Cuaz-Perolin C. Billiet L. Bauge E. Copin C. Scott-Algara D. Genze F. Buchele B. Syrovets T. Simmet T. Rouis M. Antiinflammatory and antiatherogenic effects of the NF-kappaB inhibitor acetyl-11-keto-beta-boswellic acid in LPS-challenged ApoE-/- mice. Arteriosclerosis, Thrombosis & Vascular Biology. 28(2):272-7, 2008 OBJECTIVE: In this article, we studied the effect of acetyl-11-keto-beta-boswellic acid (AKbetaBA), a natural inhibitor of the proinflammatory transcription factor NF-kappaB on the development of atherosclerotic lesions in apolipoprotein E-deficient (apoE-/-) mice. METHODS AND RESULTS: Atherosclerotic lesions were induced by weekly LPS injection in apoE-/- mice. LPS alone increased atherosclerotic lesion size by approximately 100%, and treatment with AKbetaBA significantly reduced it by approximately 50%. Moreover, the activity of NF-kappaB was also reduced in the atherosclerotic plaques of LPS-injected apoE-/- mice treated with AKbetaBA. As a consequence, AKbetaBA treatment led to a significant downregulation of several NF-kappaB-dependent genes such as MCP-1, MCP-3, IL-1alpha, MIP-2, VEGF, and TF. By contrast, AKbetaBA did not affect the plasma concentrations of triglycerides, total cholesterol, antioxidized LDL antibodies, and various subsets of lymphocyte-derived cytokines. Moreover, AKbetaBA potently inhibited the IkappaB kinase (IKK) activity immunoprecipitated from LPS-stimulated mouse macrophages and mononuclear cells leading to decreased phosphorylation of IkappaB alpha and inhibition of p65/NF-kappaB activation. Comparable AKbetaBA-mediated inhibition was also observed in LPS-stimulated human macrophages. CONCLUSIONS: The inhibition of NF-kappaB activity by plant resins from species of the Boswellia family might represent an alternative for classical medicine treatments for chronic inflammatory diseases such as atherosclerosis.
Madisch A. Miehlke S. Eichele O. Mrwa J. Bethke B. Kuhlisch E. Bastlein E. Wilhelms G. Morgner A. Wigginghaus B. Stolte M. Boswellia serrata extract for the treatment of collagenous colitis. A double-blind, randomized, placebo-controlled, multicenter trial. International Journal of Colorectal Disease. 22(12):1445-51, 2007 BACKGROUND AND AIMS: The objective of this study was to investigate the effect of Boswellia serrata extract (BSE) on symptoms, quality of life, and histology in patients with collagenous colitis. MATERIALS AND METHODS: Patients with chronic diarrhea and histologically proven collagenous colitis were randomized to receive either oral BSE 400 mg three times daily for 6 weeks or placebo. Complete colonoscopy and histology were performed before and after treatment. Clinical symptoms and quality of life were assessed by standardized questionnaires and SF-36. The primary endpoint was the percentage of patients with clinical remission after 6 weeks (stool frequency<or=3 soft /solid stools per day on average during the last week). Patients of the placebo group with persistent diarrhea received open-label BSE therapy for a further 6 weeks. RESULTS: Thirty-one patients were randomized; 26 patients were available for per-protocol-analysis. After 6 weeks, the proportion of patients in clinical remission was higher in the BSE group than in the placebo group (per protocol 63.6%; 95%CI, 30.8-89.1 vs 26.7%, 95%CI, 7.7-55.1; p=0.04; intention-to-treat 43.8% vs 26.7%, p=0.25). Compared to placebo, BSE treatment had no effect on histology and quality of life. Five patients discontinued BSE treatment prematurely. Discontinuation was due to adverse events (n=1), unwillingness to continue (n=3), or loss to follow-up for unknown reasons (n=1). Seven patients received open-label BSE therapy, five of whom achieved complete remission. CONCLUSIONS: Our study suggests that BSE might be clinically effective in patients with collagenous colitis. Larger trials are clearly necessary to establish the clinical efficacy of BSE.
Camarda L. Dayton T. Di Stefano V. Pitonzo R. Schillaci D. Chemical composition and antimicrobial activity of some oleogum resin essential oils from Boswellia spp. (Burseraceae). Annali di Chimica. 97(9):837-44, 2007 The chemical composition of Boswellia carteri (Somalia), B. papyrifera (Ethiopia), B. serrata (India) and B. rivae (Ethiopia) oleogum resin essential oils was investigated using GC-MS to identify chemotaxonomy marker components. Total ion current peak areas gave good approximations to relative concentrations based on GC-MS peak areas. B. carteri and B. serrata oleogum resin oils showed similar chemical profiles, with isoincensole and isoincensole acetate as the main diterpenic components. Both n-octanol and n-octyl acetate, along with the diterpenic components incensole and incensole acetate, were the characteristic compounds of B. papyrifera oleogum resin oil. Hydrocarbon and oxygenated monoterpenes were the most abundant classes of compounds identified in the B. rivae oleogum resin oil. The antimicrobial activities of the essential oils were individually evaluated against different microorganisms including fungi, Gram-positive and Gram-negative bacteria strains. The essential oils with the best activity against fungal strains were those obtained from B. carteri and B. papyrifera with MIC values as low as 6.20 microg/ml. The essential oil of B. rivae resin showed the best activity against C. albicans with a MIC value of 2.65 microg/ml.
Moussaieff A. Shohami E. Kashman Y. Fride E. Schmitz ML. Renner F. Fiebich BL. Munoz E. Ben-Neriah Y. Mechoulam R. Incensole acetate, a novel anti-inflammatory compound isolated from Boswellia resin, inhibits nuclear factor-kappa B activation. Molecular Pharmacology. 72(6):1657-64, 2007Boswellia resin is a major anti-inflammatory agent in herbal medical tradition, as well as a common food supplement. Its anti-inflammatory activity has been attributed to boswellic acid and its derivatives. Here, we re-examined the anti-inflammatory effect of the resin, using inhibitor of nuclear factor-kappaB alpha (IkappaB alpha) degradation in tumor necrosis factor (TNF) alpha-stimulated HeLa cells for a bioassay-guided fractionation. We thus isolated two novel nuclear factor-kappaB (NF-kappaB) inhibitors from the resin, their structures elucidated as incensole acetate (IA) and its nonacetylated form, incensole (IN). IA inhibited TAK/TAB-mediated IkappaB kinase (IKK) activation loop phosphorylation, resulting in the inhibition of cytokine and lipopolysaccharide-mediated NF-kappaB activation. It had no effect on IKK activity in vitro, and it did not suppress IkappaB alpha phosphorylation in costimulated T-cells, indicating that the kinase inhibition is neither direct nor does it affect all NF-kappaB activation pathways. The inhibitory effect seems specific; IA did not interfere with TNFalpha-induced activation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase. IA treatment had a robust anti-inflammatory effect in a mouse inflamed paw model. Cembrenoid diterpenoids, specifically IA and its derivatives, may thus constitute a potential novel group of NF-kappaB inhibitors, originating from an ancient anti-inflammatory herbal remedy.
Kavitha JV. Rosario JF. Chandran J. Anbu P. Bakkiyanathan. Hypoglycemic and other related effects of Boswellia glabra in alloxan-induced diabetic rats. Indian Journal of Physiology & Pharmacology. 51(1):29-39, 2007 The hypoglycemic effect of the aqueous extract of the leaves and roots of Boswellia glabra was examined using alloxan-induced diabetic rats. A single oral administration of Boswellia glabra leaf and root extract decreased the blood glucose level. The continued use of leaf and root extract for 28 days produced significant hypoglycemic effects; also there was a decrease in serum glucose, cholesterol, triglyceride, urea and creatinine levels and enzyme activities (alkaline phosphatase and glucose-6-phosphatase). Ultra structural studies of beta cell of alloxan-induced diabetic rats treated with root extract showed numerous granulated sacs in comparison to rats treated with leaf extract. Thus, rats treated with root extract showed less degranulated sacs and more number of filled secretory granules in comparison to diabetic rats. Thus the use of aqueous extract of Boswellia glabra increased the synthesis of secretory granules in the beta-cell.
Gayathri B. Manjula N. Vinaykumar KS. Lakshmi BS. Balakrishnan A. Pure compound from Boswellia serrata extract exhibits anti-inflammatory property in human PBMCs and mouse macrophages through inhibition of TNFalpha, IL-1beta, NO and MAP kinases. International Immunopharmacology. 7(4):473-82, 2007 The aim of the present study is to probe the anti-inflammatory potential of the plant Boswellia serrata by studying the effect of the crude extract and the pure compound isolated from it on key inflammatory mediators like TNFalpha, IL-1beta, and NO thus enabling the understanding of the key signaling events involved. The crude methanolic extract and the pure compound were analysed for their inhibitory effect on TNFalpha, IL-1beta and IL-6. The results demonstrated that all three cytokines are down regulated when PBMCs are cultured in the presence of crude extract or the pure compound at various time points. Observations on Th1/Th2 cytokines revealed marked down regulation of Th1 cytokines IFNgamma and IL-12 while the Th2 cytokines IL-4 and IL-10 were up regulated upon treatment with crude extract and pure compound. The extract and the pure compound isolated also showed considerable inhibition of NO production in activated RAW 264.7 cells, possibly via suppression of inducible NO synthase mRNA expression. Further to elucidate the underlying mechanism of action the effect of 12-ursene 2-diketone on LPS-induced activation of MAPK has also been examined. Our results demonstrated that 12-ursene 2-diketone inhibits the expression of pro-inflammatory cytokines and mediators via inhibition of phosphorylation of the MAP kinases JNK and p38 while no inhibition was seen in ERK phosphorylation in LPS-stimulated PBMCs. The above study therefore indicates that the crude methanolic extract and the isolated pure compound are capable of carrying out a natural anti-inflammatory activity at sites where chronic inflammation is present by switching off the pro-inflammatory cytokines and mediators, which initiate the process.
Flavin DF. A lipoxygenase inhibitor in breast cancer brain metastases. Journal of Neuro-Oncology. 82(1):91-3, 2007 The complication of multiple brain metastases in breast cancer patients is a life threatening condition with limited success following standard therapies. The arachidonate lipoxygenase pathway appears to play a role in brain tumor growth as well as inhibition of apoptosis in in-vitro studies. The down regulation of these arachidonate lipoxygenase growth stimulating products therefore appeared to be a worthwhile consideration for testing in brain metastases not responding to standard therapy. Boswellia serrata, a lipoxygenase inhibitor was applied for this inhibition. Multiple brain metastases were successfully reversed using this method in a breast cancer patient who had not shown improvement after standard therapy. The results suggest a potential new area of therapy for breast cancer patients with brain metastases that may be useful as an adjuvant to our standard therapy.
Buchele B. Zugmaier W. Estrada A. Genze F. Syrovets T. Paetz C. Schneider B. Simmet T. Characterization of 3alpha-acetyl-11-keto-alpha-boswellic acid, a pentacyclic triterpenoid inducing apoptosis in vitro and in vivo. Planta Medica. 72(14):1285-9, 2006 3Alpha-acetyl-11-keto-alpha-boswellic acid (3alpha-acetoxy-11-oxo-olean-12-en-24-oic acid, 1) was synthesized by a radical-type reaction using bromine and 3alpha-acetyl-alpha-boswellic acid isolated from the oleo-gum-resin of Boswellia carterii. 1D and 2D NMR (COSY, HMBC, ROESY) at 500 MHz were used for shift assignments and structure verification. The compound investigated is present in a herbal preparation extracted from Boswellia serrata oleo-gum-resin, it inhibits the growth of chemotherapy-resistant human PC-3 prostate cancer cells in vitro and induces apoptosis as shown by activation of caspase 3 and the induction of DNA fragmentation. In addition, compound 1 is active IN VIVO as shown by inhibition of proliferation and induction of apoptosis in PC-3 prostate cancer cells xenotransplanted onto the chick chorioallantoic membrane.
Ammon HP. Boswellic acids in chronic inflammatory diseases. [Review] [69 refs] Planta Medica. 72(12):1100-16, 2006 Oleogum resins from BOSWELLIA species are used in traditional medicine in India and African countries for the treatment of a variety of diseases. Animal experiments showed anti-inflammatory activity of the extract. The mechanism of this action is due to some boswellic acids. It is different from that of NSAID and is related to components of the immune system. The most evident action is the inhibition of 5-lipoxygenase. However, other factors such as cytokines (interleukins and TNF-alpha) and the complement system are also candidates. Moreover, leukocyte elastase and oxygen radicals are targets. Clinical studies, so far with pilot character, suggest efficacy in some autoimmune diseases including rheumatoid arthritis, Crohn's disease, ulcerative colitis and bronchial asthma. Side effects are not severe when compared to modern drugs used for the treatment of these diseases.
Banno N. Akihisa T. Yasukawa K. Tokuda H. Tabata K. Nakamura Y. Nishimura R. Kimura Y. Suzuki T. Anti-inflammatory activities of the triterpene acids from the resin of Boswellia carteri. Journal of Ethnopharmacology. 107(2):249-53, 2006 Boswellic acids are the main well-known active components of the resin of Boswellia carteri (Burseraceae) and these are still dealing with the ethnomedicinal use for the treatment of rheumatoid arthritis and other inflammatory diseases. Although several studies have already been reported on the pharmacological properties, especially on the anti-inflammatory activity, of Boswellia carteri resin and boswellic acids, the ethnomedicinal importance of Boswellia carteri and its components, boswellic acids, prompted us to undertake detailed investigation on the constituents of the resin and their anti-inflammatory activity. Fifteen triterpene acids, viz., seven of the beta-boswellic acids (ursane-type) (1-7), two of the alpha-boswellic acids (oleanane-type) (8, 9), two of the lupeolic acids (lupane-type) (10, 11), and four of the tirucallane-type (12-14, 16), along with two cembrane-type diterpenes (17, 18), were isolated and identified from the methanol extract of the resin of Boswellia carteri. Upon evaluation of 17 compounds, 1-14 and 16-18, and compound 15, semi-synthesized from 14 by acetylation, for their inhibitory activity against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation (1 microg/ear) in mice, all of the compounds, except for 18, exhibited marked anti-inflammatory activity with a 50% inhibitory dose (ID(50)) of 0.05-0.49 mg/ear.
Weber CC. Reising K. Muller WE. Schubert-Zsilavecz M. Abdel-Tawab M. Modulation of Pgp function by boswellic acids. Planta Medica. 72(6):507-13, 2006 Boswellic acids, the main active ingredients of Boswellia serrata, are gaining more and more importance in the treatment of peritumoural oedema and chronic inflammatory diseases. They may be even considered as alternative drugs to corticosteroids in reducing cerebral peritumoural oedema. An important focus for drugs acting in the central nervous system is achieving a high extent of brain penetration. Today there is increasing evidence for the importance of transporters, especially P-glycoprotein (Pgp), for drug disposition and resulting clinical response. Pharmacokinetic studies revealed that the concentrations of the potent keto derivatives, the 11-keto-beta-boswellic acid (KBA) and the acetyl-11-keto-beta-boswellic acid (AKBA), in proportion to boswellic acids lacking a keto group, like the beta-boswellic acid, are much lower in plasma than in the orally administered extract. Moreover the brain/plasma ratio for KBA and AKBA determined in preliminary experiments on rats was only about 0.51 and 0.81, respectively, in spite of their lipophilicity. Until now little is known about the cerebral pharmacokinetics of boswellic acids and how it may be influenced. Since many drugs are known to interact with Pgp at the level of the intestine and the blood-brain barrier the modulatory potencies of the Boswellia serrata extract of H15(R) and the major boswellic acids on the transport activity of Pgp have been determined in two in vitro assays. A human lymphocytic leukaemia cell line (VLB cells) expressing Pgp was chosen as model for human Pgp, and porcine brain capillary endothelial cells (PBCEC cells) were taken as model for the blood-brain barrier using calcein acetoxymethyl ester (calcein-AM) as Pgp substrate. It was found that the Boswellia extract, as well as the keto-boswellic acids inhibit the transport activity of Pgp in the micromolecular range in both cell types. No modulation was observed using those boswellic acids which have no keto group in their structure. The inhibition of Pgp at the blood-brain barrier by Boswellia extract is probably not relevant for the brain availability of other Pgp substrates, because of the low plasma levels determined for KBA and AKBA. However the presented data could not exclude the possibility of drug interactions caused by modulation of Pgp by extracts of Boswellia serrata on the gastrointestinal level.
Borrelli F. Capasso F. Capasso R. Ascione V. Aviello G. Longo R. Izzo AA. Effect of Boswellia serrata on intestinal motility in rodents: inhibition of diarrhoea without constipation. British Journal of Pharmacology. 148(4):553-60, 2006 Clinical studies suggest that the Ayurvedic plant Boswellia serrata may be effective in reducing diarrhoea in patients with inflammatory bowel disease. In the present study, we evaluated the effect of a Boswellia serrata gum resin extract (BSE) on intestinal motility and diarrhoea in rodents. BSE depressed electrically-, acetylcholine-, and barium chloride-induced contractions in the isolated guinea-pig ileum, being more potent in inhibiting the contractions induced by acetylcholine and barium chloride. The inhibitory effect of BSE on acetylcholine-induced contractions was reduced by the L-type Ca(2+) channel blockers verapamil and nifedipine, but not by the sarcoplasmic reticulum Ca(2+)-ATPase inhibitor cyclopiazonic acid, by the phosphodiesterase type IV inhibitor rolipram or by the lipoxygenase inhibitor zileuton. 3-acetyl-11-keto-beta-boswellic acid, one of the main active ingredients of B. serrata, inhibited acetylcholine-induced contractions. BSE inhibited upper gastrointestinal transit in croton oil-treated mice as well as castor oil-induced diarrhoea. However, BSE did not affect intestinal motility in control mice, both in the small and in the large intestine. It is concluded that BSE directly inhibits intestinal motility with a mechanism involving L-type Ca(2+) channels. BSE prevents diarrhoea and normalizes intestinal motility in pathophysiological states without slowing the rate of transit in control animals. These results could explain, at least in part, the clinical efficacy of this Ayurvedic remedy in reducing diarrhoea in patients with inflammatory bowel disease.
Roy S. Khanna S. Krishnaraju AV. Subbaraju GV. Yasmin T. Bagchi D. Sen CK. Regulation of vascular responses to inflammation: inducible matrix metalloproteinase-3 expression in human microvascular endothelial cells is sensitive to antiinflammatory Boswellia. Antioxidants & Redox Signaling. 8(3-4):653-60, 2006 Endothelial cells are critical elements in the pathophysiology of inflammation. Tumor necrosis factor (TNF) alpha potently induces inflammatory responses in endothelial cells. Recently we have examined the genetic basis of the antiinflammatory effects of Boswellia extract (BE) in a system of TNFalpha-induced gene expression in human microvascular endothelial cells (HMECs). Of the 522 genes induced by TNFalpha in HMECs, 113 genes were sensitive to BE. BE prevented the TNFalpha-induced expression of matrix metalloproteinases (MMPs). In the current work, we sought to test the effects of BE on TNFalpha-inducible MMP expression in HMECs. Acetyl-11-ketobeta- boswellic acid (AKBA) is known to be an active principle in BE. To evaluate the significance of AKBA in the antiinflammatory properties of BE, effects of BE containing either 3% (BE3%) or 30% (BE30%, 5- Loxin) were compared. Pretreatment of HMECs for 2 days with BE potently prevented TNFalpha-induced expression and activity of MMP-3, MMP-10, and MMP-12. In vivo, BE protected against experimental arthritis. In all experiments, both in vitro and in vivo, BE30% was more effective than BE3%. In sum, this work lends support to our previous report that BE has potent antiinflammatory properties both in vitro as well as in vivo.
Fan AY. Lao L. Zhang RX. Zhou AN. Wang LB. Moudgil KD. Lee DY. Ma ZZ. Zhang WY. Berman BM. Effects of an acetone extract of Boswellia carterii Birdw. (Burseraceae) gum resin on adjuvant-induced arthritis in lewis rats. Journal of Ethnopharmacology. 101(1-3):104-9, 2005 Ruxiang (Gummi olibanum), the dried gum resin of Boswellia carterii (BC), has been used in traditional Chinese medicine to alleviate pain and inflammation for thousands of years. In this random, blinded study, the anti-arthritic effects of a BC extract were observed and compared to vehicle control in a Lewis rat adjuvant arthritis model (n=8/group). Arthritis was induced by injecting CFA subcutaneously into the base of the tail, and the extract was administered orally (i.g.) for 10 consecutive days beginning on day 16 after the injection. Arthritic scores, paw edema, and the local tissue pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) were assessed. Toxicity and adverse effects of the extract were evaluated. At 0.90 g/kg per day, BC significantly decreased arthritic scores between days 20 and 25 (p<0.05) and reduced paw edema on days 18, 20 and 22 compared to control (p<0.05). It also significantly suppressed local tissue TNF-alpha and IL-1beta (p<0.05). No major adverse effects were observed in animals during the repeated-dose treatment profile although mild fur discoloration was noted. The data show that BC extract has significant anti-arthritic and anti-inflammation effects and suggest that these effects may be mediated via the suppression of pro-inflammatory cytokines.
Pandey RS. Singh BK. Tripathi YB. Extract of gum resins of Boswellia serrata L. inhibits lipopolysaccharide induced nitric oxide production in rat macrophages along with hypolipidemic property. Indian Journal of Experimental Biology. 43(6):509-16, 2005Boswellia serrata, Linn F (Burseraceae) is commonly used in Indian system of medicine (Ayurvedic) as an anti-inflammatory, analgesic, anti-arthritic and anti-proliferative agent. This study was planned to investigate the water-soluble fraction of the oleoresin gum of Boswellia serrata (BS extract) on lipopolysaccharide (LPS) induced nitric oxide (NO) production by macrophages under in vivo and in vitro conditions. In the previous condition, rats were fed on atherogenic diet (2.5% cholesterol, 1% cholic acid, 15.7 % saturated fat) along with the BS extract for 90 days. Blood was collected for lipid profile and toxicological safety parameters. Peritoneal macrophages were isolated and cultured to see the LPS induced NO production. Under in vivo experiment, BS extract significantly reduced serum total cholesterol (38-48 %), increased serum high-density lipoprotein- cholesterol (HDL-cholesterol, 22-30%). Under in vitro experiments with thioglycolate activated macrophages, it inhibited LPS induced (NO) production with IC 50 value at 662 ng /ml. Further, this fraction, in the dose of 15 mg/100 g body wt for 90 days, did not show any increase in serum glutamate-pyruvate transaminase (SGPT) and blood urea, in normal control animals. However, it significantly reversed the raised SGPT and blood urea in the atherogenic diet-fed animals. Transverse section of liver and kidney also supported its protective effect. Thus it may be concluded that water extract of Boswellia serrata possesses strong hypocholesterolemic property along with increase in serum HDL. It inhibits the LPS induced NO production by the activated rat peritoneal macrophages and show hepato-protective and reno-protective property.
Chevrier MR. Ryan AE. Lee DY. Zhongze M. Wu-Yan Z. Via CS. Boswellia carterii extract inhibits TH1 cytokines and promotes TH2 cytokines in vitro. Clinical & Diagnostic Laboratory Immunology. 12(5):575-80, 2005 Traditional herbal formulas used to treat inflammatory arthritis in China and India include Boswellia carterii or Boswellia serrata. They both contain boswellic acids (BAs) which have been shown to exhibit anti-inflammatory and antiarthritic properties. This study tests the hypothesis that mixtures of BAs derived from B. carterii have immunomodulatory properties. B. carterii plant resin obtained from China was prepared as an ethanol extract, and the presence of seven BAs was confirmed by column chromatography, high-performance liquid chromatography, and UV laser desorption/ionization tandem mass spectroscopy. The extract was then tested for its ability to alter in vitro production of TH1 cytokines (interleukin-2 [IL-2] and gamma interferon) and TH2 cytokines (IL-4 and IL-10) by murine splenocytes. Delivery of the resin extract using ethanol as a solvent resulted in significant cellular toxicity not seen with the addition of ethanol alone. By contrast, delivery of the resin extract using a sesame oil solvent resulted in a dose-dependent inhibition of TH1 cytokines coupled with a dose-dependent potentiation of TH2 cytokines. These results indicate that a purified mixture of BAs from B. carterii plant resin exhibits carrier-dependent immunomodulatory properties in vitro.
Kiela PR. Midura AJ. Kuscuoglu N. Jolad SD. Solyom AM. Besselsen DG. Timmermann BN. Ghishan FK. Effects of Boswellia serrata in mouse models of chemically induced colitis. American Journal of Physiology - Gastrointestinal & Liver Physiology. 288(4):G798-808, 2005 Extracts from Boswellia serrata have been reported to have anti-inflammatory activity, primarily via boswellic acid-mediated inhibition of leukotriene synthesis. In three small clinical trials, boswellia was shown to improve symptoms of ulcerative colitis and Crohn's disease, and because of its alleged safety, boswellia was considered superior over mesalazine in terms of a benefit-risk evaluation. The goal of this study was to evaluate the effectiveness of boswellia extracts in controlled settings of dextran sulfate- or trinitrobenzene sulfonic acid-induced colitis in mice. Our results suggest that boswellia is ineffective in ameliorating colitis in these models. Moreover, individual boswellic acids were demonstrated to increase the basal and IL-1beta-stimulated NF-kappaB activity in intestinal epithelial cells in vitro as well as reverse proliferative effects of IL-1beta. We also observed hepatotoxic effect of boswellia with pronounced hepatomegaly and steatosis. Hepatotoxity and increased lipid accumulation in response to boswellia were further confirmed in vitro in HepG2 cells with fluorescent Nile red binding/resazurin reduction assay and by confocal microscopy. Microarray analyses of hepatic gene expression demonstrated dysregulation of a number of genes, including a large group of lipid metabolism-related genes, and detoxifying enzymes, a response consistent with that to hepatotoxic xenobiotics. In summary, boswellia does not ameliorate symptoms of colitis in chemically induced murine models and, in higher doses, may become hepatotoxic. Potential implications of prolonged and uncontrolled intake of boswellia as an herbal supplement in inflammatory bowel disease and other inflammatory conditions should be considered in future clinical trials with this botanical.
Tripathi YB. Reddy MM. Pandey RS. Subhashini J. Tiwari OP. Singh BK. Reddanna P. Anti-inflammatory properties of BHUx, a polyherbal formulation to prevent atherosclerosis. Inflammopharmacology. 12(2):131-52, 2004 BHUx is a polyherbal formulation consisting of water-soluble fractions of five medicinal plants (Commiphora mukul, Terminalia arjuna, Boswellia serrata, Semecarpus anacardium and Strychnos nux vomica). The present study was undertaken to evaluate its antioxidant and antiinflammatory effects. BHUx, standardized by HPLC fingerprinting and filtered through 0.2 microm filter paper, was employed for different studies under in vivo and in vitro conditions. Under in vivo conditions, BHUx significantly reduced inflammation in the carrageenan-induced rat paw oedema model of inflammation, suggesting its anti-inflammatory properties. In order to test the mechanism of action of BHUx, further in vitro studies were undertaken on cumene-hydroperoxide-induced lipid peroxidation (CHP) in liver homogenate, LPS-induced NO production in peritoneal macrophages and on key enzymes of arachidonic acid cascade, involved in the mediation of inflammation. Under the conditions, BHUx showed concentration-dependent inhibition of CHP-induced lipid peroxidation in liver homogenate, suggesting its antioxidant properties. Similarly the potent anti-inflammatory effects of BHUx are evident by (a) preferential inhibition of COX-2 (IC50 for COX-2 = 80 microg/ml and IC50 for COX-1 = 169 microg/ml), (b) low ratios in the IC50 values of COX-2/COX-1 (0.47), (c) decreased production of NO in LPS-induced peritoneal macrophages and (d) inhibition of 5-LOX (IC50 = 795 microg/ml). BHUx also showed a preference for inhibiting 15-lipoxygenase (IC50 = 44 microg/ml), a key enzyme implicated in LDL oxidation. These studies suggest that BHUx is acting mainly at three levels, i.e., as a potent natural antioxidant, by reduction of key inflammatory mediators of arachidonic acid cascade and by preventing 15-LOX-mediated LDL oxidations, to prevent atherosclerosis.
Pungle P. Banavalikar M. Suthar A. Biyani M. Mengi S. Immunomodulatory activity of boswellic acids of Boswellia serrata Roxb. Indian Journal of Experimental Biology. 41(12):1460-2, 2003 Extract of gum resin of B. serrata containing 60% acetyl 11-keto beta boswellic acid (AKBA) along with other constituents such as 11-keto beta-boswellic acid (KBA), acetyl beta-boswellic acid and beta-boswellic acid has been evaluated for antianaphylactic and mast cell stabilizing activity using passive paw anaphylaxis and compound 48/80 induced degranulation of mast cell methods. The extract inhibited the passive paw anaphylaxis reaction in rats in dose-dependant manner (20, 40 and 80 mg/kg, po). However, the standard dexamethasone (0.27 mg/kg, po) revealed maximum inhibition of edema as compared to the extract. A significant inhibition in the compound 48/80 induced degranulation of mast cells in dose-dependant manner (20, 40 and 80 mg/kg, po) was observed thus showing mast cell stabilizing activity. The standard disodium cromoglycate (50 mg/kg, ip) was found to demonstrate maximum per cent protection against degranulation as compared to the extract containing 60% AKBA. The results suggest promising antianaphylactic and mast cell stabilizing activity of the extract.
Kimmatkar N. Thawani V. Hingorani L. Khiyani R. Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee--a randomized double blind placebo controlled trial. Phytomedicine. 10(1):3-7, 2003. Osteoarthritis is a common, chronic, progressive, skeletal, degenerative disorder, which commonly affects the knee joint. Boswellia serrata tree is commonly found in India. The therapeutic value of its gum (guggulu) has been known. It posses good anti-inflammatory, anti-arthritic and analgesic activity. A randomized double blind placebo controlled crossover study was conducted to assess the efficacy, safety and tolerability of Boswellia serrata Extract (BSE) in 30 patients of osteoarthritis of knee, 15 each receiving active drug or placebo for eight weeks. After the first intervention, washout was given and then the groups were crossed over to receive the opposite intervention for eight weeks. All patients receiving drug treatment reported decrease in knee pain, increased knee flexion and increased walking distance. The frequency of swelling in the knee joint was decreased. Radiologically there was no change. The observed differences between drug treated and placebo being statistically significant, are clinically relevant. BSE was well tolerated by the subjects except for minor gastrointestinal ADRs. BSE is recommended in the patients of osteoarthritis of the knee with possible therapeutic use in other arthritis.
Hostanska K. Daum G. Saller R. Cytostatic and apoptosis-inducing activity of boswellic acids toward malignant cell lines in vitro. Anticancer Research. 22(5):2853-62, 2002. Boswellic acids from frankincense were indentified as the active compounds which inhibit leukotriene biosynthesis, 5-lipoxygenase and exert antiproliferative activity toward a variety of malignant cells. Because of the relevance for the clinical application, we tested the ethanolic extract of Boswellia serrata gum resin containing a defined amount of boswellic acids for its cytotoxic, cytostatic and apoptotic activity on five leukemia (HL-60, K 562, U937, MOLT-4, THP-1) and two brain tumor (LN-18, LN-229) cell lines by WST-1 assay and flow cytometry. The Boswellia serrata extract induced dose-dependent antiproliferative effects on all human malignant cells tested with GI50 values (extract concentration producing 50% cell growth inhibition) between 57.0 and 124.1 micrograms/ml. In three haematological cell lines (K562, U937, MOLT-4) the effect of total extract expressed in GI50 was 2.8-, 3.3- and 2.3-times more potent (p < 0.05) than pure 3-O-acetyl-11-keto-beta-boswellic acid (AKBA). Morphological changes after 24-27 hours and the detection of apoptotic cells by AnnexinV-binding and/or by the detection of propidium iodide-labelled DNA with flow cytometry, confirmed the apoptotic cell death. The results of this study suggest the effectiveness of Boswellia serrata extract with defined content of boswellic acids.
Liu JJ. Nilsson A. Oredsson S. Badmaev V. Zhao WZ. Duan RD. Boswellic acids trigger apoptosis via a pathway dependent on caspase-8 activation but independent on Fas/Fas ligand interaction in colon cancer HT-29 cells. Carcinogenesis. 23(12):2087-93, 2002. Boswellic acids are the effective components of gum resin of Boswellia serrata, which has anti-inflammatory properties. Recent studies on brain tumors and leukemic cells indicate that boswellic acids may have antiproliferative and apoptotic effects with the mechanisms being not studied in detail. We studied their antiproliferative and apoptotic effects on colon cancer cells and the pathway leading to apoptosis. HT-29 cells were treated with beta-boswellic acid (BA), keto-beta-boswellic acid (K-BA) and acetyl-keto-beta-boswellic acid (AK-BA), respectively. Apoptosis was determined by flow cytometry, by cytoplasmic DNA-histone complex and the activity of caspase-3. The cleavage of poly-(ADP-ribose)-polymerase (PARP) and expression of Fas were examined by western blot. Specific caspase inhibitors, polyclonal Fas antibody, and antagonistic Fas antibody ZB4 were employed to elucidate apoptotic pathways. DNA synthesis and cell viability were examined. Both K-BA and AK-BA increased cytoplasmic DNA-histone complex dose-dependently and increased pre-G(1) peak in flow cytometer analysis, with the effects of AK-BA being stronger than K-BA. BA only increased the formation of DNA-histone complex at a high concentration. K-BA and AK-BA increased caspase-8, caspase-9 and caspase-3 activities accompanied by cleavage of PARP. The effects of AK-BA on formation of cytoplasmic DNA histone and on caspase-3 activation were 3.7- and 3.4-fold, respectively, more effective than those induced by camptothecin. The apoptosis induced by AK-BA was inhibited completely by caspase-3 or caspase-8 inhibitor and partially by caspase-9 inhibitor. ZB4 blocked exogenous Fas ligand-induced apoptosis, but had no effect on AK-BA-induced apoptosis. AK-BA had no significant effect on expression of Fas. Apart from apoptotic effect, these acids also inhibited [(3)H]thymidine incorporation and cell viability to different extent. In conclusion, boswellic acids, particularly AK-BA and K-BA have antiproliferative and apoptotic effects in human HT-29 cells. The apoptotic effect is mediated via a pathway dependent on caspase-8 activation but independent of Fas/FasL interaction.
Park YS. Lee JH. Bondar J. Harwalkar JA. Safayhi H. Golubic M. Cytotoxic action of acetyl-11-keto-beta-boswellic acid (AKBA) on meningioma cells. Planta Medica. 68(5):397-401, 2002. Acetyl-11-keto-beta-boswellic acid (AKBA) is a naturally occurring pentacyclic triterpene isolated from the gum resin exudate of the tree Boswellia serrata (frankincense). Because pentacyclic triterpenes have antiproliferative and cytotoxic effects against different tumor types, we investigated whether AKBA would act in a similar fashion on primary human meningioma cell cultures. Primary cell cultures were established from surgically removed meningioma specimens. The number of viable cells in the absence/presence of AKBA was determined by the non-radioactive cell proliferation assay. The activation status of the proliferative cell marker, extracellular signal-regulated kinase-1 and -2 (Erk-1 and Erk-2) was determined by immunoblotting with the antibody that recognizes the activated form of these proteins. Treatment of meningioma cells by AKBA revealed a potent cytotoxic activity with half-maximal inhibitory concentrations in the range of 2 - 8 microM. At low micromolar concentrations, AKBA rapidly and potently inhibited the phosphorylation of Erk-1/2 and impaired the motility of meningioma cells stimulated with platelet-derived growth factor BB. The cytotoxic action of AKBA on meningioma cells may be mediated, at least in part, by the inhibition of the Erk signal transduction pathway. Because of the central role the Erk pathway plays in signal transduction and tumorigenesis, further investigation into the potential clinical use for AKBA and related boswellic acids is warranted.
