensitivity (DTH), hemagglutination titer (HA), spleen cellularity, splenocytes proliferation, as well as spleen and bone marrow histopathological assessment were evaluated. Results: Our findings showed that melittin has no gross pathological effect on the spleen and bone marrow. It was also demonstrated that melittin has no any significant effect on hematological parameters. Melittin did not cause any significant changes to proliferation response of splenocytes to PHA and LPS, spleen cellularity, DTH response, as well as the production of anti-SRBC antibodies. According to our results, melittin at 0.75 and 1.5 mg/kg doses could not induce significant changes on immune parameters and as a result, melittin was found to be safe for the mice immune system. [ABSTRACT FROM AUTHOR]

Background: Apitherapy is an emerging field in cancer research, particularly in developing communities. The potency of Melittin (MEL), a major constituent in bee venom is accounted for the cytotoxic capacity against cancer cells. It is postulated that the genotype of bees and the time of venom collection influences its specific activity against certain types of cancer. Method: Hereby, Jordanian crude bee venom (JCBV) was collected during different seasons of the year, specifically spring, summer and autumn and investigated for in vitro antitumour effects. Venom collected during springtime comprised the highest quantity of MEL in comparison to venom collected some other time. Springtime-collected JCBV extract and MEL were tested on an immortal myelogenous leukaemia cell line, namely K562 leukemic cells. Treated cells were examined for cell modality via flow cytometry analysis and cell death mediating gene expressions. Results: Springtime-collected JCBV extract and MEL showed an IC50 of 3.7 ± 0.37 μg/ml and 1.84 ± 0.75 μg/ml, respectively. In comparison to JCBV and positive control, MEL-treated cells exhibited late apoptotic death with a moderate cellular arrest at G0/G1 and an increase of cell number at G2/M phase. Expression of NF-κB/MAPK14 axis was inhibited in MEL and JCBV-treated cells, as well as expression of c-MYC and CDK4. Moreover, marked upregulation in ABL1, JUN and TNF was observed. In conclusion, springtime-collected JCBV showed the highest content of MEL while both JCBV and pure MEL showed apoptotic, necrotic, and cell cycle arrest efficiency against K562 leukemic cells. Conclusion: Integration of bee venom in chemotherapy needs more investigation and should be carefully translated into clinical use. During such translation, the correlation of bee genotype, collection time and concentration of MEL in CBV should be profiled. [ABSTRACT FROM AUTHOR]

Background: Allergy to Apis dorsata (Giant Asian Honeybee) venom is the commonest insect allergy in Sri Lanka and South East Asia. However, laboratory diagnosis is difficult as the pure venom and diagnostic reagents are not commercially available. Objective: This study assessed the use of four recombinant allergens of A. mellifera venom and the passive basophil activation test in the diagnosis of A. dorsata venom anaphylaxis. Methods: Serum IgE levels to four recombinant allergens of A. mellifera, rApi m 1, 2, 5 and 10 were assessed and compared with serum IgE to the crude venom of A. mellifera or V. vulgaris by Phadia ImmunoCAP, in patients who developed anaphylaxis to A. dorsata stings. Basophil activation in response to venom of A. dorsata or V. affinis was assessed using a passive basophil activation test. Association of the severity of the reaction with basophil activation was compared. Results: rApi m 1 and 10 combinedly had significant correlation (r = 0.722; p < 0.001) with the crude venom of A. mellifera (Western honeybee) and a higher positivity rate of 90% (27/30). Whereas, IgE reactivity to rApi m 2 or 5 had significant correlation (p = 0.02 and p = 0.005 respectively) with V. vulgaris crude venom. All 30 (100%) were positive to A. dorsata venom in passive BAT; 70% (21/30) had over 80% activation, 96.7% (29/30) had over 60% activation and 100% had over 50% activation. Percentage activation of basophils in patients who had mild or moderate reactions (n = 20) was significantly low (p = 0.02) from that of patients who had severe reactions (n = 10). Conclusions: rApi m 1 and 10 when combined was sensitive for the diagnosis of A. dorsata allergy. This combination had the lowest cross-reactivity rate with Vespula vulgaris. The passive BAT is highly sensitive in A. dorsata allergy. The basophil reactivity was significantly higher in severe anaphylaxis compared to mild/moderate anaphylaxis. This finding should be further explored in further studies. [ABSTRACT FROM AUTHOR]

Background: Anaphylaxis occurs in up to 3.5% of hymenoptera stings and can be a life-threatening emergency. Venom immunotherapy (VIT) provides excellent protection from further episodes of anaphylaxis and is well tolerated. In this study the frequency of anaphylactic reactions in pediatric patients undergoing rush bee venom immunotherapy was assessed as well as possible risk factors and modified up-dosing schemes are reported. Methods: 19 consecutive pediatric patients, who had previously experienced an anaphylactic reaction following a bee sting and showed IgE-mediated sensitization to bee venom, underwent inpatient rush immunotherapy with bee venom extract. We retrospectively compared serological findings (total IgE, serum tryptase level, sensitization to Api m1, Api m3 and Api m10 bee venom allergens) and possible risk factors between patients who experienced an anaphylactic reaction during immunotherapy and patients who did not. Results: Three of the included 19 patients (15.8%) developed anaphylactic reactions to rush bee venom immunotherapy, all of them between administration of 40 and 80 µg of bee venom extract. However, all three patients reached the standard maintenance dose of 100 µg of bee venom following a modified VIT schedule without any further complications. Total serum IgE levels as well as Api m3 sensitization levels were significantly higher in patients showing an adverse reaction to bee VIT compared to those who did not experience any complications. There were no statistically significant differences concerning age, pre-existing conditions, type and severity of the initial reaction and Api m1, Api m10 and serum tryptase levels between the two subgroups. Conclusion: Even if anaphylactic reactions occur during the build-up phase of VIT for bee venom in children and adolescents, venom immunotherapy can and should be continued in most cases. [ABSTRACT FROM AUTHOR]

Background: Hymenoptera venom immunotherapy (VIT) is a clinically effective treatment. However, little is known about its long-term clinical efficacy and biological effects. Several mechanisms have been proposed to account for VIT efficacy, including reduction of specific IgE and induction of allergen-specific IgG4, but the overall picture remains elusive. We investigated Vespula VIT clinical efficacy up to 8 years after discontinuation and the kinetics of Vespula-specific IgE and IgG4. Out of 686 consecutive patients we retrospectively selected and analysed a series of 23 patients with Vespula allergy that underwent a 5-year IT course, followed by a prolonged follow-up. Methods: Clinical efficacy of VIT was assessed as number and severity of reactions to Vespula re-stinging events. The presence of Vespula-specific IgE and IgG4 was also monitored over time. Results: During the VIT treatment, patients were protected, reporting no reactions or mild reactions in occasion of re-stinging events. This protection was entirely maintained during the follow-up, up to 8 years. Skin reactivity (reflecting mast cell-bound Vespula-specific IgE) and circulating Vespula-specific IgE levels declined substantially during VIT. Notably, this reduction was maintained over time during the follow-up. Moreover, all the patients were analysed for IgG4. A robust induction of Vespula-specific IgG4 was observed during the VIT course, with a substantial decline during the follow-up. Conclusions: We conclude that Vespula VIT is a clinically effective treatment, which induces long-term protection after discontinuation. The reduction of specific IgE, assessed by skin tests and RAST, closely matches the VIT- induced protection, while the IgG4 induction seems not to be associated with VIT clinical efficacy in the long term. [ABSTRACT FROM AUTHOR]

Background: Galetin 3,6-dimethyl ether (FGAL) is a flavonoid isolated from aerial parts of Piptadenia stipulacea. Previously, FGAL was shown to inhibit both carbachol- and oxytocin-induced phasic contractions in the rat uterus, which was more potent with oxytocin. Thus, in this study, we aimed to investigate the tocolytic action mechanism of FGAL on the rat uterus. Methods: Segments of rat uterus ileum were suspended in organ bath containing modified Locke-Ringer solution at 32 °C, bubbled with carbogen mixture under a resting tension of 1 g. Isotonic contractions were registered using kymographs and isometric contractions using force transducer. Results: FGAL was more potent in relaxing uterus pre-contracted with oxytocin than with KCl. Additionally, FGAL shifted oxytocin-induced cumulative contractions curves to the right in a non-parallel manner, with Emax reduction, indicating a pseudo-irreversible noncompetitive antagonism of oxytocin receptors (OTR) or a downstream pathway target. Moreover, FGAL shifted CaCl2-induced cumulative contraction curves to the right in a non-parallel manner in depolarizing medium, nominally without Ca2+, with Emax reduction, suggesting the inhibition of Ca2+ influx through CaV. The relaxant potency of FGAL was reduced by CsCl, a non-selective K+ channel blocker, suggesting positive modulation of these channels. Furthermore, in presence of apamin, 4-aminopyridine, glibenclamide or 1 mM TEA+, the relaxant+ potency of FGAL was attenuated, indicating the participation of SKCa, KV, KATP and highlighting BKCa. Aminophylline, a non-selective phosphodiesterase (PDE) blocker, did not affect the FGAL relaxant potency, excluding the modulation of cyclic nucleotide PDEs pathway by FGAL. Conclusion: Tocolytic effect of FGAL on rat uterus occurs by pseudo-irreversible noncompetitive antagonism of OTR and activation of K+ channels, primarily BKCa, leading to calcium influx reduction through CaV. [ABSTRACT FROM AUTHOR]

Background: Cytokine fusion protein that modulates the immune response holds great potential for cancer immunotherapy. IL-2 is an effective treatment against advanced cancers. However, the therapeutic efficacy of IL-2 is limited by severe systemic toxicity. Several mutants recombinant IL-2 can increase antitumor activity and minimize systemic toxicity. Melittin is an attractive anticancer candidate because of its wide-spectrum lytic properties. We previously generated a bifunctional fusion protein melittin-MIL-2, composed of melittin and a mutant IL-2. The melittin-MIL-2 inhibited the growth of human ovarian cancer SKOV3 cells in vitro and in vivo tumor growth. However, whether this antitumor effect could also be used in cancer immunotherapy was unknown. To assess its cancer immunotherapy potential, we further investigated its more effective antitumor immune response and antitumor effect against cancers of different tissue origins in vitro and in vivo.Methods: The specific IL-2 activity of the melittin-MIL-2 fusion protein was tested on the cytokine growth dependent cell line CTLL-2. The cytolytic activity was detected by standard 4-h (51)Cr-release assays. PBMC stimulation in response to the melittin-MIL-2 was determined by IFN-γ release assay. We observed the cancer cell proliferation of different tissue origins by MTT assay. The ability of melittin-MIL-2 to inhibit tumor growth in vivo was evaluated by using human liver (SMMC-7721 cancer cells), lung (A549 cancer cells) and ovarian (SKOV3 cancer cells) cancer xenograft models. To assess the immunity within the tumor microenvironment, the level of some cytokines including IFN-γ, TNF-α, IL-12 and IL-4 was analyzed by ELISA. We injected the MDA-MB-231 cells and the melittin-MIL-2 into mice, and the anti-metastatic effect was examined by counting nodules in the lung.Results: The melittin-MIL-2 was more effective in inducing T cell and NK-cell cytotoxicity. The fusion protein significantly increased IFN-γ production in PBMCs. In vitro, the melittin-MIL-2 mediated immune cells killing or directly killed the cancer cell lines of different tissue origins. In vivo, the fusion protein exhibited stronger inhibition on the growth of transplanted human tumors compared to rIL-2. The melittin-MIL-2 treatment promoted the IFN-γ secretion in tumor tissues and decreased the immunosuppressive cells in vivo. Furthermore, the fusion protein reduced lung metastasis of breast cancer.Conclusions: This study provides the evidence that the melittin-MIL-2 can produce stronger immune stimulation and antitumor effects, and the fusion protein is a potent candidate for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a severe neuroinflammatory disease. CD4(+)Foxp3(+) regulatory T cells (Tregs) modulate various inflammatory diseases via suppressing Th cell activation. There are increasing evidences that Tregs have beneficial roles in neurodegenerative diseases. Previously, we found the population of Treg cells was significantly increased by bee venom phospholipase A2 (bvPLA2) treatment in vivo and in vitro.Methods: To examine the effects of bvPLA2 on AD, bvPLA2 was administered to 3xTg-AD mice, mouse model of Alzheimer's disease. The levels of amyloid beta (Aβ) deposits in the hippocampus, glucose metabolism in the brain, microglia activation, and CD4(+) T cell infiltration were analyzed to evaluate the neuroprotective effect of bvPLA2.Results: bvPLA2 treatment significantly enhanced the cognitive function of the 3xTg-AD mice and increased glucose metabolism, as assessed with 18F-2 fluoro-2-deoxy-D-glucose ([F-18] FDG) positron emission tomography (PET). The levels of Aβ deposits in the hippocampus were dramatically decreased by bvPLA2 treatment. This neuroprotective effect of bvPLA2 was associated with microglial deactivation and reduction in CD4(+) T cell infiltration. Interestingly, the neuroprotective effects of bvPLA2 were abolished in Treg-depleted mice.Conclusions: The present studies strongly suggest that the increase of Treg population by bvPLA2 treatment might inhibit progression of AD in the 3xTg AD mice. [ABSTRACT FROM AUTHOR]

Background: Diluted bee venom (BV) is known to have anti-nociceptive and anti-inflammatory effects. We therefore assessed whether perineural bee venom pretreatment could attenuate the development of neuropathic pain in the spinal nerve ligation injured animal model. Methods: Neuropathic pain was surgically induced in 30 male Sprague Dawley rats by ligation of the L5 and L6 spinal nerves, with 10 rats each treated with saline and 0.05 and 0.1 mg BV. Behavioral testing for mechanical, cold, and thermal allodynia was conducted on postoperative days 3 to 29. Three rats in each group and 9 sham operated rats were sacrificed on day 9, and the expression of transient receptor potential vanilloid type 1 (TRPV1), ankyrin type 1 (TRPA1), and melastatin type 8 (TRPM8) receptors in the ipsilateral L5 dorsal root ganglion was analyzed. Results: The perineural administration of BV to the spinal nerves attenuated the development of mechanical, thermal, and cold allodynia, and the BV pretreatment reduced the expression of TRPV1, TRPA1, TRPM8 and c -- Fos in the ipsilateral dorsal root ganglion. Conclusion: The current study demonstrates that the perineural pretreatment with diluted bee venom before the induction of spinal nerve ligation significantly suppresses the development of neuropathic pain. Furthermore, this bee venom induced suppression was strongly related with the involvement of transient receptor potential family members. [ABSTRACT FROM AUTHOR]

Background: In practically every human culture, the use of arthropods as medicinal resources has been reported. In Mexico, the Mayan people mainly use plants but occasionally also animals and minerals in their medicine. This article is the first to report the traditional use of the tarantula Brachypelma vagans by medicine men in the Chol community, an ancient indigenous group that inhabits the southeastern part of Mexico. We also describe the utility of such arachnids in traditional medicine. Methods: This study was carried out in different Chol communities in the states of Chiapas and Campeche (southeastern Mexico) from 2003 until 2007. We interviewed the local medicine men, patients and non-Chol people in each village visited to collect information about the rituals involved and the effectiveness of this traditional medicine and also their opinion of this traditional medicine. Results: In all independent villages, the people who present an illness called 'aire de tarantula' or tarantula wind with symptoms including chest pain, coughing and asthma, were treated by the medicine man (called 'hierbatero') with a tarantula-based beverage. From village to village, the beverage has a similar base composition but some variations occur in additional ingredients depending on the individual medicine man. Like in all traditional Mayan medicine, the ritual of the ceremony consists of drinking the tarantula-based beverage and this is principally accompanied by chants and burning of incense. Conclusions: The recipe of the tarantula-based beverage and the procedure of this ritual ceremony were fairly constant in all the villages visited. Our work shows that despite the tarantula's bad image in several cultures, in others positive use is made of these spiders, as in modern medicine. [ABSTRACT FROM AUTHOR]

Background: Chronic neck pain (CNP) is a common painful medical condition with a significant socioeconomic impact. In spite of widespread usage, the effectiveness and safety of combined treatments between conventional and complementary alternative medical treatment modalities has not been fully established in a rigorous randomized clinical trial (RCT). This pilot study will provide the clinical evidence to evaluate the feasibility and refine the protocol for a full-scale RCT on combined treatment of bee venom acupuncture (BVA) and non-steroidal anti-inflammatory drugs (NSAIDs) in patients with CNP.Methods/design: This is a randomized, single-blind clinical trial with three parallel arms. Sixty patients between 18 and 65 years of age with non-specific, uncomplicated neck pain lasting for at least three months will be enrolled. Participants will be randomly allocated into the BVA, NSAIDs or combined treatment group. Assessors and statisticians will be blinded to the random allocation. All researchers will receive training to ensure their strict adherence to the study protocol. Patients from the BVA and combined treatment group will be treated with a bee venom increment protocol into predefined acupoints for six sessions over a three week period. BVA intervention is developed through a comprehensive discussion among interdisciplinary spine disorder experts, according to the guidelines of Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA). Patients from the NSAIDs and combined treatment groups will be prescribed loxoprofen (one tablet to be taken orally, three times a day for three weeks). Bothersomeness from CNP measured using a visual analogue scale (VAS) will be the primary outcome assessed at screening, visit two (baseline), four, six, eight (4th week assessment) and nine (8th week assessment) follow-up session. VAS for pain intensity, neck disability index (NDI), quality of life, depressive status and adverse experiences will also be analyzed.Discussion: Our study results will contribute to feasibility evaluation and to relevant RCT protocol development for a full-scale RCT on combined treatment of BVA and NSAIDs for CNP patients.Trial Registration: This study is registered with the United States (US) National Institutes of Health Clinical Trials Registry: NCT01922466. [ABSTRACT FROM AUTHOR]

Background: Chronic non-specific low back pain is the most common medical problem for which patients seek complementary and alternative medical treatment, including bee venom acupuncture. However, the effectiveness and safety of such treatments have not been fully established by randomized clinical trials. The aim of this study is to determine whether bee venom acupuncture is effective for improving pain intensity, functional status and quality of life of patients with chronic non-specific low back pain.Methods/design: This study is a randomized, double-blinded, sham-controlled clinical trial with two parallel arms. Fifty-four patients between 18 and 65 years of age with non-radicular chronic low back pain experiencing low back pain lasting for at least the previous three months and ≥ 4 points on a 10-cm visual analog scale for bothersomeness at the time of screening will be included in the study. Participants will be randomly allocated into the real or sham bee venom acupuncture groups and treated by the same protocol to minimize non-specific and placebo effects. Patients, assessors, acupuncturists and researchers who prepare the real or sham bee venom acupuncture experiments will be blinded to group allocation. All procedures, including the bee venom acupuncture increment protocol administered into predefined acupoints, are designed by a process of consensus with experts and previous researchers according to the Standards for Reporting Interventions in Clinical Trials of Acupuncture. Bothersomeness measured using a visual analogue scale will be the primary outcome. Back pain-related dysfunction, pain, quality of life, depressive symptoms and adverse experiences will be measured using the visual analogue scale for pain intensity, the Oswestry Disability Index, the EuroQol 5-Dimension, and the Beck's Depression Inventory. These measures will be recorded at baseline and 1, 2, 3, 4, 8 and 12 weeks.Discussion: The results from this study will provide clinical evidence on the efficacy and safety of bee venom acupuncture in patients with chronic non-specific low back pain.Trial Registration: This study is registered with the United States National Institutes of Health Clinical Trials Registry: NCT01491321. [ABSTRACT FROM AUTHOR]