Melittin as anti-inflammatory agent – BVT is the real sting!

Dr. Weeks’ Comment:   Since I started using bee venom for the treatment of people with  chronic degenerative diseases in 1982, the scientific support for this “folk remedy” has grown more impressive each year.   Why does bee venom help reduce the symptoms of MS and arthritis?

Scan the research below and cultivate more appreciation for “the nature cures” around us.

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Am J Chin Med. 2010;38(6):1039-49.

The anti-arthritic effects of synthetic melittin on the complete Freund’s adjuvant-induced rheumatoid arthritis model in rats.

Li J, Ke T, He C, Cao W, Wei M, Zhang L, Zhang JX, Wang W, Ma J, Wang ZR, Shao ZJ.

Department of Chinese Traditional Medicine, Xijing Hospital, China.

Abstract

Bee venom (BV) has been used for millennia in Chinese traditional medicine to treat rheumatoid arthritis (RA). However, its components and mechanism remain unclear, which has hampered its development and application for the treatment of RA. In this study, we examined the anti-arthritis effects of melittin, which composes nearly 50% of the dry weight of whole BV, on the complete Freund’s adjuvant-induced (CFA-induced) RA model in rats. The RA animal models were treated with solutions of BV, melittin, and saline by injection into a specific acupoint (Zusanli). The BV and melittin treatments statistically diminished the thickness of the arthroses in the injected side of the paw, compared to the saline treatment. Melittin therapy also significantly reduced arthritis-induced nociceptive behaviors, as assessed by the thermal hyperalgesia test. In addition, CFA-induced Fos expression in the superficial layer of the lumbar spinal cord was significantly suppressed by the BV and melittin treatments, compared to the saline treatment. These results indicate that melittin is an effective anti-arthritis component of whole bee venom, making it a promising candidate as an anti-arthritis drug.

PMID: 21061459 [PubMed – in process]

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J Ethnopharmacol. 2010 Feb 17;127(3):662-8. Epub 2009 Dec 5.

Bee venom suppresses PMA-mediated MMP-9 gene activation via JNK/p38 and NF-kappaB-dependent mechanisms.

Cho HJ, Jeong YJ, Park KK, Park YY, Chung IK, Lee KG, Yeo JH, Han SM, Bae YS, Chang YC.

Research Institute of Biomedical Engineering, Department of Medicine, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Bee venom has been used for the treatment of inflammatory diseases such as rheumatoid arthritis and for the relief of pain in traditional oriental medicine.

AIM OF THE STUDY: The purpose of this study is to elucidate the effects of bee venom on MMP-9 expression and determine possible mechanisms by which bee venom relieves or prevents the expression of MMP-9 during invasion and metastasis of breast cancer cells. We examined the expression and activity of MMP-9 and possible signaling pathway affected in PMA-induced MCF-7 cells.

MATERIAL AND METHODS: Bee venom was obtained from the National Institute of Agricultural Science and Technology of Korea. Matrigel invasion assay, wound-healing assay, zymography assay, western blot assay, electrophoretic mobility shift assay and luciferase gene assay were used for assessment.

RESULTS: Bee venom inhibited cell invasion and migration, and also suppressed MMP-9 activity and expression, processes related to tumor invasion and metastasis, in PMA-induced MCF-7 cells. Bee venom specifically suppressed the phosphorylation of p38/JNK and at the same time, suppressed the protein expression, DNA binding and promoter activity of NF-kappaB. The levels of phosphorylated ERK1/2 and c-Jun did not change. We also investigated MMP-9 inhibition by melittin, apamin and PLA(2), representative single component of bee venom. We confirmed that PMA-induced MMP-9 activity was significantly decreased by melittin, but not by apamin and phospholipase A(2). These data demonstrated that the expression of MMP-9 was abolished by melittin, the main component of bee venom.

CONCLUSION: Bee venom inhibits PMA-induced MMP-9 expression and activity by inhibition of NF-kappaB via p38 MAPK and JNK signaling pathways in MCF-7 cells. These results indicate that bee venom can be a potential anti-metastatic and anti-invasive agent. This useful effect may lead to future clinical research on the anti-cancer properties of bee venom.

Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

PMID: 19969058 [PubMed – indexed for MEDLINE]

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J Inflamm (Lond). 2008 May 29;5:7.

JNK pathway is involved in the inhibition of inflammatory target gene expression and NF-kappaB activation by melittin.

Park HJ, Lee HJ, Choi MS, Son DJ, Song HS, Song MJ, Lee JM, Han SB, Kim Y, Hong JT.

College of Pharmacy, Chungbuk National University, 12 Gaesin-dong, Heungduk-gu, Cheongju, Chungbuk 361-763, Korea. jinthong@chungbuk.ac.kr.

Abstract

ABSTRACT:

BACKGROUND: Bee venom therapy has been used to treat inflammatory diseases including rheumatoid arthritis in humans and in experimental animals. We previously found that bee venom and melittin (a major component of bee venom) have anti-inflammatory effect by reacting with the sulfhydryl group of p50 of nuclear factor-kappa B (NF-kappaB) and IkappaB kinases (IKKs). Since mitogen activated protein (MAP) kinase family is implicated in the NF-kappaB activation and inflammatory reaction, we further investigated whether activation of MAP kinase may be also involved in the anti-inflammatory effect of melittin and bee venom.

METHODS: The anti-inflammatory effects of melittin and bee venom were investigated in cultured Raw 264.7 cells, THP-1 human monocytic cells and Synoviocytes. The activation of NF-kappaB was investigated by electrophoretic mobility shift assay. Nitric oxide (NO) and prostaglandin E2 (PGE2) were determined either by Enzyme Linked Immuno Sorbent Assay or by biochemical assay. Expression of IkappaB, p50, p65, inducible nitric oxide synthetase (iNOS), cyclooxygenase-2 (COX-2) as well as phosphorylation of MAP kinase family was determined by Western blot.

RESULTS: Melittin (0.5-5 mug/ml) and bee venom (5 and 10 mug/ml) inhibited lipopolysaccharide (LPS, 1 mug/ml) and sodium nitroprusside (SNP, 200 muM)-induced activation of c-Jun NH2-terminal kinase (JNK) in RAW 264.7 cells in a dose dependent manner. However, JNK inhibitor, anthra [1,9-cd]pyrazole-6 (2H)-one (SP600215, 10-50 muM) dose dependently suppressed the inhibitory effects of melittin and bee venom on NF-kappaB dependent luciferase and DNA binding activity via suppression of the inhibitory effect of melittin and bee venom on the LPS and SNP-induced translocation of p65 and p50 into nucleus as well as cytosolic release of IkappaB. Moreover, JNK inhibitor suppressed the inhibitory effects of melittin and bee venom on iNOS and COX-2 expression, and on NO and PGE2 generation.

CONCLUSION: These data show that melittin and bee venom prevent LPS and SNP-induced NO and PGE2 production via JNK pathway dependent inactivation of NF-kappaB, and suggest that inactivation of JNK pathways may also contribute to the anti-inflammatory and anti-arthritis effects of melittin and bee venom.

PMID: 18507870 [PubMed – in process]PMCID: PMC2442592Free PMC Article

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J Pharmacol Sci. 2008 Jan;106(1):162-6.

Effects of melittin on the production of matrix metalloproteinase-1 and -3 in rheumatoid arthritic fibroblast-like synoviocytes.

Nah SS, Ha E, Mun SH, Won HJ, Chung JH.

Division of Allergy and Rheumatology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.

Abstract

Bee venom (BV) has been used in patients with rheumatoid arthritis, a condition characterized by rheumatoid joint destruction mediated, in large part, by matrix metalloproteinases (MMPs). We investigated the effects of melittin, a major component of bee venom, on the production of MMPs in human rheumatoid arthritic fibroblast-like synoviocytes (FLS). Lipopolysaccharide (LPS)-stimulated MMP3 production was significantly inhibited by melittin, which also inhibited LPS-induced DNA binding by nuclear factor kappaB (NF-kappaB). Mellitin had no effect on IL-1beta- or TNF-alpha-induced MMP1 or MMP3 production and did not decrease LPS-induced secretion of MMP1. Taken together, these findings suggest that melittin may exert its anti-rheumatoid effects, at least in part, by inhibiting MMP3 production, most likely through inhibition of NF-kappaB activity.

PMID: 18212480 [PubMed – indexed for MEDLINE]Free Article

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J Immunol. 2007 Jul 1;179(1):655-64.

Apis mellifera venom and melittin block neither NF-kappa B-p50-DNA interactions nor the activation of NF-kappa B, instead they activate the transcription of proinflammatory genes and the release of reactive oxygen intermediates.

Stuhlmeier KM.

Ludwig Boltzmann Institute for Rheumatology and Balneology, Vienna, Austria. karlms@excite.com

Abstract

Many alternative treatment approaches, originating from Asia, are becoming increasingly popular in the Western hemisphere. Recently, an article published in a renowned journal reported that venom of apis mellifera (bee venom (BV)) and melittin mediate immune-modulating effects by blocking the activation of the transcription factor NF-kappaB. Such a modus operandi would corroborate the many claims of beneficial effects of BV treatment and give immediate credit to this form of therapy. Fibroblast-like synoviocytes from rheumatoid arthritis patients and dermal fibroblast cells and white blood cells from healthy volunteers were used to study the effects of BV and melittin on the activation of NF-kappaB and a series of genes that are markers of inflammation. EMSAs demonstrate that neither BV nor melittin blocked IL-1beta-induced NF-kappaB activation; neither did they affect phosphorylation or degradation of IkappaB. Contrary to published data, even high concentrations of BV and melittin were without any effect on NF-kappaB-p50-DNA interactions. More importantly, in fibroblast-like synoviocytes, but also in dermal fibroblasts as well as in mononuclear cells exposed to BV or melittin, mRNA levels of several proinflammatory genes are significantly increased, and Western blot data show elevated cyclooxygenase-2 protein levels. Furthermore, exposure to BV higher than 10 mug/ml resulted in disintegration of all cell types tested. In addition, large quantities of oxygen radicals are produced in a dose-dependent manner in leukocytes exposed to BV. Taken together, data presented in this work do not corroborate an earlier report regarding the effectiveness of BV as an inhibitor of the transcription factor NF-kappaB.

PMID: 17579088 [PubMed – indexed for MEDLINE]Free Article

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Pharmacol Ther. 2007 Aug;115(2):246-70. Epub 2007 May 6.

Therapeutic application of anti-arthritis, pain-releasing, and anti-cancer effects of bee venom and its constituent compounds.

Son DJ, Lee JW, Lee YH, Song HS, Lee CK, Hong JT.

College of Pharmacy and CBITRC, Chungbuk National University, 48 Gaesin-dong, Heungduk-gu, Cheongju, Chungbuk 361-763, Korea.

Abstract

Bee venom (BV) therapy (BVT), the therapeutic application of BV, has been used in traditional medicine to treat diseases, such as arthritis, rheumatism, pain, cancerous tumors, and skin diseases. BV contains a variety of peptides, including melittin, apamin, adolapin, the mast-cell-degranulating (MCD) peptide, enzymes (i.e., phospholipase [PL] A(2)), biologically active amines (i.e., histamine and epinephrine), and nonpeptide components which have a variety of pharmaceutical properties. BV has been reported to have anti-arthritis effects in several arthritis models. Melittin, a major peptide component of BV, has anti-inflammatory and anti-arthritis properties, and its inhibitory activity on nuclear factor kappaB (NF-kappaB) may be essential for the effects of BV. The anti-nociceptive effects of BV have also been demonstrated in thermal, visceral, and inflammatory pain models. Apcupoint stimulation (apipuncture) therapy into subcutaneous region may be important in the BV-induced anti-nociceptive effects. Multiple mechanisms, such as activation of the central and spinal opiod receptor, and alpha(2)-adrenergic activity, as well as activation of the descending serotonergic pathway have been suggested. The inhibition of c-Fos expression in the spinal cord by BV apipuncture in several nociceptive models is also reported to be a possible mechanism. BV also has anti-cancer activity. The cell cytotoxic effects through the activation of PLA(2) by melittin have been suggested to be the critical mechanism for the anti-cancer activity of BV. The conjugation of cell lytic peptide (melittin) with hormone receptors and gene therapy carrying melittin can be useful as a novel targeted therapy for some types of cancer, such as prostate and breast cancer.

PMID: 17555825 [PubMed – indexed for MEDLINE]

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Toxicon. 2007 May;49(6):881-5. Epub 2006 Dec 28.

Inhibitory effects of melittin on the production of lipopolysaccharide-induced matrix metalloproteinase 3 in human osteoarthritic chondrocytes.

Nah SS, Ha E, Lee HJ, Chung JH.

Division of Allergy and Rheumatology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.

Abstract

In continuation of our previous study which explored the effect of bee venom (BV) on the global gene expression profiles in lipopolysaccharide (LPS)-treated human chondrosarcoma cells, we investigated herein the effect of melittin, a major component of BV, on the productions of matrix metalloproteinases (MMPs) 1, 3, and 13 in primary cultured human arthritic chondrocytes. Increased generations of MMPs 1, 3, and 13 were observed by MMPs stimulating agents LPS, tumor necrosis factor alpha (TNF-alpha), and interleukin 1beta (IL-1beta). The generations of LPS (1 microg/ml)-induced MMPs 1 and 13 were not decreased by melittin, whereas that of LPS-stimulated MMP 3 was significantly inhibited by melittin. IL-1beta (10ng/ml) and TNF-alpha (10ng/ml)-induced MMPs 1, 3 and 13, however, were not decreased by melittin. Immunoblot analysis revealed that melittin exerted no effect on the LPS-stimulated expression levels of MMPs 1 and 13 but attenuated the LPS-induced MMP 3, which is consistent with the enzyme-linked immunosorbent assay (ELISA) data. Taken together, these findings suggest melittin may exert its anti-arthritic effect, at least in part, by inhibiting LPS-stimulated MMP 3 production in human osteoarthritic chondrocytes.

PMID: 17303203 [PubMed – indexed for MEDLINE]

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Biochem Pharmacol. 2007 Jan 15;73(2):237-47. Epub 2006 Sep 29.

Melittin inhibits inflammatory target gene expression and mediator generation via interaction with IkappaB kinase.

Park HJ, Son DJ, Lee CW, Choi MS, Lee US, Song HS, Lee JM, Hong JT.

College of Pharmacy, Chungbuk National University, 12 Gaesin-dong, Heungduk-gu, Cheongju, Chungbuk 361-763, Republic of Korea.

Abstract

We previously found that bee venom (BV) and melittin (a major component of BV) has anti-inflammatory effect by reacting with the sulfhydryl group of p50 of NF-kappaB. Since the sulfhydryl group is present in IkappaB kinase (IKKalpha and IKKbeta), anti-inflammatory effect of melittin via interaction with IKKs was investigated. We first examined binding of melittin to IKKs using surface plasmon resonance analyzer. Melittin binds to IKKalpha (K(d) = 1.34 x 10(-9) M) and IKKbeta (K(d) = 1.01 x 10(-9) M). Consistent with the high binding affinity, melittin (5 and 10 microg/ml) and BV (0.5, 1 and 5 microg/ml) suppressed sodium nitroprusside, TNF-alpha and LPS induced-IKKbeta and IKKbeta activities, IkappaB release, and NF-kappaB activity as well as the expressions of iNOS and COX-2, and the generation of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) in Raw 264.7 mouse macrophages and synoviocytes obtained from rheumatoid arthritis patients. The binding affinities of melittin to mutant IKKs, was reduced, and the inhibitory effect of melittin on IKK and NF-kappaB activities, and NO and PGE(2) generation were abrogated by the reducing agents or in Raw 264.7 transfected with mutant plasmid IKKalpha (C178A) or IKKbeta (C179A). These results suggest that melittin binding to the sulfhydryl group of IKKs resulted in reduced IKK activities, IkappaB release, NF-kappaB activity and generation of inflammatory mediators, indicating that IKKs may be also anti-inflammatory targets of BV.

PMID: 17067557 [PubMed – indexed for MEDLINE]

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Zhong Yao Cai. 2003 Jun;26(6):456-8.

[Advances in the study of bee venom and its clinical uses]

[Article in Chinese]

Liu H, Tong F.

College of Zoological Sciences, Zhejiang University, Hangzhou 310029, Zhejiang, China.

PMID: 14669739 [PubMed – indexed for MEDLINE]

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Inflammation. 1986 Jun;10(2):175-82.

Bee venom melittin blocks neutrophil O2- production.

Somerfield SD, Stach JL, Mraz C, Gervais F, Skamene E.

Abstract

Bee venom (BV) is used in folk medicine to treat arthritis. It has antiinflammatory effects in animal models of rheumatic disease. We have studied the effects of BV on human neutrophil production of superoxide (O2-) and hydrogen peroxide, finding potent, nontoxic, dose-dependent production inhibition. Melittin, the major fraction of BV (50-70%) shows high-affinity calmodulin binding (Kd 3 nM). Drugs which bind calmodulin, such as trifluoperazine, inhibit O2- production by human neutrophils. For these reasons we have investigated the effect of melittin and other BV peptides on O2- production by human peripheral blood leukocytes. We show that melittin inhibited O2- production both pre- and poststimulation in contrast to other BV fractions which were without effect. Oxygen radicals and their derivatives from inflammatory cells are implicated in the tissue damage occurring during inflammation. The inhibition is due to a direct effect on cells, and not indicator medium, dismutation, toxic or scavenging effects. We propose that melittin may serve as a prototype small (mol wt 1280), cationic, amphipathic, calmodulin-binding, membrane-active, superoxide-production-inhibiting peptide, providing a model for peptides which could have a role in in vivo regulation of radical production.

PMID: 3011670 [PubMed – indexed for MEDLINE]

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