Effects of boswellic acids extracted from a herbal medicine on the biosynthesis of leukotrienes and the course of experimental autoimmune encephalomyelitis.
Wildfeuer A,Neu I S,Safayhi H,Metzger G,Wehrmann M,Vogel U,Ammon H P
Arzneimittel-Forschung
Mixed acetylboswellic acids, pentacyclic triterpenes extracted from the gum resin of Boswellia serrata Roxb., significantly inhibited the ionophore-stimulated release of the leukotrienes (LT) B4 and C4 from intact human polymorphonuclear neutrophil leukocytes (PMNLs), with IC50 values of 8.48 micrograms/ml and 8.43 micrograms/ml, respectively. Purified acetyl-11-keto-beta-boswellic acid was about three times more potent as inhibitor of the formation of both LTB4 (IC50 = 2.53 micrograms/ml) and LTC4 (IC50 = 2.26 micrograms/ml) from human PMNLs in the same assay. The comparative agent MK 886 (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]- 2,2-dimethylpropanoic acid, L-663,536, CAS 118, 414-82-7) was about 10 to 100-fold more active than the boswellic acids in inhibiting the formation of 5-lipoxygenase products in human PMNLs, with IC50 values of 0.0068 microgram/ml (LTB4) and 0.49 microgram/ml (LTC4). After daily intraperitoneal dosage the extract of mixed acetylboswellic acids (20 mg/kg) significantly reduced the clinical symptoms in guinea pigs with experimental autoimmune encephalomyelitis (EAE) between days 11 and 21. However, the inflammatory infiltrates in the brain and the spinal cord were not significantly less extensive in the treated animals than in the respective control group. The multiple intraperitoneal application of boswellic acids did not inhibit the ionophore-challenged ex vivo release of leukotrienes B4 and C4 from PMNLs separated from the blood of guinea pigs with EAE. The boswellic acids have thus been characterized as selective, non-redox and potent inhibitors of the biosynthesis of leukotrienes in vitro.
Acetyl-boswellic acids inhibit lipopolysaccharide-mediated TNF-alpha induction in monocytes by direct interaction with IkappaB kinases.
Syrovets Tatiana,Büchele Berthold,Krauss Christine,Laumonnier Yves,Simmet Thomas
Journal of immunology (Baltimore, Md. : 1950)
Expression of proinflammatory cytokines by monocytes is tightly regulated by transcription factors such as NF-kappaB. In this study, we show that, in LPS-stimulated human peripheral monocytes, the pentacyclic triterpenes acetyl-alpha-boswellic acid (AalphaBA) and acetyl-11-keto-beta-boswellic acid (AKbetaBA) down-regulate the TNF-alpha expression. AalphaBA and AKbetaBA inhibited NF-kappaB signaling both in LPS-stimulated monocytes as detected by EMSA, as well as in a NF-kappaB-dependent luciferase gene reporter assay. By contrast, the luciferase expression driven by the IFN-stimulated response element was unaffected, implying specificity of the inhibitory effect observed. Both AalphaBA and AKbetaBA did not affect binding of recombinant p50/p65 and p50/c-Rel dimers to DNA binding sites as analyzed by surface plasmon resonance. Instead, both pentacyclic triterpenes inhibited the LPS-induced degradation of IkappaBalpha, as well as phosphorylation of p65 at Ser(536) and its nuclear translocation. AalphaBA and AKbetaBA inhibited specifically the phosphorylation of recombinant IkappaBalpha and p65 by IkappaBalpha kinases (IKKs) immunoprecipitated from LPS-stimulated monocytes. In line with this, AalphaBA and AKbetaBA also bound to and inhibited the activities of active human recombinant GST-IKKalpha and His-IKKbeta. The LPS-triggered induction of TNF-alpha in monocytes is dependent on IKK activity, as confirmed by IKK-specific antisense oligodeoxynucleotides. Thus, via their direct inhibitory effects on IKK, AalphaBA and AKbetaBA convey inhibition of NF-kappaB and subsequent down-regulation of TNF-alpha expression in activated human monocytes. These findings provide a molecular basis for the anti-inflammatory properties ascribed to AalphaBA- and AKbetaBA-containing drugs and suggest acetyl-boswellic acids as tools for the development of novel therapeutic interventions.
10.4049/jimmunol.174.1.498
Boswellic acid blocks signal transducers and activators of transcription 3 signaling, proliferation, and survival of multiple myeloma via the protein tyrosine phosphatase SHP-1.
Kunnumakkara Ajaikumar B,Nair Asha S,Sung Bokyung,Pandey Manoj K,Aggarwal Bharat B
Molecular cancer research : MCR
Activation of signal transducers and activators of transcription-3 (STAT-3) has been linked with survival, proliferation, chemoresistance, and angiogenesis of tumor cells, including human multiple myeloma (MM). Thus, agents that can suppress STAT3 activation have potential as cancer therapeutics. In our search for such agents, we identified acetyl-11-keto-beta-boswellic acid (AKBA), originally isolated from Boswellia serrata. Our results show that AKBA inhibited constitutive STAT3 activation in human MM cells. AKBA suppressed IL-6-induced STAT3 activation, and the inhibition was reversible. The phosphorylation of both Jak 2 and Src, constituents of the STAT3 pathway, was inhibited by AKBA. Interestingly, treatment of cells with pervanadate suppressed the effect of AKBA to inhibit the phosphorylation of STAT3, thus suggesting the involvement of a protein tyrosine phosphatase. We found that AKBA induced Src homology region 2 domain-containing phosphatase 1 (SHP-1), which may account for its role in dephosphorylation of STAT3. Moreover, deletion of the SHP-1 gene by small interfering RNA abolished the ability of AKBA to inhibit STAT3 activation. The inhibition of STAT3 activation by AKBA led to the suppression of gene products involved in proliferation (cyclin D1), survival (Bcl-2, Bcl-xL, and Mcl-1), and angiogenesis (VEGF). This effect correlated with the inhibition of proliferation and apoptosis in MM cells. Consistent with these results, overexpression of constitutive active STAT3 significantly reduced the AKBA-induced apoptosis. Overall, our results suggest that AKBA is a novel inhibitor of STAT3 activation and has potential in the treatment of cancer.
10.1158/1541-7786.MCR-08-0154
Boswellia serrata Protects Against Glutamate-Induced Oxidative Stress and Apoptosis in PC12 and N2a Cells.
Rajabian Arezoo,Boroushaki Mohammad Taher,Hayatdavoudi Parichehr,Sadeghnia Hamid Reza
DNA and cell biology
This study was designed to investigate whether the extract from Boswellia serrata oleo-gum resin (BSE) can protect against glutamate-induced oxidative damage and cytotoxicity in PC12 and N2a cell lines. Using a simple and reliable reverse-phase high-performance liquid chromatography (HPLC), the amount of 3-acetyl-11-keto-β-boswellic acid (AKBA) in the BSE was found to be 18.5% w/w. The results confirmed that BSE and AKBA, at concentrations as high as 100 μg/mL or 10 μM, respectively, caused no significant cytotoxicity or apoptotic cell death. Co- and pretreatment with BSE (25-100 μg/mL) or AKBA (5 μM) restored the viability of PC12 and N2a cells under glutamate toxicity (8 mM). Treatment with BSE and AKBA also attenuated the toxic effects of glutamate on intracellular reactive oxygen species, lipid peroxidation, superoxide dismutase activity, and oxidative DNA damage compared with the untreated glutamate-injured cells. Furthermore, BSE and AKBA decreased the apoptotic cell population in the sub-G1 region and the rate of both early and late-stage apoptosis induced by glutamate in the cells. Our data suggest that the protective effects of Boswellia extract and AKBA against glutamate toxicity in PC12 and N2a cells may be mediated through the amelioration of the oxidative stress and the resultant apoptosis.
10.1089/dna.2016.3332
Protective Effect and Mechanism of Boswellic Acid and Myrrha Sesquiterpenes with Different Proportions of Compatibility on Neuroinflammation by LPS-Induced BV2 Cells Combined with Network Pharmacology.
Miao Xiao-Dong,Zheng Li-Jie,Zhao Zi-Zhang,Su Shu-Lan,Zhu Yue,Guo Jian-Ming,Shang Er-Xin,Qian Da-Wei,Duan Jin-Ao
Molecules (Basel, Switzerland)
Frankincense and myrrha (FM), commonly used as a classical herbal pair, have a wide range of clinical applications and definite anti-inflammatory activity. However, anti-neuroinflammation effects and mechanisms are not clear. In this study, we adopted a lipopolysaccharide (LPS)-induced microglial (BV2) cell model and a network pharmacology method to reveal the anti-neuroinflammatory effects and mechanisms of boswellic acid (BA) and myrrha sesquiterpenes (MS) with different proportions of compatibility. The data showed that the different ratios of BA and MS had different degrees of inhibition of interleukin-1β (IL-1β), IL-6, and inducible nitric oxide synthase (iNOS) mRNA expression, down-regulated the phosphor-nuclear factor kappa B/nuclear factor kappa B (p-NF-ҡB)/(NF-ҡB), phosphorylated protein kinase b/protein kinase b (p-AKT/AKT), and Toll-like receptor 4 (TLR4) protein expression levels, and increased phospho-PI3 kinase (p-PI3K) protein expression levels. When the ratios of BA and MS were 10:1, 5:1, and 20:1, better effective efficacy was exhibited. According to the correlation analysis between the effect index and bioactive substances, it was suggested that 2-methoxy-5-acetoxy -fruranogermacr-1(10)-en-6-one (Compound 1), 3-acetyloxylanosta-8,24-dien-21-oic acid (Compound 2), 11-keto-boswellic acid (Compound 3), and 3-acetyl-11-keto- -boswellic acid (Compound 4) made important contributions to the treatment of neuroinflammation. Furthermore, based on the network pharmacological analysis, it was found that these four active compounds acted on 31 targets related to neuroinflammation and were involved in 32 signaling pathways which mainly related to the immune system, cardiovascular system, and nervous system, suggesting that BA and MS could be used to treat neuroinflammation.
10.3390/molecules24213946
Boswellia serrata, a potential antiinflammatory agent: an overview.
Indian journal of pharmaceutical sciences
The resin of Boswellia species has been used as incense in religious and cultural ceremonies and in medicines since time immemorial. Boswellia serrata (Salai/Salai guggul), is a moderate to large sized branching tree of family Burseraceae (Genus Boswellia), grows in dry mountainous regions of India, Northern Africa and Middle East. Oleo gum-resin is tapped from the incision made on the trunk of the tree and is then stored in specially made bamboo basket for removal of oil content and getting the resin solidified. After processing, the gum-resin is then graded according to its flavour, colour, shape and size. In India, the States of Andhra Pradesh, Gujarat, Madhya Pradesh, Jharkhand and Chhattisgarh are the main source of Boswellia serrata. Regionally, it is also known by different names. The oleo gum-resins contain 30-60% resin, 5-10% essential oils, which are soluble in the organic solvents, and the rest is made up of polysaccharides. Gum-resin extracts of Boswellia serrata have been traditionally used in folk medicine for centuries to treat various chronic inflammatory diseases. The resinous part of Boswellia serrata possesses monoterpenes, diterpenes, triterpenes, tetracyclic triterpenic acids and four major pentacyclic triterpenic acids i.e. β-boswellic acid, acetyl-β-boswellic acid, 11-keto-β-boswellic acid and acetyl-11-keto-β-boswellic acid, responsible for inhibition of pro-inflammatory enzymes. Out of these four boswellic acids, acetyl-11-keto-β-boswellic acid is the most potent inhibitor of 5-lipoxygenase, an enzyme responsible for inflammation.
10.4103/0250-474X.93507
Protective effects of nimesulide (COX Inhibitor), AKBA (5-LOX Inhibitor), and their combination in aging-associated abnormalities in mice.
Bishnoi M,Patil C S,Kumar A,Kulkarni S K
Methods and findings in experimental and clinical pharmacology
Several inflammatory processes play a critical role in brain aging and are associated with increased vulnerability to neurodegeneration. Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX), two enzymes involved in the oxygenation of the arachidonic acid, are upregulated in the central nervous system during aging and are associated with different aging-related brain pathologies. The present experiment was performed to study the effects of 5-LOX inhibitor, acetyl-11-keto-beta-boswellic acid (AKBA), nimesulide (preferential COX-2 inhibitor), and their combination on cognitive performance of young and aged mice, using elevated plus maze test. Chronic administration of AKBA (100 mg/kg, p.o.) and nimesulide (2.42 mg/kg, p.o.) for 15 days significantly reversed the aging-induced retention deficit in mice. Coadministration of AKBA and nimesulide enhanced the cognitive performance in aged mice when compared with that in per se treatment. The aging-related increase in oxidative damage (increased LPO and decreased GSH) was reversed by AKBA, nimesulide, and their combination. Further, per se COX and LOX inhibitors and their combination did not produce any alteration in gastrointestinal parameters; they also reversed the aging-induced motor dysfunction in the aged animals. On the basis of these observations, present findings indicated that the combination of COX and LOX inhibitors (dual inhibitors) may provide a new therapeutic innovation for the treatment of aging-related brain disorders such as Alzheimer's disease and different motor dysfunctions with adequate gastrointestinal tolerability.
10.1358/mf.2005.27.7.920929
Targeting NF-kappa B with a natural triterpenoid alleviates skin inflammation in a mouse model of psoriasis.
Wang Honglin,Syrovets Tatiana,Kess Daniel,Büchele Berthold,Hainzl Heidi,Lunov Oleg,Weiss Johannes M,Scharffetter-Kochanek Karin,Simmet Thomas
Journal of immunology (Baltimore, Md. : 1950)
Psoriasis vulgaris is a common chronic inflammatory skin disease involving cytokines and an activated cellular immune system. At variance to skin from patients with atopic dermatitis or from healthy subjects, human psoriatic skin lesions exhibit strong activation of transcription factor NF-kappaB that is mainly confined to dermal macrophages, whereas only a few dendritic cells but no CD3+ lymphocytes show activated NF-kappaB. Since NF-kappaB signaling is required for the induction and/or function of many cytokines and aberrant cytokine expression has been proposed as an underlying cause of psoriasis, we investigated whether NF-kappaB targeting would affect the course of the disease in the CD18 hypomorphic (CD18(hypo)) mouse model of psoriasis. When mice with severe psoriasiform lesions were treated systemically or locally with the IkappaB kinase inhibitor acetyl-11-keto-beta-boswellic acid (AKbetaBA), NF-kappaB signaling and the subsequent NF-kappaB-dependent cytokine production as shown by the TNF-alpha production of macrophages were profoundly suppressed. Additionally, application of the compound counteracted the intradermal MCP-1, IL-12, and IL-23 expression in previously lesional skin areas, led to resolution of the abundant immune cell infiltrates, and significantly reduced the increased proliferation of the keratinocytes. Overall, the AKbetaBA treatment was accompanied by a profound improvement of the psoriasis disease activity score in the CD18(hypo) mice with reconstitution of a nearly normal phenotype within the chosen observation period. Our data demonstrate that NF-kappaB signaling is pivotal for the pathogenesis in the CD18(hypo) mouse model of psoriasis. Therefore, targeting NF-kappaB might provide an effective strategy for the treatment of psoriasis.
10.4049/jimmunol.0900521
Boswellic acids reduce Th17 differentiation via blockade of IL-1β-mediated IRAK1 signaling.
Stürner Klarissa Hanja,Verse Nina,Yousef Sara,Martin Roland,Sospedra Mireia
European journal of immunology
Interferon-gamma producing CD4(+) T (Th1) cells and IL-17-producing CD4(+) T (Th17) cells are involved in the pathogenesis of several autoimmune diseases including multiple sclerosis. Therefore, the development of treatment strategies controlling the generation and expansion of these effector cells is of high interest. Frankincense, the resin from trees of the genus Boswellia, and particularly its prominent bioactive compound acetyl-11-keto-β-boswellic acid (AKBA), have potent anti-inflammatory properties. Here, we demonstrate that AKBA is able to reduce the differentiation of human CD4(+) T cells to Th17 cells, while slightly increasing Th2- and Treg-cell differentiation. Furthermore, AKBA reduces the IL-1β-triggered IL-17A release of memory Th17 cells. AKBA may affect IL-1β signaling by preventing IL-1 receptor-associated kinase 1 phosphorylation and subsequently decreasing STAT3 phosphorylation at Ser727, which is required for Th17-cell differentiation. The effects of AKBA on Th17 differentiation and IL-17A release make the compound a good candidate for potential treatment of Th17-driven diseases.
10.1002/eji.201343629
11-Keto-β-Boswellic Acids Prevent Development of Autoimmune Reactions, Insulitis and Reduce Hyperglycemia During Induction of Multiple Low-Dose Streptozotocin (MLD-STZ) Diabetes in Mice.
Shehata A M,Quintanilla-Fend L,Bettio S,Jauch J,Scior T,Scherbaum W A,Ammon H P T
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
The aim of the work was to study whether or not 11-keto-β-boswellic acids prevent induction of autoimmune reactions, insulitis, and hyperglycemia in the model of multiple low-dose streptozotocin (MLD-STZ) diabetes. Using male mice (n = 6) diabetes was induced by daily i.p. injections of 40 mg/kg STZ for 5 days. In a second series together with STZ, daily i. p. injections of 11-keto-β-boswellic acid (KBA) and O-acetyl-11-keto-β-boswellic acid (AKBA) (7.5 and 15.0 mg/kg) were applied for 10 days. Thereafter, pro-and anti-inflammatory cytokines in the blood, histochemistry of pancreatic islets, and blood glucose levels were assayed. Five days after the last injection of STZ, a significant burst of pro-and anti-inflammatory cytokines in the blood, infiltration of lymphocytes (CD3) into pancreatic islets, and appearance of peri-insular apoptotic cells were observed. Plasma glucose increased significantly (124.4 ± 6.65 vs. 240.2 ± 27.36 mg/dl, p <0.05). Simultaneous treatment with KBA and AKBA significantly reduced pro-and anti-inflammatory cytokines (IFN-γ p < 0.01, p < 0.01; IL-1A p < 0.001, p < 0.001; IL-1B p < 0.001, p < 0.001; IL-2 p < 0.001, p < 0.001; IL-6 p < 0.01, p < 0.001; TNF-α p < 0.05, p < 0.001; IL-4 p < 0.01, p < 0.001; IL-10 p < 0.001, p < 0.001) in the blood. No infiltration of lymphocytes into pancreatic islets and appearance of peri-insular cells were detected. Moreover, KBA and AKBA reduced STZ-mediated increase of blood glucose on day 10 to 163.25 ± 16.6 (p < 0.05) and 187.6 ± 19.5 mg/dl (p < 0.05), respectively. In the model of MLD-STZ induced diabetes KBA and AKBA prevent cytokine burst, development of insulitis and reduce increase of blood glucose through "silencing" a forced-up immune reaction.
10.1055/s-0035-1547293
Acetyl-11-keto-beta-boswellic acid potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis by suppressing NF-kappa B and NF-kappa B-regulated gene expression.
Takada Yasunari,Ichikawa Haruyo,Badmaev Vladimir,Aggarwal Bharat B
Journal of immunology (Baltimore, Md. : 1950)
Acetyl-11-keto-beta-boswellic acid (AKBA), a component of an Ayurvedic therapeutic plant Boswellia serrata, is a pentacyclic terpenoid active against a large number of inflammatory diseases, including cancer, arthritis, chronic colitis, ulcerative colitis, Crohn's disease, and bronchial asthma, but the mechanism is poorly understood. We found that AKBA potentiated the apoptosis induced by TNF and chemotherapeutic agents, suppressed TNF-induced invasion, and inhibited receptor activator of NF-kappaB ligand-induced osteoclastogenesis, all of which are known to require NF-kappaB activation. These observations corresponded with the down-regulation of the expression of NF-kappaB-regulated antiapoptotic, proliferative, and angiogenic gene products. As examined by DNA binding, AKBA suppressed both inducible and constitutive NF-kappaB activation in tumor cells. It also abrogated NF-kappaB activation induced by TNF, IL-1beta, okadaic acid, doxorubicin, LPS, H2O2, PMA, and cigarette smoke. AKBA did not directly affect the binding of NF-kappaB to the DNA but inhibited sequentially the TNF-induced activation of IkappaBalpha kinase (IKK), IkappaBalpha phosphorylation, IkappaBalpha ubiquitination, IkappaBalpha degradation, p65 phosphorylation, and p65 nuclear translocation. AKBA also did not directly modulate IKK activity but suppressed the activation of IKK through inhibition of Akt. Furthermore, AKBA inhibited the NF-kappaB-dependent reporter gene expression activated by TNFR type 1, TNFR-associated death domain protein, TNFR-associated factor 2, NF-kappaB-inducing kinase, and IKK, but not that activated by the p65 subunit of NF-kappaB. Overall, our results indicated that AKBA enhances apoptosis induced by cytokines and chemotherapeutic agents, inhibits invasion, and suppresses osteoclastogenesis through inhibition of NF-kappaB-regulated gene expression.
10.4049/jimmunol.176.5.3127
NEUROPROTECTIVE EFFECT OF BOSWELLIA SERRATA AND ITS ACTIVE CONSTITUENT ACETYL 11-KETO-β-BOSWELLIC ACID AGAINST OXYGEN-GLUCOSE-SERUM DEPRIVATION-INDUCED CELL INJURY.
Sadeghnia Hamid Reza,Arjmand Fatemeh,Ghorbani Ahmad
Acta poloniae pharmaceutica
Oxidative stress plays a key role in pathophysiology of brain ischemia. This study aimed to test whether B. serrata hydroalcoholic extract (BSE) and its active constituent 3-acetyl-1 1-keto-β-boswellic acid (AKBA) could protect neurons against ischemic condition induced by oxygen, glucose and serum deprivation (OGSD). First, PC12 neural cells were incubated with BSE (0-400 pg/mL) or AKBA (0-40 pg/mL) for 24 h to find non-cytotoxic concentrations of BSE and AKBA. Then, the cells were pre- (for 2 h) and co-treated with 1.5-6 μg/mL BSE or 0.5-2.5 pg/mL AKBA, and then exposed to OGSD condition for 6 h. The IC50. values of BSE and AKBA were 95 and 12.2 μg/mL, respectively. BSE (3 and 6 pg/mL) and AKBA (1 and 2.5 pg/mL) significantly increased viability of ischemic cells, in a concertation-dependent manner. The levels of intracellular oxygen free radicals, lipid peroxidation and oxidative DNA damage were also significantly and concentration-dependently decreased following treatment of ischemic cells with BSE or AKBA. Using HPLC analysis, the mount of AKBA in a sample of BSE was found to be 9.2%. In conclusion, B. sernata and AKBA reduce neuronal cell death induced by OGSD and this neuroprotective effect is mediated via attenuation of oxidative stress.
Co-administration of acetyl-11-keto-beta-boswellic acid, a specific 5-lipoxygenase inhibitor, potentiates the protective effect of COX-2 inhibitors in kainic acid-induced neurotoxicity in mice.
Bishnoi Mahendra,Patil C S,Kumar Anil,Kulkarni Shrinivas K
Pharmacology
Cyclooxygenase (COX) and lipoxygenase (LOX) are responsible for the metabolism of arachidonic acid into inflammatory metabolites, prostaglandins and leukotrienes, respectively. The upregulation of these enzymes in the central nervous system has been demonstrated to be responsible for the increased neuronal vulnerability to degeneration. Kainic acid, a glutamate receptor agonist and responsible for neuronal excitotoxicity and oxidative damage via different mechanisms, is capable of stimulating mRNA of both COX-2 and 5-LOX in the brain. The present study was designed to study the effects of COX inhibitors (indomethacin, nimesulide, rofecoxib) and a 5-LOX inhibitor (acetyl-11-keto-beta-boswellic acid; AKBA) and the combination of these inhibitors (dual inhibition) on kainic acid induced excitotoxicity and oxidative and nitrosative damage in mice. The results from the present study indicated that AKBA, indomethacin, and nimesulide per se did not produce any change in the behavioural parameters after kainic acid administration; however, rofecoxib per seproduced a significant increase in the latency of clonic (seizure-like) movement and a decrease in mortality rate as compared with kainic acid treated animals. In combination studies AKBA, rofecoxib, and nimesulide produced a more pronounced effect than either of these drugs alone. Further, the effect of AKBA combined with rofecoxib was significantly more marked when compared with AKBA combined with nimesulide. Besides this, identical results were found for the effect of these agents and their combination against oxidative damage induced by kainic acid. These findings indicate the potential role of COX-2 inhibitors and also their combination with the 5-LOX inhibitor in kainic acid induced excitotoxicity and oxidative damage by virtue of their antioxidant effect and suggest the need for the development of dual inhibitors for the treatment of neuronal excitotoxicity.
10.1159/000097627
Antiinflammatory and antiatherogenic effects of the NF-kappaB inhibitor acetyl-11-keto-beta-boswellic acid in LPS-challenged ApoE-/- mice.
Cuaz-Pérolin Clarisse,Billiet Ludivine,Baugé Eric,Copin Corinne,Scott-Algara Daniel,Genze Felicitas,Büchele Berhold,Syrovets Tatiana,Simmet Thomas,Rouis Mustapha
Arteriosclerosis, thrombosis, and vascular biology
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.
10.1161/ATVBAHA.107.155606
[Acetyl-11-keto-beta-boswellic acid and arsenic trioxide regulate the productions and activities of matrix metalloproteinases in human skin fibroblasts and human leukemia cell line THP-1].
Liang Ya-hui,Li Ping,Zhao Jing-xia,Liu Xin,Huang Qi-fu
Zhong xi yi jie he xue bao = Journal of Chinese integrative medicine
OBJECTIVE:In order to reveal the treatment mechanism of Chinese medicine with the effect of activating blood and resolving putridity, we selected acetyl-11-keto-beta-boswellic acid (AKBA) and arsenic trioxide (ATO), the main monomeric components of frankincense and arsenolite which are two most commonly used Chinese medicine with effect of activating blood and resolving putridity. We combined AKBA and ATO as a compound, and explored its regulatory role in productions and activities of matrix metalloproteinase (MMP)-1, MMP-2 and MMP-9 in human skin fibroblasts (HSFbs) and human acute monocytic leukemia cell line THP-1 in inflammatory state. METHODS:In order to simulate the inflammatory micro-environment of chronic wounds, we established 3 cell models: HSFb model activated by tumor necrosis factor-alpha (TNF-α), THP-1 cell model activated by phorbol-12-myristate-13-acetate (PMA) and HSFb-THP-1 cell coculture system. AKBA and ATO were cocultured with these cell models. Enzyme-linked immunosorbent assay (ELISA), gelatin zymography assay and reverse transcription-polymerase chain reaction (RT-PCR) were used to test the secretions, activities and mRNA expressions of MMP-1, MMP-2 and MMP-9. In the study of the regulatory mechanism of AKBA and ATO on MMPs, AKBA and ATO were cocultured with the cell models. ELISA was used to test the secretions of TNF-α and interleukin-1beta (IL-β) and Western blot was used to test the phosphorylation levels of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38 mitogen-activated proteinkinase (p38MAPK). RESULTS:Compound of AKBA and ATO inhibited MMP-1, MMP-2 and MMP-9 mRNA expressions, secretions and activities respectively in HSFbs and THP-1 cells in inflammatory state (P<0.05, P<0.01). Also compound of AKBA and ATO inhibited secretions of TNF-α and IL-1β in THP-1 cells and cell coculture system (P<0.01). It also decreased the phosphorylation of ERK1/2 and p38 MAPK in HSFbs and THP-1 cells (P<0.05, P<0.01). CONCLUSION:The combined use of AKBA and ATO which in line with the rule of activating blood and resolving putridity inhibits fibroblasts and inflammatory cells in producing MMPs in inflammatory state through inhibiting the release of inflammatory factors and MAPK cascade pathway.
Acetyl-11-keto-β-boswellic acid ameliorates cognitive deficits and reduces amyloid-β levels in APPswe/PS1dE9 mice through antioxidant and anti-inflammatory pathways.
Wei Chao,Fan Jiao,Sun Xuan,Yao Jiarui,Guo Yane,Zhou Bo,Shang Yanchang
Free radical biology & medicine
Alzheimer's disease (AD) is a complex disease involved oxidative stress and inflammation in its pathogenesis. Acetyl-11-keto-β-boswellic acid (AKBA) is an active triterpenoid compound from extracts of Boswellia serrata, which has been widely used as an antioxidant and anti-inflammatory agent. The present study was to determine whether AKBA, a novel candidate, could protect against cognitive and neuropathological impairments in AD. We found that AKBA treatment resulted in a significant improvement of learning and memory deficits, a dramatic decrease in cerebral amyloid-β (Aβ) levels and plaque burden, a profound alleviation in oxidative stress and inflammation, and a marked reduction in activated glial cells and synaptic defects in the APPswe/PS1dE9 mice. Furthermore, amyloid precursor protein (APP) processing was remarkably suppressed with AKBA treatment by inhibiting beta-site APP cleaving enzyme 1 (BACE1) protein expression to produce Aβ in the APPswe/PS1dE9 mice brains. Mechanistically, AKBA modulated antioxidant and anti-inflammatory pathways via increasing nuclear erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression, and via declining phosphorylation of inhibitor of nuclear factor-kappa B alpha (IκBα) and p65. Collectively, our findings provide evidence that AKBA protects neurons against oxidative stress and inflammation in AD, and this neuroprotective effect involves the Nrf2/HO-1 and nuclear factor-kappa B (NF-κB) signaling pathways.
10.1016/j.freeradbiomed.2020.02.022
Acetyl-11-keto-β-boswellic acid suppresses invasion of pancreatic cancer cells through the downregulation of CXCR4 chemokine receptor expression.
Park Byoungduck,Sung Bokyung,Yadav Vivek R,Cho Sung-Gook,Liu Mingyao,Aggarwal Bharat B
International journal of cancer
Ninety percent of cancer-mediated deaths are due to metastasis of the tumor; however, the mechanisms controlling metastasis remain poorly understood. Thus, no therapy targeting this process has yet been approved. Chemokines and their receptors are mediators of chronic inflammation and have been linked to the metastasis of numerous cancers. More recently, the Cysteine X Cysteine (CXC) chemokine receptor 4 (CXCR4) has emerged as a key mediator of tumor metastasis; therefore, identification of inhibitors of this receptor has the potential to abrogate metastasis. In this report, we demonstrate that acetyl-11-keto-β-boswellic acid (AKBA), a component of the therapeutic plant Boswellia serrata, can downregulate CXCR4 expression in pancreatic cancer cells. The reduction in CXCR4 induced by this terpenoid was found to be cell-type specific, as its expression was also abrogated in leukemia, myeloma and breast cancer cell lines. Neither proteasome inhibitors nor lysosomal stabilization could prevent the AKBA-induced reduction in CXCR4 expression. This downregulation occurred at the transcriptional level. Suppression of CXCR4 by AKBA was accompanied by the inhibition of pancreatic cancer cell invasion, which is induced by CXCL12, the ligand for CXCR4. In addition, abrogation of the expression of chemokine receptor by AKBA was found in human pancreatic tissues from orthotopic animal model. AKBA also abolished breast tumor cell invasion, and this effect correlated with the disappearance of both the CXCR4 messenger RNA and CXCR4 protein. Overall, our results show that AKBA is a novel inhibitor of CXCR4 expression and, thus, has the potential to suppress the invasion and metastasis of cancer cells.
10.1002/ijc.25966
Acetyl-11-keto-β-boswellic acid (AKBA) inhibits human gastric carcinoma growth through modulation of the Wnt/β-catenin signaling pathway.
Zhang Yu-Sheng,Xie Ji-Zhen,Zhong Julia-Li,Li Yuan-Yuan,Wang Rui-Qi,Qin Yi-Zhuo,Lou Hong-Xiang,Gao Zu-Hua,Qu Xian-Jun
Biochimica et biophysica acta
BACKGROUND:Acetyl-11-keto-beta-boswellic acid (AKBA) is a derivative of boswellic acid, an active component of Boswellia serrata gum resin. We examined the effect of AKBA on human gastric carcinoma growth and explored the underlying molecular mechanisms. METHODS:Inhibition of cancer cell growth was estimated by colorimetric and clonogenic assays. Cell cycle distribution was analyzed by flow cytometry and apoptosis determined using Annexin V-FITC/PI staining and DNA ladder quantification. After three weeks of oral AKBA administration in nude mice bearing cancer xenografts, animals were sacrificed and xenografts removed for TUNEL staining and western blot analysis. RESULTS:AKBA exhibited anti-cancer activity in vitro and in vivo. With oral application in mice, AKBA significantly inhibited SGC-7901 and MKN-45 xenografts without toxicity. This effect might be associated with its roles in cell cycle arrest and apoptosis induction. The results also showed activation of p21(Waf1/Cip1) and p53 in mitochondria and increased cleaved caspase-9, caspase-3, and PARP and Bax/Bcl-2 ratio after AKBA treatment. Further analysis suggested that these effects might arise from AKBA's modulation of the aberrant Wnt/β-catenin signaling pathway. Upon AKBA treatment, β-catenin expression in nuclei was inhibited, and membrane β-catenin was activated. In the same sample, active GSK3β was increased and its non-active form decreased. Levels of cyclin D1, PCNA, survivin, c-Myc, MMP-2, and MMP-7, downstream targets of Wnt/β-catenin, were inhibited. CONCLUSIONS:AKBA effects on human gastric carcinoma growth were associated with its activity in modulating the Wnt/β-catenin signaling pathway. GENERAL SIGNIFICANCE:AKBA could be useful in the treatment of gastric cancers.
10.1016/j.bbagen.2013.03.003
Acetyl-11-keto-β-boswellic acid extracted from promotes Schwann cell proliferation and sciatic nerve function recovery.
Jiang Xiao-Wen,Zhang Bin-Qing,Qiao Lu,Liu Lin,Wang Xue-Wei,Yu Wen-Hui
Neural regeneration research
Frankincense can promote blood circulation. Acetyl-11-keto-β-boswellic acid (AKBA) is a small molecule with anti-inflammatory properties that is derived from Boswellia serrata. Here, we hypothesized that it may promote regeneration of injured sciatic nerve. To address this hypothesis, we established a rat model of sciatic nerve injury using a nerve clamping method. Rats were administered AKBA once every 2 days at doses of 1.5, 3, and 6 mg/kg by intraperitoneal injection for 30 days from the 1 day after injury. Sciatic nerve function was evaluated using the sciatic functional index. Degree of muscle atrophy was measured using the triceps surae muscle Cuadros index. Neuropathological changes were observed by hematoxylin-eosin staining. Western blot analysis was used to detect expression of phospho-extracellular signal-regulated kinase 1 and 2 (p-ERK1/2) in injured nerve. S100 immunoreactivity in injured nerve was detected by immunohistochemistry. In vivo experiments showed that 3 and 6 mg/kg AKBA significantly increased sciatic nerve index, Cuadros index of triceps muscle, p-ERK1/2 expression, and S100 immunoreactivity in injured sciatic nerve of sciatic nerve injury model rats. Furthermore, for in vitro experiments, Schwann cells were treated with AKBA at 0-20 μg/mL. Proliferation of Schwann cells was detected by Cell Counting Kit-8 colorimetry assay. The results showed that 2 μg/mL AKBA is the optimal therapeutic concentration. In addition, ERK phosphorylation levels increased following 2 μg/mL AKBA treatment. In the presence of the ERK1/2 inhibitor, PD98059 (2.5 μL/mL), the AKBA-induced increase in p-ERK1/2 protein expression was partially abrogated. In conclusion, our study shows that AKBA promotes peripheral nerve regeneration with ERK protein phosphorylation playing a key role in this process.
10.4103/1673-5374.228732
Neuroprotection by acetyl-11-keto-β-Boswellic acid, in ischemic brain injury involves the Nrf2/HO-1 defense pathway.
Scientific reports
Stroke is a complex disease involved oxidative stress-related pathways in its pathogenesis. The nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway has been considered a potential target for neuroprotection in stroke. Acetyl-11-Keto-β-Boswellic Acid (AKBA) is an active triterpenoid compound from the extract of Boswellia serrate. The present study was to determine whether AKBA, a novel Nrf2 activator, can protect against cerebral ischemic injury. The stroke model was produced in Sprague-Dawley rats via middle cerebral artery occlusion. To model ischemia-like conditions in vitro, primary cultured cortical neurons were exposed to transient oxygen and glucose deprivation (OGD). Treatment of AKBA significantly reduced infarct volumes and apoptotic cells, and also increased neurologic scores by elevating the Nrf2 and HO-1 expression in brain tissues in middle cerebral artery occlusion (MCAO) rats at 48 hours post reperfusion. In primary cultured neurons, AKBA increased the Nrf2 and HO-1 expression, which provided protection against OGD-induced oxidative insult. Additionally, AKBA treatment increased Nrf2 binding activity to antioxidant-response elements (ARE). The protective effect of AKBA was attenuated by knockdown of Nrf2 or HO-1. In conclusion, these findings provide evidence that AKBA protects neurons against ischemic injury, and this neuroprotective effect involves the Nrf2/HO-1 pathway.
10.1038/srep07002
3-Acetyl-11-keto-β-boswellic acid attenuated oxidative glutamate toxicity in neuron-like cell lines by apoptosis inhibition.
Rajabian Arezoo,Sadeghnia Hamid Reza,Hosseini Azar,Mousavi Seyed Hadi,Boroushaki Mohammad Taher
Journal of cellular biochemistry
3-Acetyl-11-keto-β-boswellic acid (AKBA), a pentacyclic triterpenic acid present in gum resin of Boswellia serrata, has been found to possess antioxidant and neuroprotective properties. In this study, we aimed to examine protective properties of AKBA against glutamate-induced neuronal injury. To investigate the effects of AKBA (2.5-10 µM) on glutamate injury in neuron-like cells PC12 and N2a, two treatment regimens (incubation for 2 or 0 hours before glutamate exposure) were used. Then, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method was used to determine viability of the cells. Cellular redox status was evaluated using fluorimetry and comet assays. Annexin V/propidium iodide double staining and Western blot analysis of relative apoptotic proteins were conducted. Based on the results, 24 hours incubation with glutamate (8 mM) increased the cell mortality of PC12 and N2a (P < .001). However, AKBA (2.5-10 µM) enhanced the cell viability in both treatment regimens (P < .001). Also co- and pretreatment with AKBA significantly attenuated lipid peroxidation, reactive oxygen species production, and DNA injury (P < .05 and P < .001). AKBA also restored the activity of cellular superoxide dismutase under glutamate toxicity; this effect was seen to be more significant during the pretreatment regimen (P < .001). Moreover, Western blot analysis indicated that AKBA inhibited glutamate-induced programmed cell death through depressing the elevation of the expression ratio of Bax/Bcl-2 and cleaved-caspase-3 proteins, concentration-dependently. Overall, the present findings suggest the neuroprotective activities of AKBA against glutamate-induced cell injury probably by inhibiting oxidative damage and reducing apoptotic cell death.
10.1002/jcb.29413
Acetyl-11-Keto-β-Boswellic Acid Promotes Osteoblast Differentiation by Inhibiting Tumor Necrosis Factor-α and Nuclear Factor-κB Activity.
Bai Fan,Chen Xuewu,Yang Hui,Xu Hong-Guang
The Journal of craniofacial surgery
Tumor necrosis factor (TNF) -α plays a crucial role in rheumatoid arthritis (RA)-related bone loss disease. The main mechanism of action of RA induced bone loss is the significant inhibitory effect of TNF-α on osteoblast differentiation. TNF-α inhibits osteoblast differentiation mainly by activating nuclear factor (NF) -κB signaling pathway. Owing to the crucial role of TNF-α and NF-κB in the inhibition of osteoblast differentiation, they are considered as targets for the development of therapeutic drugs. In the present study, we evaluated the NF-κB inhibitor Boswellic acid (BA) and its derivatives in the regulation of osteoblast differentiation and the molecular mechanism. Based on the cell model of TNF-α induced inhibition of osteoblast differentiation of MC3T3-E1, the regulatory role of BAs was studied. The result of MTT assay indicated that bone morphogenetic protein (BMP) -2, TNF-α, or acetyl-11-keto-β-BA (AKBA) impact no significant effect for cell viability of MC3T3-E1. The results of alkaline phosphatase (ALP activity assay and real-time polymerase chain reaction indicated that AKBA blocked TNF-α-induced inhibition of the expression of osteoblast markers, suggesting that AKBA rescued osteoblast differentiation from TNF-α-induced inhibition. Additionally, AKBA stimulated the BMP-2-induced expression of osteoblast markers, suggesting that AKBA promotes osteoblast differentiation directly. The results of western blotting and luciferase assay indicated that N-κB signaling was activated by TNF-α. The overexpression of NF-κB component p65 in MC3T3-E1 was found to attenuate the positive effect of AKBA in osteoblast differentiation, suggesting that AKBA potentiates osteoblast differentiation by inhibiting NF-κB signaling. Collectively, AKBA promotes osteoblast differentiation by inhibiting TNF-α and NF-κB. Our study revealed a new discovery of AKBA in regulating osteoblast differentiation, and demonstrated that AKBA may be a potential anabolic agent in the treatment of RA-derived bone loss disease.
10.1097/SCS.0000000000004691
Enhanced Neuroprotection of Acetyl-11-Keto-β-Boswellic Acid (AKBA)-Loaded O-Carboxymethyl Chitosan Nanoparticles Through Antioxidant and Anti-Inflammatory Pathways.
Ding Yi,Qiao Youbei,Wang Min,Zhang Huinan,Li Liang,Zhang Yikai,Ge Jie,Song Ying,Li Yuwen,Wen Aidong
Molecular neurobiology
Acetyl-11-keto-β-boswellic acid (AKBA), a main active constituent from Boswellia serrata resin, is a novel candidate for therapy of cerebral ischemia-reperfusion (I/R) injury. Nevertheless, its poor solubility in aqueous solvent, bioavailability, and rapid clearance limit its curative efficacy. To enhance its potency, in our study, AKBA-loaded o-carboxymethyl chitosan nanoparticle (AKBA-NP) delivery system was synthesized. The transmission electron microscopy and transmission electron microscope images of AKBA-NPs suggested that particle size was 132 ± 18 nm, and particles were spherical in shape with smooth morphology. In pharmacokinetics study, AKBA-NPs apparently increases the area under the curve of plasma concentration-time and prolonged half-life compared with AKBA. The tissue distribution study confirmed that AKBA-NPs had a better brain delivery efficacy in comparison with AKBA. The results from our pharmacodynamic studies showed that AKBA-NPs possess better neuroprotection compared with AKBA in primary neurons with oxygen-glucose deprivation (OGD) model and in animals with middle cerebral artery occlusion (MCAO) model. Additionally, AKBA-NPs modulate antioxidant and anti-inflammatory pathways more effectively than AKBA by increasing nuclear erythroid 2-related factor 2 and heme oxygenase-1 expression, and by decreasing nuclear factor-kappa B and 5-lipoxygenase expression. Collectively, our results suggest that AKBA-NPs serve as a potent delivery vehicle for AKBA in cerebral ischemic therapy.
10.1007/s12035-015-9333-9
Acetyl-11-keto-β-boswellic acid inhibits the secretion of cytokines by dendritic cells via the TLR7/8 pathway in an imiquimod-induced psoriasis mouse model and in vitro.
Wang Ming-Xing,Zhao Jing-Xia,Meng Yu-Jiao,Di Ting-Ting,Xu Xiao-Long,Xie Xiang-Jiang,Lin Yan,Zhang Lu,Wang Ning,Li Ping,Wang Yan
Life sciences
AIMS:Psoriasis vulgaris is mediated by T and dendritic cells. This study aimed to investigate the effects of acetyl-11-keto-β-boswellic acid (AKBA) on activated dendritic cells (DCs) using an imiquimod (IMQ)-induced psoriasis-like mouse model and murine bone marrow-derived dendritic cells (BMDCs) stimulated with resiquimod (R848) in vitro. MATERIALS AND METHODS:The mice were treated with IMQ and intragastrically administered 25-100 mg/kg/day of AKBA, 1 mg/kg/day of methotrexate (MTX), or normal saline. The inflammation of skin lesions in IMQ mice were evaluated by psoriasis area and severity index (PASI) and pathological staining. The related proteins of Toll-like receptor (TLR)7/8 pathways were assessed using Western blotting, and the expression levels of interleukin (IL)-23 and IL-12p40 mRNA using reverse transcription-polymerase chain reaction. The numbers of DCs and marker-positive BMDCs were assessed using flow cytometry and the levels of inflammatory factors using the enzyme-linked immunosorbent assay. KEY FINDINGS:AKBA and MTX obviously improved the psoriasis-like skin lesions of IMQ-treated mice. AKBA also obviously decreased the PASI score, reduced the thickness of epidermis, ameliorated the infiltration of CD3+ and CD11c+ cells in skin lesions, decreased the activation of local DCs, inhibited the mRNA expression and secretion of inflammatory factors IL-12 and IL-23, inhibited the maturation and differentiation of DCs to promote T-cell differentiation, and inhibited the activation of TLR7/8 and IRF signaling pathways. SIGNIFICANCE:This study implied that AKBA might have an anti-inflammatory effect on psoriasis by inhibiting the maturation and activation of DCs via the TLR8 and IRF signaling pathways.
10.1016/j.lfs.2018.05.044
Role of 3-Acetyl-11-Keto-Beta-Boswellic Acid in Counteracting LPS-Induced Neuroinflammation via Modulation of miRNA-155.
Sayed Aya Shoukry,Gomaa Iman Emam Omar,Bader Michael,El Sayed Nesrine Salah El Dine
Molecular neurobiology
Neuroinflammation is one of the most important mechanisms underlying neurodegeneration. Lipopolysaccharide (LPS) is a potent inflammogen which causes cognitive dysfunction. Boswellia serrata is known since many years as a powerful anti-inflammatory herbal drug. Its beneficial effect mainly arises from inhibition of 5-lipoxygenase (5-LO) enzyme. 3-acetyl-11-keto-β-boswellic acid (AKBA) is the most potent 5-LO inhibitor extracted from the oleo-gum-resin of Boswellia serrata. The aim of the present work is to study the molecular mechanisms underlying the anti-inflammatory and neuroprotective effects of AKBA and dexamethasone (DEX) in LPS-induced neuroinflammatory model. A single intraperitoneal (i.p.) dose of LPS (0.8 mg/kg) was injected to induce cognitive dysfunction. The LPS-treated mice were administered for 7 days with either AKBA or DEX at intraperitoneal doses of 5 and 1 mg/kg, respectively. Cognitive, locomotor functions, and anxiety level were first examined. The level of the phosphorylated inhibitory protein for NF-κB, IκB-α (P-IκB-α), was measured, and the expression levels of the inflammatory microRNA-155 (miR-155) and its target gene, suppressor of cytokine signaling-1 (SOCS-1), were determined in the brain. Moreover, the level of carbonyl proteins as a measure of oxidative stress and several cytokines as well as markers for apoptosis and amyloidogenesis was detected. Results showed that AKBA and DEX reversed the behavioral dysfunction induced by LPS. AKBA decreased P-IκB-α, miRNA-155 expression level, and carbonyl protein content. It restored normal cytokine level and increased SOCS-1 expression level. It also showed anti-apoptotic and anti-amyloidogenic effects in LPS-injected mice. These findings suggest AKBA as a therapeutic drug for alleviating the symptoms of neuroinflammatory disorders.
10.1007/s12035-017-0801-2
Co-administration of 3-Acetyl-11-Keto-Beta-Boswellic Acid Potentiates the Protective Effect of Celecoxib in Lipopolysaccharide-Induced Cognitive Impairment in Mice: Possible Implication of Anti-inflammatory and Antiglutamatergic Pathways.
Sayed Aya Shoukry,El Sayed Nesrine Salah El Dine
Journal of molecular neuroscience : MN
Neuro-inflammation is known to initiate the underlying pathogenesis of several neurodegenerative disorders which may progress to cognitive, behavioral, and functional impairment. Boswellia serrata is a well-known powerful anti-inflammatory agent used to treat several inflammatory diseases. The aim of the current study is to investigate the effect of the combination therapy of 3-acetyl-11-keto-β-boswellic acid (AKBA), a 5-lipoxygenase (5-LOX) inhibitor and celecoxib, and a selective cyclooxygenase-2 (COX-2) inhibitor as dual enzyme inhibitors compared to monotherapies with celecoxib and AKBA. Cognitive dysfunction is induced by intraperational injection of lipopolysaccharide (LPS) in mice. Radial maze, Y maze, and novel object recognition (NOR) were performed to evaluate the possible behavioral changes. Moreover, estimation of glutamate and tumor necrosis factor-alpha (TNF-α), as well as an immunohistochemical investigation of amyloid beta peptide (Aβ) was performed to evaluate the molecular changes that followed the LPS or drug treatment. The results showed that the combination therapy of AKBA and celecoxib reversed the behavioral and molecular changes caused by LPS cognitive dysfunction model that predispose cognitive dysfunction in mice. This study showed the effectiveness of the dual therapy with AKBA and celecoxib as anti-inflammatory, antiglutamatergic, and anti-amyloidogenic agents in the management of cognitive dysfunction.
10.1007/s12031-016-0734-7
Acetyl-11-keto-β-boswellic acid (AKBA) Attenuates Oxidative Stress, Inflammation, Complement Activation and Cell Death in Brain Endothelial Cells Following OGD/Reperfusion.
Ahmad Saif,Khan Shah Alam,Kindelin Adam,Mohseni Tasha,Bhatia Kanchan,Hoda Md Nasrul,Ducruet Andrew F
Neuromolecular medicine
Brain endothelial cells play an important role in maintaining blood flow homeostasis in the brain. Cerebral ischemia is a major cause of endothelial dysfunction which can disrupt the blood-brain barrier (BBB). Oxygen-glucose deprivation (OGD)/reperfusion promote cell death and BBB breakdown in brain endothelial cells. Acetyl-11-keto-β-boswellic acid (AKBA), a biologically active phytoconstituent of the medicinal plant Boswellia serrata, has been shown to be protective against various inflammatory diseases as well as ischemic brain injury. The molecular mechanisms underlying these beneficial characteristics of AKBA are poorly understood. We subjected bEND.3 cells to OGD/reperfusion to investigate the protective role of AKBA in this model. We found that AKBA treatment attenuated endothelial cell death and oxidative stress assessed by means of TUNEL assay, cleaved-caspase-3, and dihydroethidium (DHE) staining. Furthermore, OGD downregulated tight junction proteins ZO-1 and Occludin levels, and increased the expressions of inflammatory cytokines TNF-α, ICAM-1, and complement C3a receptor (C3aR). We also noticed the increased phosphorylation of ERK 1/2 in bEND.3 cells in OGD group. AKBA treatment significantly attenuated expression levels of these inflammatory proteins and prevented the degradation of ZO-1 and Occludin following OGD. In conclusion, AKBA treatment provides protection against endothelial cell dysfunction following OGD by attenuating oxidative stress and inflammation.
10.1007/s12017-019-08569-z
Acetyl-11-keto-β-boswellic acid regulates the repair of rat sciatic nerve injury by promoting the proliferation of Schwann cells.
Jiang Xiaowen,Wang Yao,Zhang Binqing,Fei Xue,Guo Xu,Jia Yongzhen,Yu Wenhui
Life sciences
AIMS:This study aimed to study the effects of acetyl-11-keto-β-boswellic acid (AKBA) on the regeneration of injured peripheral nerves and the ability of the extracellular signal-regulated kinase (ERK) signaling pathway to regulate the proliferation of Schwann cells and the formation of myelin. MAIN METHODS:A sciatic nerve crush injury model rats were randomly divided into the model control, low-, medium-, and high-dose AKBA groups. The repair of myelin damage was observed through Luxol Fast Blue staining and the expression of neurofilament-200 (NF200) protein was detected through immunohistochemical tests. The relative expression levels of ERK, Phosphorylated-ERK (p-ERK), c-Jun N-terminal Kinase (JNK), and Phosphorylated-JNK (p-JNK) proteins were detected in vitro in Schwann cells treated with AKBA. The effect of AKBA on P0 and P75 protein expression in Schwann cells was detected through siRNA-mediated ERK gene knockout. KEY FINDINGS:AKBA promotes the repair of rat sciatic nerve injury by elevating the phosphorylation of the ERK signaling pathway and by regulating the proliferation and myelination of Schwann cells. SIGNIFICANCE:This test can provide data support for AKBA to repair sciatic nerve injury, provide a theoretical basis for further revealing AKBA repair mechanism, and provide reference for clinical development of sciatic nerve injury drugs.
10.1016/j.lfs.2019.116887