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Bee Venom and Its Sub-Components: Characterization, Pharmacology, and Therapeutics
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Bee Venom and Its Sub-Components: Characterization, Pharmacology, and Therapeutics

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Animal Venoms".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 50330

Special Issue Editor

Prof. Dr. Woojin Kim

E-Mail Website
Guest Editor
Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul 02453, Republic of Korea
Interests: chemotherapy-induced side effects; neuropathic pain; anorexia; bee venom; herbal medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Bee venom has been reported to be efficient against various diseases, including neuropathic pain, progressive muscle atrophy, idiopathic Parkinson’s disease, and cancer in humans and animals. However, despite its ability to treat these diseases, its mechanism of action remains poorly understood.

Thus, this Special Issue of Toxins is devoted to understanding the mechanisms of action of bee venom and its sub-components (i.e., apamin, melittin, Phospholipase A2, etc.). We welcome all research that is focused on the characterization, pharmacology, and therapeutics of bee venom and its sub-components. Topics of interest include, but are not limited to: bee venom acupuncture; cancers; pain, including neuropathic pain, immune modulation, and action on the central and peripheral nervous system; and various receptors and ion channels.

Prof. Dr. Woojin Kim
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • bee venom
  • bee venom acupuncture
  • cancer
  • immune modulation
  • melittin
  • pain
  • neuropathic pain
  • phospholipase A2

Published Papers (12 papers)

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Editorial

Jump to: Research, Review

2 pages, 212 KiB  
Editorial
Bee Venom and Its Sub-Components: Characterization, Pharmacology, and Therapeutics
by Woojin Kim
Toxins 2021, 13(3), 191; https://doi.org/10.3390/toxins13030191 - 07 Mar 2021
Cited by 14 | Viewed by 2767
Abstract
Bee venom, which is a complex substance produced by Apis mellifera, is widely used to treat various diseases, such as pain [...] Full article
(This article belongs to the Special Issue Bee Venom and Its Sub-Components: Characterization, Pharmacology, and Therapeutics)

Research

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13 pages, 1971 KiB  
Article
Bee Venom Acupuncture Attenuates Oxaliplatin-Induced Neuropathic Pain by Modulating Action Potential Threshold in A-Fiber Dorsal Root Ganglia Neurons
by Ji Hwan Lee, Juan Gang, Eunhee Yang, Woojin Kim and Young-Ho Jin
Toxins 2020, 12(12), 737; https://doi.org/10.3390/toxins12120737 - 24 Nov 2020
Cited by 17 | Viewed by 2401
Abstract
Oxaliplatin is a third-generation platinum-based chemotherapeutic drug widely used in colorectal cancer treatment. Although potent against this tumor, it can induce cold and mechanical allodynia even after a single injection. The currently used drugs to attenuate this allodynia can also cause unwanted effects, [...] Read more.
Oxaliplatin is a third-generation platinum-based chemotherapeutic drug widely used in colorectal cancer treatment. Although potent against this tumor, it can induce cold and mechanical allodynia even after a single injection. The currently used drugs to attenuate this allodynia can also cause unwanted effects, which limit their use. Bee venom acupuncture (BVA) is widely used in Korean medicine to treat pain. Although the effect of BVA on oxaliplatin-induced neuropathic pain has been addressed in many studies, its action on dorsal root ganglia (DRG) neurons has never been investigated. A single oxaliplatin injection (6 mg/kg, intraperitoneally) induced cold and mechanical allodynia, and BVA (0.1 and 1 mg/kg, subcutaneous, ST36) dose-dependently decreased allodynia in rats. On acutely dissociated lumbar 4–6 DRG neurons, 10 min application of oxaliplatin (100 μM) shifted the voltage-dependence of sodium conductance toward negative membrane potentials in A- but not C-fibers. The resting membrane potential remained unchanged, but the action potential threshold decreased significantly compared to that of the control (p < 0.05). However, 0.1 μg/mL of BVA administration increased the lowered action potential threshold. In conclusion, these results suggest that BVA may attenuate oxaliplatin-induced neuropathic pain by altering the action potential threshold in A-fiber DRG neurons. Full article
(This article belongs to the Special Issue Bee Venom and Its Sub-Components: Characterization, Pharmacology, and Therapeutics)
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18 pages, 4232 KiB  
Article
Melittin Induces Local Order Changes in Artificial and Biological Membranes as Revealed by Spectral Analysis of Laurdan Fluorescence
by Bogdan Zorilă, George Necula, Mihai Radu and Mihaela Bacalum
Toxins 2020, 12(11), 705; https://doi.org/10.3390/toxins12110705 - 08 Nov 2020
Cited by 11 | Viewed by 2757
Abstract
Antimicrobial peptides (AMPs) are a class of molecules widely used in applications on eukaryotic and prokaryotic cells. Independent of the peptide target, all of them need to first pass or interact with the plasma membrane of the cells. In order to have a [...] Read more.
Antimicrobial peptides (AMPs) are a class of molecules widely used in applications on eukaryotic and prokaryotic cells. Independent of the peptide target, all of them need to first pass or interact with the plasma membrane of the cells. In order to have a better image of the peptide action mechanism with respect to the particular features of the membrane it is necessary to better understand the changes induced by AMPs in the membranes. Laurdan, a lipid membrane probe sensitive to polarity changes in the environment, is used in this study for assessing changes induced by melittin, a well-known peptide, both in model and natural lipid membranes. More importantly, we showed that generalized polarization (GP) values are not always efficient or sufficient to properly characterize the changes in the membrane. We proved that a better method to investigate these changes is to use the previously described log-normal deconvolution allowing us to infer other parameters: the difference between the relative areas of elementary peak (ΔSr), and the ratio of elementary peaks areas (Rs). Melittin induced a slight decrease in local membrane fluidity in homogeneous lipid membranes. The addition of cholesterol stabilizes the membrane more in the presence of melittin. An opposite response was observed in the case of heterogeneous lipid membranes in cells, the local order of lipids being diminished. RS proved to be the most sensitive parameter characterizing the local membrane order, allowing us to distinguish among the responses to melittin of both classes of membrane we investigated (liposomes and cellular membranes). Molecular simulation of the melittin pore in homogeneous lipid bilayer suggests that lipids are more closely packed in the proximity of the melittin pore (a smaller area per lipid), supporting the experimental observation. Full article
(This article belongs to the Special Issue Bee Venom and Its Sub-Components: Characterization, Pharmacology, and Therapeutics)
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12 pages, 2582 KiB  
Article
Long-Lasting and Additive Analgesic Effects of Combined Treatment of Bee Venom Acupuncture and Venlafaxine on Paclitaxel-Induced Allodynia in Mice
by Daxian Li, Ju Hyuk Yoo and Sun Kwang Kim
Toxins 2020, 12(10), 620; https://doi.org/10.3390/toxins12100620 - 28 Sep 2020
Cited by 13 | Viewed by 2409
Abstract
Paclitaxel, a primary chemotherapeutic agent used to treat numerous solid malignancies, is commonly associated with debilitating peripheral neuropathy. However, a satisfactory gold-standard monotherapy for this neuropathic pain is not currently available. A combination strategy of two or more medications with different properties may [...] Read more.
Paclitaxel, a primary chemotherapeutic agent used to treat numerous solid malignancies, is commonly associated with debilitating peripheral neuropathy. However, a satisfactory gold-standard monotherapy for this neuropathic pain is not currently available. A combination strategy of two or more medications with different properties may achieve more beneficial effects than monotherapy. Thus, we investigated the analgesic efficacies and spinal mechanisms of the combination strategy, including bee venom acupuncture (BVA) and venlafaxine (VLX) against paclitaxel-induced allodynia in mice. Four intraperitoneal infusions of paclitaxel on alternating days (2 mg/kg/day) induced cold and mechanical allodynia for at least 1 week as assessed using acetone and the von Frey hair test, respectively. Co-treatment of BVA (1.0 mg/kg, s.c., ST36) with VLX (40 mg/kg, i.p.) at the medium dose produced a longer-lasting and additive effect than each monotherapy at the highest dose (BVA, 2.5 mg/kg; VLX, 60 mg/kg). Spinal pre-administration of idazoxan (α2-adrenergic receptor antagonist, 10 μg), methysergide (mixed 5-HT1/5-HT2 receptor antagonist, 10 μg), or MDL-72222 (5-HT3 receptor antagonist, 10 μg) abolished this analgesia. These results suggest that the combination therapy with BVA and VLX produces long-lasting and additive analgesic effects on paclitaxel-induced allodynia, via the spinal noradrenergic and serotonergic mechanism, providing a promising clinical strategy. Full article
(This article belongs to the Special Issue Bee Venom and Its Sub-Components: Characterization, Pharmacology, and Therapeutics)
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13 pages, 2939 KiB  
Article
Redox-Sensitive Nanocomplex for Targeted Delivery of Melittin
by Bei Cheng and Peisheng Xu
Toxins 2020, 12(9), 582; https://doi.org/10.3390/toxins12090582 - 10 Sep 2020
Cited by 19 | Viewed by 3448
Abstract
Although peptide therapeutics have been explored for decades, the successful delivery of potent peptides in vitro and in vivo remains challenging due to the poor stability, low cell permeability, and off-target effects. We developed a redox sensitive polymer-based nanocomplex which can efficiently and [...] Read more.
Although peptide therapeutics have been explored for decades, the successful delivery of potent peptides in vitro and in vivo remains challenging due to the poor stability, low cell permeability, and off-target effects. We developed a redox sensitive polymer-based nanocomplex which can efficiently and stably deliver the peptide drug melittin for cancer therapy. The nanocomplex selectively targets cancer cells through lactobionic acid mediated endocytosis and releases melittin intracellularly upon the trigger of elevated redox potential. In vivo study proved that the targeted nanocomplex shows excellent potency in inhibiting tumor growth in a xenograft colon cancer mouse model. Thus, the polymer/melittin nanocomplexes will provide a new approach for melittin based cancer therapy. Full article
(This article belongs to the Special Issue Bee Venom and Its Sub-Components: Characterization, Pharmacology, and Therapeutics)
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13 pages, 3126 KiB  
Article
Bee Venom Melittin Protects against Cisplatin-Induced Acute Kidney Injury in Mice via the Regulation of M2 Macrophage Activation
by Hyunseong Kim, Jin Young Hong, Wan-Jin Jeon, Seung Ho Baek and In-Hyuk Ha
Toxins 2020, 12(9), 574; https://doi.org/10.3390/toxins12090574 - 06 Sep 2020
Cited by 12 | Viewed by 3235
Abstract
Inflammation is an essential biological response that eliminates pathogenic bacteria and repairs tissue after injury. Acute kidney injury (AKI) is associated with systemic and intrarenal inflammation as the inflammatory process decreases renal function and promotes progression to advanced chronic kidney disease. Macrophages are [...] Read more.
Inflammation is an essential biological response that eliminates pathogenic bacteria and repairs tissue after injury. Acute kidney injury (AKI) is associated with systemic and intrarenal inflammation as the inflammatory process decreases renal function and promotes progression to advanced chronic kidney disease. Macrophages are key mediators of the inflammatory response; their activation influences the immune system and may have various effects. Classically activated type I macrophages (M1) produce a variety of pro-inflammatory cytokines at the lesion site. However, anti-inflammatory type II macrophages (M2) are alternatively activated upon exposure to anti-inflammatory cytokines and are associated with wound healing and tissue repair following AKI. Here, we used melittin from bee venom to enhance the polarization of M2 macrophages and promote renal recovery after AKI. Melittin was administered to mice intraperitoneally for 5 days at various concentrations (10, 50, and 100 µg/kg); serum creatinine and blood urea nitrogen (BUN) levels were analyzed 72 h after cisplatin administration to confirm renal dysfunction. Melittin inhibited the cisplatin-induced increase in creatinine and BUN, an indicator of renal dysfunction. The expression of M1 markers (CD16/32) decreased significantly, whereas that of M2 markers (CD206, Arg1nase I) increased after melittin administration. Consistently, tubular necrosis was substantially reduced in melittin-treated mice. Thus, melittin alleviates cisplatin-induced AKI by regulating M2 macrophage expression. Full article
(This article belongs to the Special Issue Bee Venom and Its Sub-Components: Characterization, Pharmacology, and Therapeutics)
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12 pages, 1481 KiB  
Article
Quantitative Measurement of Melittin in Asian Honeybee Venom Using a New Method Including UPLC-QqTOF-MS
by Sheng Huang, Jianhua Wang, Zeqin Guo, Yan Wang and Chundong Liu
Toxins 2020, 12(7), 437; https://doi.org/10.3390/toxins12070437 - 04 Jul 2020
Cited by 9 | Viewed by 3528
Abstract
Asian honeybee venom is widely used in traditional oriental medicine. Melittin is the main component of Asian honeybee venom. In the present study, an ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QqTOF-MS) method was used for accurate qualitative and quantitative analyses of melittin in [...] Read more.
Asian honeybee venom is widely used in traditional oriental medicine. Melittin is the main component of Asian honeybee venom. In the present study, an ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QqTOF-MS) method was used for accurate qualitative and quantitative analyses of melittin in Asian honeybee venom. The results showed that the dynamic linear range of melittin was from 0.094 to 20 μg/mL, and the limit of quantification was 0.3125 μg/mL. The spiking recovery of melittin in honeybee venom ranged from 84.88% to 93.05%. Eighteen Asian honeybee venom samples in eighteen batches were collected from two different zones of China, and their melittin contents were measured. The contents of melittin in Asian honeybee venom samples was 33.9–46.23% of dry weight. This method proved a useful tool for the rapid evaluation of the authenticity and quality of Asian honeybee venom in terms of the melittin contents, and will contribute to a broader understanding of Asian honeybee venom. Full article
(This article belongs to the Special Issue Bee Venom and Its Sub-Components: Characterization, Pharmacology, and Therapeutics)
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14 pages, 3704 KiB  
Article
Bee Venom Phospholipase A2 Induces Regulatory T Cell Populations by Suppressing Apoptotic Signaling Pathway
by Hyunjung Baek, Seon-Young Park, Su Jeong Ku, Kihyun Ryu, Younsub Kim, Hyunsu Bae and Ye-Seul Lee
Toxins 2020, 12(3), 198; https://doi.org/10.3390/toxins12030198 - 22 Mar 2020
Cited by 19 | Viewed by 4438
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Bee Venom and Its Sub-Components: Characterization, Pharmacology, and Therapeutics)
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13 pages, 1275 KiB  
Article
Extending Metabolomic Studies of Apis mellifera Venom: LC-MS-Based Targeted Analysis of Organic Acids
by Magdalena Pawlak, Agnieszka Klupczynska, Zenon J Kokot and Jan Matysiak
Toxins 2020, 12(1), 14; https://doi.org/10.3390/toxins12010014 - 28 Dec 2019
Cited by 19 | Viewed by 3415
Abstract
Organic acids are important active small molecules present in venoms and toxins, which have not been fully explored yet. The aim of the study was the determination of organic acids in honeybee venom (HBV) samples by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Two [...] Read more.
Organic acids are important active small molecules present in venoms and toxins, which have not been fully explored yet. The aim of the study was the determination of organic acids in honeybee venom (HBV) samples by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Two protocols for sample preparation were employed. A solid-phase extraction was used for the determination of malonic acid, fumaric acid, glutaric acid, and kynurenic acid. A dilute-and-shoot method was optimal for: citric acid, malic acid, and succinic acid. Chromatographic separation was performed using a Synergi Hydro-RP column. Detection was performed on a triple-quadrupole mass spectrometer operating in multiple reaction monitoring mode. Among the analytes, glutaric acid and kynurenic acid were present in HBV samples in the lowest concentrations, whereas citric acid was the most abundant acid in each sample, and accounted for an average of 86 mg/g (8.6%) of the venom dry weight. Organic acids were discussed in terms of function. This is the first study in the available literature that provides specific data on the content of organic acids in HBV using a validated quantitative method. Full article
(This article belongs to the Special Issue Bee Venom and Its Sub-Components: Characterization, Pharmacology, and Therapeutics)
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Review

Jump to: Editorial, Research

25 pages, 1652 KiB  
Review
Clinical Applications of Bee Venom Acupoint Injection
by Ting-Yen Lin and Ching-Liang Hsieh
Toxins 2020, 12(10), 618; https://doi.org/10.3390/toxins12100618 - 27 Sep 2020
Cited by 23 | Viewed by 7109
Abstract
Bee venom is a complex natural mixture with various pharmaceutical properties. Among these properties, its peptides and enzymes have potential medical therapy for pain relief and inflammation. In clinical settings, this therapy has been used widely to treat diseases by injecting into acupoints. [...] Read more.
Bee venom is a complex natural mixture with various pharmaceutical properties. Among these properties, its peptides and enzymes have potential medical therapy for pain relief and inflammation. In clinical settings, this therapy has been used widely to treat diseases by injecting into acupoints. In this article, we have conducted various research from PubMed, Cochrane Library, and Clinical Key from inception of July 2020. The results revealed that bee venom therapy has been reported effective in anti-inflammatory, antiapoptosis, and analgesic effects. Moreover, bee venom acupuncture has been commonly used for clinical disorders such as Parkinson disease, neuropathic pain, Alzheimer disease, intervertebral disc disease, spinal cord injury, musculoskeletal pain, arthritis, multiple sclerosis, skin disease and cancer. Full article
(This article belongs to the Special Issue Bee Venom and Its Sub-Components: Characterization, Pharmacology, and Therapeutics)
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17 pages, 916 KiB  
Review
Antimicrobial Properties of Apis mellifera’s Bee Venom
by Hesham El-Seedi, Aida Abd El-Wahed, Nermeen Yosri, Syed Ghulam Musharraf, Lei Chen, Moustafa Moustafa, Xiaobo Zou, Saleh Al-Mousawi, Zhiming Guo, Alfi Khatib and Shaden Khalifa
Toxins 2020, 12(7), 451; https://doi.org/10.3390/toxins12070451 - 11 Jul 2020
Cited by 64 | Viewed by 9397
Abstract
Bee venom (BV) is a rich source of secondary metabolites from honeybees (Apis mellifera L.). It contains a variety of bioactive ingredients including peptides, proteins, enzymes, and volatile metabolites. The compounds contribute to the venom’s observed biological functions as per its anti-inflammatory [...] Read more.
Bee venom (BV) is a rich source of secondary metabolites from honeybees (Apis mellifera L.). It contains a variety of bioactive ingredients including peptides, proteins, enzymes, and volatile metabolites. The compounds contribute to the venom’s observed biological functions as per its anti-inflammatory and anticancer effects. The antimicrobial action of BV has been shown in vitro and in vivo experiments against bacteria, viruses, and fungi. The synergistic therapeutic interactions of BV with antibiotics has been reported. The synergistic effect contributes to a decrease in the loading and maintenance dosage, a decrease in the side effects of chemotherapy, and a decrease in drug resistance. To our knowledge, there have been no reviews on the impact of BV and its antimicrobial constituents thus far. The purpose of this review is to address the antimicrobial properties of BV and its compounds. Full article
(This article belongs to the Special Issue Bee Venom and Its Sub-Components: Characterization, Pharmacology, and Therapeutics)
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Graphical abstract

17 pages, 390 KiB  
Review
Therapeutic Effects of Apamin as a Bee Venom Component for Non-Neoplastic Disease
by Hyemin Gu, Sang Mi Han and Kwan-Kyu Park
Toxins 2020, 12(3), 195; https://doi.org/10.3390/toxins12030195 - 19 Mar 2020
Cited by 44 | Viewed by 4126
Abstract
Bee venom is a natural toxin produced by honeybees and plays an important role in defending bee colonies. Bee venom has several kinds of peptides, including melittin, apamin, adolapamine, and mast cell degranulation peptides. Apamin accounts for about 2%–3% dry weight of bee [...] Read more.
Bee venom is a natural toxin produced by honeybees and plays an important role in defending bee colonies. Bee venom has several kinds of peptides, including melittin, apamin, adolapamine, and mast cell degranulation peptides. Apamin accounts for about 2%–3% dry weight of bee venom and is a peptide neurotoxin that contains 18 amino acid residues that are tightly crosslinked by two disulfide bonds. It is well known for its pharmacological functions, which irreversibly block Ca2+-activated K+ (SK) channels. Apamin regulates gene expression in various signal transduction pathways involved in cell development. The aim of this study was to review the current understanding of apamin in the treatment of apoptosis, fibrosis, and central nervous system diseases, which are the pathological processes of various diseases. Apamin’s potential therapeutic and pharmacological applications are also discussed. Full article
(This article belongs to the Special Issue Bee Venom and Its Sub-Components: Characterization, Pharmacology, and Therapeutics)
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