Network Pharmacology and Experimental Verifications to Discover Scutellaria baicalensis Georgi's Effects on Joint Inflammation, Destruction, and Pain in Osteoarthritis.

Osteoarthritis is the most common type of arthritis, characterized by joint pain and a decline in physiological function. Scutellaria baicalensis Georgi (SB) is potentially effective against osteoarthritis because of its wide range of anti-inflammatory pharmacological activities. This study aimed to identify the mode of action of SB against osteoarthritis using network pharmacology prediction and experimental verification. Networks were constructed to key compounds, hub targets, and pathways essential for SB's effectiveness against osteoarthritis. Additionally, in vivo and in vitro tests were performed, including investigations on weight bearing in hind limbs, the acetic acid-induced writhing response, lipopolysaccharide-stimulated RAW264.7 cells, and serum cytokine responses. We identified 15 active compounds and 14 hub targets, supporting the anti-osteoarthritis effects of SB. The Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that fluid shear stress, atherosclerosis, phosphatidylinositol 3-kinase-Akt signaling, and cellular senescence pathways were important. SB showed substantial anti-inflammatory, analgesic, and joint tissue-protective effects against osteoarthritis. Our study shows that SB has the potential value to be further investigated as a candidate material for the treatment of osteoarthritis in the future.

Herbal medicine for external use in acute gouty arthritis: A PRISMA-compliant systematic review and meta-analysis.

BACKGROUND: Acute gouty arthritis is accompanied by severe pain during an acute attack. This systematic review aimed to evaluate the efficacy and safety of herbal medicines acting directly on the affected area of acute gouty arthritis for external use. METHODS: An envelope search was performed using 4 electronic databases (CNKI, PubMed, EMBASE, Cochrane), resulting in 27 clinical studies from inception to February 2023. Randomized controlled trials on external use herbal medicines for acute gouty arthritis were considered. The assessed outcomes were total effective rate, uric acid level, pain score, and inflammatory factor levels such as erythrocyte sedimentation rate and C-reactive protein. Quality assessment and meta-analysis of the included randomized controlled trials were also performed. RESULTS: Twenty-seven randomized controlled trials with a total of 1951 participants were included in the meta-analysis. All assessed outcomes including pain, inflammation, and uric acid levels, indicated that the treatment effects in the external use herbal medicine group were significantly better than those of the western medicine control group. Of the 10 studies mentioning side effects, no side effects were reported in 4, and in the remaining 6, the incidence of complications in the intervention group was much lower than that in the control group. CONCLUSIONS: This systematic review and meta-analysis suggests that external use herbal medicines may be a safe and effective alternative for treatment of pain and symptoms of acute gouty arthritis. However, owing to the heterogeneity of interventions, outcomes, and regional bias, further high-quality clinical trials on this topic are needed to confirm the level of evidence.

Stem of Sorbus commixta Hedl. Extract Inhibits Cartilage Degradation and Arthritic Pain in Experimental Model via Anti-Inflammatory Activity.

Osteoarthritis (OA) is a widespread joint disease that affects millions of people worldwide. Conventional treatments for OA, including non-steroidal anti-inflammatory drugs (NSAIDs) and steroids, have a risk of various adverse events, including liver, gastrointestinal, cardiovascular, and kidney disease, which are unsatisfactory in their effectiveness. In this study, Sorbus commixta Hedl. Stem extracts (SCE) were evaluated in animal models as potential inhibitors for the progression of OA. Sorbus commixta Hedl., which was found to have substantial anti-inflammatory and antioxidant activities in earlier investigations, has shown potential as a candidate for OA treatment. To mimic human OA symptoms, male rats were injected using sodium iodoacetate (MIA) in their knee joints. SCE significantly reduced MIA-induced weight-bearing loss in rats after the MIA injection and alleviated cartilage degradation and subchondral bone injury caused by MIA. In addition, SCE administration reduced levels of TNF-α and IL-1ß such as pro-inflammatory cytokines in serum, as well as the levels of matrix metalloproteinases (MMPs) such as MMP-1, -3, -8 and -13 in the joint cartilage. SCE significantly inhibited the writhing responses in acetic acid-administered mice and was used to quantify pain. In lipopolysaccharide (LPS)-activated RAW264.7, SCE suppressed NO production and reduced the expression of TNF-α, PGE2, IL-6, IL-1ß, MMP1, MMP3, MMP8, and MMP-13. Our study showed that SCE alleviated inflammation and cartilage degradation in arthritis through its anti-inflammatory activities on multiple targets.

Network analysis, in vivo, and in vitro experiments identified the mechanisms by which Piper longum L. [Piperaceae] alleviates cartilage destruction, joint inflammation, and arthritic pain.

Osteoarthritis (OA) is characterized by irreversible joint destruction, pain, and dysfunction. Piper longum L. [Piperaceae] (PL) is an East Asian herbal medicine with reported anti-inflammatory, analgesic, antioxidant, anti-stress, and anti-osteoporotic effects. This study aimed to evaluate the efficacy of PL in inhibiting pain and progressive joint destruction in OA based on its anti-inflammatory activity, and to explore its potential mechanisms using in vivo and in vitro models of OA. We predicted the potential hub targets and signaling pathways of PL through network analysis and molecular docking. Network analysis results showed that the possible hub targets of PL against OA were F2R, F3, MMP1, MMP2, MMP9, and PTGS2. The molecular docking results predicted strong binding affinities for the core compounds in PL: piperlongumine, piperlonguminine, and piperine. In vitro experiments showed that PL inhibited the expression of LPS-induced pro-inflammatory factors, such as F2R, F3, IL-1ß, IL-6, IL-17A, MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, NOS2, PTGS2, PGE2, and TNF-ß. These mechanisms and effects were dose-dependent in vivo models. Furthermore, PL inhibited cartilage degradation in an OA-induced rat model. Thus, this study demonstrated that multiple components of PL may inhibit the multilayered pathology of OA by acting on multiple targets and pathways. These findings highlight the potential of PL as a disease-modifying OA drug candidate, which warrants further investigation.

Oral administration of East Asian herbal medicine for rheumatoid arthritis: A protocol for systematic review and meta-analysis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic, inflammatory, and painful joint disease. The aim of this review is to systematically evaluate the efficacy and safety of oral administration East Asian herbal medicine monotherapy for inflammatory pain of RA, and to explore core herb material information based on collected data. METHODS: A comprehensive literature search will be conducted in 11 electronic databases including PubMed, Cochrane Library, Cumulative Index to Nursing & Allied Health Literature, Excerpta Medica database, Korean Studies Information Service System, Research Information Service System Oriental Medicine Advanced Searching Integrated System, Korea Citation Index, Chinese National Knowledge Infrastructure Database, Wanfang data, citation information by NII for randomized controlled trials from their inception until October 13, 2021. Statistical analysis will be performed in the software R version 4.1.1. and R studio program using the default settings of the "meta" and "metafor" package. When heterogeneity in studies is detected, the cause will be identified through subgroup analysis. Methodological quality will be assessed independently using the revised tool for risk of bias in randomized trials (Rob 2.0). RESULTS: This study will provide more comprehensive and specific evidence of East Asian herbal medicine monotherapy for RA pain management. CONCLUSIONS: Based on the results of this review, it is expected that the efficacy and safety of East Asian herbal medicine for inflammatory pain of RA may be confirmed. In addition, it will be possible to derivation of a core herb material information related to this research topic through additional data mining. ETHICS AND DISSEMINATION: There are no ethical issues as there are no primary data collected by directly recruiting subjects. The results of this review will be reported in a peer-reviewed scientific journal. PROSPERO REGISTRATION NUMBER: CRD42021273643.

Systematic Review and Meta-Analysis of Efficacy and Safety of Fire Needling and Warm Needling on Acute Gout.

Objectives: This study aimed to evaluate the efficacy and safety of heat stimuli (e.g., fire needling, warm needling) in acupuncture for acute gout. Methods: Four international online databases (PubMed, Cochrane, Embase, and Chinese National Knowledge Infrastructure) were searched to identify randomized, controlled trials (RCTs) that used fire needling and warm needling for acute gout. The methodological quality of the RCTs was evaluated using the Cochrane risk-of-bias (RoB) tool. Thirteen RCTs (840 patients) were included and analyzed. Three evaluation tools (total effective rate, uric acid level, and pain score) were mainly used. Comparisons were made between Western medicine (WM) and i) fire needling or warm needling treatment alone, ii) fire needling and bloodletting combination treatment, iii) combination of fire needling, bloodletting, and herbal medicine, iv) warm needling (concurrently). Heat stimuli in acupuncture alone or in combination treatment were more effective in terms of the total efficacy rates, uric acid levels, and pain scores than WM alone. Results: In all the evaluation tools, the treatment effects in the fire needling alone or warm needling alone treatment group and the fire needling and bloodletting combination intervention group were significantly better than those in the WM control group. The warm needling and WM combination intervention groups also experienced significantly better treatment effects in terms of total efficacy rates and uric acid levels. Only the pain scores in the fire needling, bloodletting, and herbal medicine combination groups demonstrated significant improvement. Only four studies mentioned adverse reactions one reported loss of appetite; three studies reported none. According to the Cochrane RoB tool, most studies showed either high or uncertain RoB. Conclusion: Heat stimuli during acupuncture could be effective for acute gout. However, as the included studies were regionally biased, more high-quality studies are needed to confirm the level of evidence.

A Meta-Analysis of Treatment Effects on Viral Pneumonia Using TCM Injections Specified in the Clinical Guideline for COVID-19 in China.

OBJECTIVES: The purpose of this study is to analyze the efficacy of traditional Chinese medicine (TCM) injections specified in the clinical guideline for COVID-19 by conducting a meta-analysis of viral pneumonia data. METHODS: TCM injections data on viral pneumonia were collected until July 31, 2021. CNKI, PubMed, EMBASE, and the Cochrane electronic database were used to collect the clinical data. "COVID-19," "Viral pneumonia," "Tanreqing," "Xiyanping," "Reduning," "Xingnaojing," "Xuebijing," "Shenmai," "Shengmai," and "Shenfu" were used as keywords. All data collected were mainly about TCM injections and viral pneumonia. Furthermore, studies that included results such as the total effective rate, cough disappearance time, antipyretic time, lung rhomboid disappearance time, and adverse drug reaction were collected for the meta-analysis to identify the efficacy of TCM injections. However, data unrelated to TCM injections specified in the clinical guidelines for COVID-19 or viral pneumonia were excluded. The quality of included RCTs was assessed by the Cochrane Risk of Bias Tool, and Review Manager 5.3 software was used to conduct the meta-analysis. RESULTS: A total of 18 studies with 1540 patients were included in this study. The results of the meta-analysis showed that the total effective rate OR = 4.61 (95% CI 2.92, 7.25, p = 1.00/ I2 = 0%); the cough disappearance time SMD -1.23 (-1.37, -1.09, p < 0.00001/ I2 = 94%); the antipyretic time SMD -1.26 (-1.40, -1.11, p < 0.00001/ I2=94%); lung rhomboid disappearance time SMD -1.17 (-1.33, -1.02, p < 0.00001/ I2 = 89%); and adverse drug reaction was OR 0.36 (95% CI 0.20, 0.64, p = 0.21/ I2 = 30%). From the results, the treatment group (TCM injection) showed better efficacy than the control group (Western medication). CONCLUSION: Xiyanping, Reduning, and Tanreqing injections may yield benefits as COVID-19 treatments. However, clinical trials on TCM injections for the treatment of COVID-19 are still lacking. More high-quality clinical trials are still required.

External application of herbal medicine for gout: A protocol for systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Gout affects a significant portion of the population worldwide annually. Numerous studies have been reported mainly in East Asia, explaining the use of traditional herbal decoctions for gout treatment. Our systematic review will be conducted to critically evaluate the evidence for the safety and effectiveness of external applications of herbal medicines on gout. METHODS: Two independent researchers will perform electronic literature searches, study selection, data extraction, and quality assessment. To identify randomized controlled trials (RCTs) involving various external applications of herbal medicine for gout, a search will be carried out using the following 7 electronic databases: MEDLINE, EMBASE, Cochrane Library, KoreaMed, Oriental Medicine Advanced Searching Integrated System, Korean Studies Information Service System, and China National Knowledge Infrastructure. Each electronic database will be searched for articles published from their inception to the present date. Studies will be selected based on predefined criteria and summarized data regarding study participants, interventions, control groups, outcome measures, side effects, and risk of bias. There are no restrictions on publication status or language. Studies that evaluated any type of external application of herbal medicines will be eligible for inclusion, and the primary outcome will be the blood uric acid level. The methodological quality of the included RCTs will be assessed using the Cochrane risk-of-bias tool. RESULTS: The present study will evaluate effectiveness and safety of external application of herbal medicines for gout. CONCLUSION: Our findings will establish evidence for the external application of herbal medicines for gout and will be informative for patients with gout, clinicians, policymakers, and researchers.The results of this systematic review will be published in a peer-reviewed journal and disseminated electronically and in print. This review will be updated to inform and guide healthcare practices.

Acupuncture to treat asymptomatic hyperuricemia: A protocol for systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Hyperuricemia (HUA) plays an important role in metabolic syndrome, cardiovascular disease, and kidney disease. HUA without resulting gout is referred to as asymptomatic HUA. The purpose of the present systematic review protocol is to provide methods to assess the effectiveness and safety of acupuncture-based treatment for asymptomatic HUA. METHODS: To identify randomized controlled trials (RCTs) involving acupuncture-based treatment for asymptomatic HUA, a search will be carried out using the following eight electronic databases: MEDLINE, EMBASE, Cochrane Library, Korea Med, Oriental Medicine Advanced Searching Integrated System, Korean Studies Information Service System, China National Knowledge Infrastructure, and Japanese Institutional Repositories Online. Manual search and email contact with the author will also be conducted if necessary. Studies will be selected based on predefined criteria and summarized data regarding study participants, interventions, control groups, outcome measures, side effects, and risk of bias. No language restrictions will be imposed. Studies that evaluated any type of acupuncture will be eligible for inclusion, and the primary outcome will be the blood uric acid level. The methodological quality of the included RCTs will be assessed using the Cochrane risk of bias tool. RESULTS: The present study will evaluate the efficacy and safety of acupuncture to treat HUA. CONCLUSION: Our findings will establish the evidence for acupuncture-based treatment of HUA and will be informative for patients with HUA, clinicians, policy makers, and researchers. REGISTRATION NUMBER: reviewregistry1054.

Analgesic and Anti-Inflammatory Effects of Aucklandia lappa Root Extracts on Acetic Acid-Induced Writhing in Mice and Monosodium Iodoacetate-Induced Osteoarthritis in Rats.

Osteoarthritis (OA) is an age-related joint disease and one of the most common degenerative bone diseases among elderly people. The currently used therapeutic strategies relying on nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids for OA are often associated with gastrointestinal, cardiovascular, and kidney disorders, despite being proven effective. Aucklandia lappa is a well-known traditional medicine. The root of A. lappa root has several bioactive compounds and has been in use as a natural remedy for bone diseases and other health conditions. We evaluated the A. lappa root extracts on OA progression as a natural therapeutic agent. A. lappa substantially reduced writhing numbers in mice induced with acetic acid. Monosodium iodoacetate (MIA) was injected into the rats through their knee joints of rats to induce experimental OA, which shows similar pathological characteristics to OA in human. A. lappa substantially reduced the MIA-induced weight-bearing of hind limb and reversed the cartilage erosion in MIA rats. IL-1ß, a representative inflammatory mediator in OA, was also markedly decreased by A. lappa in the serum of MIA rats. In vitro, A. lappa lowered the secretion of NO and suppressed the IL-1ß, COX-2, IL-6, and iNOS production in RAW264.7 macrophages activated with LPS. Based on its analgesic and anti-inflammatory effects, A. lappa could be a potential remedial agent against OA.

Anti-inflammatory effect of bee venom in phthalic anhydride-induced atopic dermatitis animal model.

Globally, many people have been affected with atopic dermatitis (AD), a chronic inflammatory skin disease. AD is associated with multiple factors such as genetic, inflammatory, and immune factors. Bee venom (BV) is now widely used for the treatment of several inflammatory diseases. However, its effect on 5% phthalic anhydride (PA)-induced AD has not been reported yet. We investigated the anti-inflammatory and anti-AD effects of BV in a PA-induced animal model of AD. Balb/c mice were treated with topical application of 5% PA to the dorsal skin and ears for induction of AD. After 24 h, BV was applied on the back and ear skin of the mice three times a week for 4 weeks. BV treatment significantly reduced the PA-induced AD clinical score, back and ear epidermal thickness, as well as IgE level and infiltration of immune cells in the skin tissues compared to those of control mice. The levels of inflammatory cytokines in the serum were significantly decreased in BV-treated group compared to PA-treated group. In addition, BV inhibited the expression of iNOS and COX-2 as well as the activation of mitogen-activated protein kinase (MAPK) and NF-Ò¡B induced by PA in the skin tissues. We also found that BV abrogated the lipopolysaccharide or TNF-α/IFN-γ-induced NO production, expression of iNOS and COX-2, as well as MAPK and NF-Ò¡B signaling pathway in RAW 264.7 and HaCaT cells. These results suggest that BV may be a potential therapeutic macromolecule for the treatment of AD.

Anti-cancer effect of bee venom on colon cancer cell growth by activation of death receptors and inhibition of nuclear factor kappa B.

Bee venom (BV) has been used as a traditional medicine to treat arthritis, rheumatism, back pain, cancerous tumors, and skin diseases. However, the effects of BV on the colon cancer and their action mechanisms have not been reported yet. We used cell viability assay and soft agar colony formation assay for testing cell viability, electro mobility shift assay for detecting DNA binding activity of nuclear factor kappa B (NF-κB) and Western blotting assay for detection of apoptosis regulatory proteins. We found that BV inhibited growth of colon cancer cells through induction of apoptosis. We also found that the expression of death receptor (DR) 4, DR5, p53, p21, Bax, cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9 was increased by BV treatment in a dose dependent manner (0-5 µg/ml). Consistent with cancer cell growth inhibition, the DNA binding activity of nuclear factor kappa B (NF-κB) was also inhibited by BV treatment. Besides, we found that BV blocked NF-κB activation by directly binding to NF-κB p50 subunit. Moreover, combination treatment with BV and p50 siRNA or NF-κB inhibitor augmented BV-induced cell growth inhibition. However, p50 mutant plasmid (C62S) transfection partially abolished BV-induced cell growth inhibiton. In addition, BV significantly suppressed tumor growth in vivo. Therefore, these results suggested that BV could inhibit colon cancer cell growth, and these anti-proliferative effects may be related to the induction of apoptosis by activation of DR4 and DR5 and inhibition of NF-κB.

Bee venom ameliorates lipopolysaccharide-induced memory loss by preventing NF-kappaB pathway.

BACKGROUND: Accumulation of beta-amyloid and neuroinflammation trigger Alzheimer's disease. We previously found that lipopolysaccharide (LPS) caused neuroinflammation with concomitant accumulation of beta-amyloid peptides leading to memory loss. A variety of anti-inflammatory compounds inhibiting nuclear factor kappaB (NF-κB) activation have showed efficacy to hinder neuroinflammation and amyloidogenesis. We also found that bee venom (BV) inhibits NF-κB. METHODS: A mouse model of LPS-induced memory loss used administration of BV (0.8 and 1.6 µg/kg/day, i.p.) to ICR mice for 7 days before injection of LPS (2.5 mg/kg/day, i.p.). Memory loss was assessed using a Morris water maze test and passive avoidance test. For in vitro study, we treated BV (0.5, 1, and 2 µg/mL) to astrocytes and microglial BV-2 cells with LPS (1 µg/mL). RESULTS: We found that BV inhibited LPS-induced memory loss determined by behavioral tests as well as cell death. BV also inhibited LPS-induced increases in the level of beta-amyloid (Aß), ß-and γ-secretases activities, NF-κB and its DNA-binding activity and expression of APP, and BACE1 and neuroinflammation proteins (COX-2, iNOS, GFAP and IBA-1) in the brain and cultured cells. In addition, pull-down assay and molecular modeling showed that BV binds to NF-κB. CONCLUSIONS: BV attenuates LPS-induced amyloidogenesis, neuroinflammation, and therefore memory loss via inhibiting NF-κB signaling pathway. Thus, BV could be useful for treatment of Alzheimer's disease.

Moxibustion treatment for knee osteoarthritis: a multi-centre, non-blinded, randomised controlled trial on the effectiveness and safety of the moxibustion treatment versus usual care in knee osteoarthritis patients.

INTRODUCTION: This study tested the effectiveness of moxibustion on pain and function in chronic knee osteoarthritis (KOA) and evaluated safety. METHODS: A multi-centre, non-blinded, parallel-group, randomised controlled trial compared moxibustion with usual care (UC) in KOA. 212 South Korean patients aged 40-70 were recruited from 2011-12, stratified by mild (Kellgren/Lawrence scale grades 0/1) and moderate-severe KOA (grades 2/3/4), and randomly allocated to moxibustion or UC for four weeks. Moxibustion involved burning mugwort devices over acupuncture and Ashi points in affected knee(s). UC was allowed. Korean Western Ontario and McMaster Universities Questionnaire (K-WOMAC), Short Form 36 Health Survey (SF-36v2), Beck Depression Inventory (BDI), physical performance test, pain numeric rating scale (NRS) and adverse events were evaluated at 5 and 13 weeks. K-WOMAC global score at 5 weeks was the primary outcome. RESULTS: 102 patients (73 mild, 29 moderate-severe) were allocated to moxibustion, 110 (77 mild, 33 moderate-severe) to UC. K-WOMAC global score (moxibustion 25.42+/-SD 19.26, UC 33.60+/-17.91, p<0.01, effect size = 0.0477), NRS (moxibustion 44.77+/-22.73, UC 56.23+/-17.71, p<0.01, effect size = 0.0073) and timed-stand test (moxibustion 24.79+/-9.76, UC 25.24+/-8.84, p = 0.0486, effect size  = 0.0021) were improved by moxibustion at 5 weeks. The primary outcome improved for mild but not moderate-severe KOA. At 13 weeks, moxibustion significantly improved the K-WOMAC global score and NRS. Moxibustion improved SF-36 physical component summary (p = 0.0299), bodily pain (p = 0.0003), physical functioning (p = 0.0025) and social functioning (p = 0.0418) at 5 weeks, with no difference in mental component summary at 5 and 13 weeks. BDI showed no difference (p = 0.34) at 5 weeks. After 1158 moxibustion treatments, 121 adverse events included first (n = 6) and second degree (n = 113) burns, pruritus and fatigue (n = 2). CONCLUSIONS: Moxibustion may improve pain, function and quality of life in KOA patients, but adverse events are common. Limitations included no sham control or blinding. TRIAL REGISTRATION: Clinical Research Information Service (CRIS) KCT0000130.

Moxibustion for treating knee osteoarthritis: study protocol of a multicentre randomised controlled trial.

BACKGROUND: The treatment of knee osteoarthritis, which is a major cause of disability among the elderly, is typically selected from multidisciplinary options, including complementary and alternative medicine. Moxibustion has been used in the treatment of knee osteoarthritis in Korea to reduce pain and improve physical activity. However, there is no sufficient evidence of its effectiveness, and it cannot therefore be widely recommended for treating knee osteoarthritis. We designed a randomised controlled clinical trial to evaluate the effectiveness, safety, cost-effectiveness, and qualitative characteristics of moxibustion treatment of knee osteoarthritis compared to usual care. METHODS/DESIGNS: This is a protocol for a multicentre, pragmatic, randomised, assessor-blinded, controlled, parallel-group study. A total of 212 participants will be assigned to the moxibustion group (n = 106) and the usual care group (n = 106) at 4 clinical research centres. The participants assigned to the moxibustion group will receive moxibustion treatment of the affected knee(s) at 6 standard acupuncture points (ST36, ST35, ST34, SP9, Ex-LE04, and SP10) 3 times per week for 4 weeks (a total of 12 sessions). Participants in the usual care group will not receive moxibustion treatment during the study period. Follow-up will be performed on the 5th and 13th weeks after random allocation. Both groups will be allowed to use any type of treatment, including surgery, conventional medication, physical treatment, acupuncture, herbal medicine, over-the-counter drugs, and other active treatments. Educational material that explains knee osteoarthritis, the current management options, and self-exercise will be provided to each group. The global scale of the Korean Western Ontario and McMaster Osteoarthritis Index (K-WOMAC) will be the primary outcome measurement used in this study. Other subscales (pain, stiffness, and function) of the K-WOMAC, the Short-Form 36v2 Health Survey, the Beck Depression Inventory, the Physical Function test, Patient Global Assessment, and the Pain Numerical Rating Scale will be used as outcome variables to evaluate the effectiveness of moxibustion. Safety will be assessed at every visit. In addition, an economic evaluation and a qualitative study will be conducted as a mixed-methods approach. DISCUSSION: This trial may contribute to developing evidence for the effectiveness and safety of moxibustion for treating knee osteoarthritis. TRIAL REGISTRATION NUMBER: KCT0000130.

Anti-cancer effect of bee venom in prostate cancer cells through activation of caspase pathway via inactivation of NF-κB.

BACKGROUND: Bee venom has been used as a traditional medicine to treat arthritis, rheumatism, back pain, cancerous tumors, and skin diseases. However, the effects of bee venom on the prostate cancer and their action mechanisms have not been reported yet. METHODS: To determine the effect of bee venom and its major component, melittin on the prostate cancer cells, apoptosis is analyzed by tunnel assay and apoptotic gene expression. For xenograft studies, bee venom was administrated intraperitoneally twice per week for 4 weeks, and the tumor growth was measured and the tumor were analyzed by immunohistochemistry. To investigate whether bee venom and melittin can inactivate nuclear factor kappa B (NF-κB), we assessed NF-κB activity in vitro and in vivo. RESULTS AND CONCLUSIONS: Bee venom (1-10 µg/ml) and melittin (0.5-2.5 µg/ml) inhibited cancer cell growth through induction of apoptotic cell death in LNCaP, DU145, and PC-3 human prostate cancer cells. These effects were mediated by the suppression of constitutively activated NF-κB. Bee venom and melittin decreased anti-apoptotic proteins but induced pro-apoptotic proteins. However, pan caspase inhibitor abolished bee venom and melittin-induced apoptotic cell death and NF-κB inactivation. Bee venom (3-6 mg/kg) administration to nude mice implanted with PC-3 cells resulted in inhibition of tumor growth and activity of NF-κB accompanied with apoptotic cell death. Therefore, these results indicated that bee venom and melittin could inhibit prostate cancer in in vitro and in vivo, and these effects may be related to NF-κB/caspase signal mediated induction of apoptotic cell death.

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

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.

Antiarthritic effect of bee venom: inhibition of inflammation mediator generation by suppression of NF-kappaB through interaction with the p50 subunit.

OBJECTIVE: To investigate the molecular mechanisms of the antiarthritic effects of bee venom (BV) and melittin (a major component of BV) in a murine macrophage cell line (Raw 264.7) and in synoviocytes obtained from patients with rheumatoid arthritis. METHODS: We evaluated the antiarthritic effects of BV in a rat model of carrageenan-induced acute edema in the paw and in a rat model of chronic adjuvant-induced arthritis. The inhibitory effects of BV and melittin on inflammatory gene expression were measured by Western blotting, and the generation of prostaglandin E(2) (PGE(2)) and nitric oxide (NO) and the intracellular calcium level were assayed. NF-kappaB DNA binding and transcriptional activity were determined by gel mobility shift assay or by luciferase assay. Direct binding of BV and melittin to the p50 subunit of NF-kappaB was determined with a surface plasmon resonance analyzer. RESULTS: BV (0.8 and 1.6 mug/kg) reduced the effects of carrageenan- and adjuvant-induced arthritis. This reducing effect was consistent with the inhibitory effects of BV (0.5, 1, and 5 mug/ml) and melittin (5 and 10 mug/ml) on lipopolysaccharide (LPS; 1 mug/ml)-induced expression of cyclooxygenase 2, cytosolic phospholipase A(2), inducible NO synthase, generation of PGE(2) and NO, and the intracellular calcium level. BV and melittin prevented LPS-induced transcriptional and DNA binding activity of NF-kappaB via the inhibition of IkappaB release and p50 translocation. BV (affinity [K(d)] = 4.6 x 10(-6)M) and melittin (K(d) = 1.2 x 10(-8)M) bound directly to p50. CONCLUSION: Target inactivation of NF-kappaB by directly binding to the p50 subunit is an important mechanism of the antiarthritic effects of BV.