acetyl-11-ketoboswellic-acid and Disease-Models--Animal

The 3-O-acetyl-11-keto-β-boswellic acid (AKBA) is the most active compound of

Topics: Amyloid beta-Peptides; Animals; Antidepressive Agents; Biomarkers; Depression; Disease Models, Animal; Glial Fibrillary Acidic Protein; Glutamic Acid; Kynurenine; Male; Mice; Treatment Outcome; Triterpenes

Topics: Animals; Cardiomyopathies; Creatine Kinase, MB Form; Disease Models, Animal; Fibrosis; Heme Oxygenase (Decyclizing); L-Lactate Dehydrogenase; Myocardium; NF-E2-Related Factor 2; Random Allocation; Rats; Rats, Sprague-Dawley; Smad Proteins; Transforming Growth Factor beta1; Triterpenes

Glioblastoma (GBM) is the most common, malignant, and lethal primary brain tumor in adults accounting for about 50% of all gliomas. Up to now, the chemotherapy approaches for GBM were limited. 3-O-acetyl-11-keto-β-boswellic acid (AKBA), the major active ingredient of the gum resin from Boswellia serrata and Boswellia carteri Birdw., was reported to inhibit the growth of many types of cancer cells; however, the underlying mechanism of its anticancer effects are still unclear.. The effects of AKBA on cell viability and its cytotoxicity were determined using CCK8 and LDH kits respectively. The EdU-DNA synthesis assay was used to evaluate inhibition of cell proliferation by AKBA. The role of AKBA in glioblastoma cell functions such as migration/invasion, and colony formation was evaluated using transwell chambers and soft agar, respectively. Flow cytometry and western blotting were used to detect AKBA-induced apoptosis. Potential mechanisms of AKBA action were explored by RNA sequencing and the identified hub genes were validated by real-time quantitative PCR and western blotting. Finally, the in vivo anti-tumor activity of AKBA was evaluated against a human glioblastoma cell line, U87-MG, in a xenograft mouse model.. AKBA inhibited cell proliferation, caused the release of LDH, decreased DNA synthesis, and inhibited the migration, invasion, and colony formation of U251 and U87-MG human glioblastoma cell lines. AKBA increased apoptosis as well as the activity of caspase 3/7 and the protein expression of cleaved-caspase 3 and cleaved PARP, while decreasing mitochondrial membrane potential. RNA-sequencing analyses showed that AKBA suppressed the expression of pRB, FOXM1, Aurora A, PLK1, CDC25C, p-CDK1, cyclinB1, Aurora B, and TOP2A while increasing the expression of p21 and GADD45A. These findings were validated by qRT-PCR and western blotting. The data are consistent with a mechanism in which AKBA arrested the cell cycle in glioblastoma cells at the G2/M phase by regulating the p21/FOXM1/cyclin B1 pathway, inhibited mitosis by downregulating the Aurora B/TOP2A pathway, and induced mitochondrial-dependent apoptosis. Oral administration of AKBA (100 mg/kg) significantly suppressed the tumorigenicity of U87-MG cells in a xenograft mouse model.. Taken together, these results suggest that AKBA (molecular weight, 512.7 Da) might be a promising chemotherapy drug in the treatment of GBM.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biomarkers; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Disease Models, Animal; G2 Phase Cell Cycle Checkpoints; Glioblastoma; Humans; Membrane Potential, Mitochondrial; Mice; Mitosis; Models, Biological; Protein Interaction Mapping; Signal Transduction; Triterpenes; Xenograft Model Antitumor Assays

On the basis of preliminary in vitro experience, we assessed whether an enriched nutritional formulation with estrogen receptor (ER)-beta agonist and anti-inflammatory properties may prevent inflammation-associated colorectal cancer (CRC) in an animal model. Study sample enclosed 110 C57BL/6J male mice. Forty underwent dietary supplement safety assessment (20 standard diet and 20 enriched formulation). Seventy were treated with azoxymethane (AOM)/dextran sulfate sodium and divided into two groups: 35 received standard diet and 35 enriched formulation (curcumin, boswellic acids, silymarin and maltodextrins). Miniature colonoscopy demonstrated colitis and solid lesion development in five mice/group 100 days after first AOM injection. Mice were killed after 10 days. In each group, four subgroups received intraperitoneal bromodeoxyuridine (BrdU) injection at 24th/48th/72nd/96th hour before killing. Anti-inflammatory effect and chemoprevention were evaluated by lesion number/size, histological inflammation/dysplasia/neoplasia assessment, pro-inflammatory cytokine messenger RNA (mRNA), ER-beta/ER-alpha/BrdU immunohistochemistry and TUNEL immunofluorescence. Standard formulation assumption was associated with colon shortening compared with enriched one (P = 0.04), which reduced solid lesion number and size (P < 0.001 for both), histological inflammation score (P = 0.04), pro-inflammatory cytokine mRNA expression (P < 0.001), number of low-grade dysplasia (LGD; P = 0.03) and high-grade dysplasia (P < 0.001) areas. CRC was observed in 69.6% in standard and 23.5% in enriched formulation assuming animals (P < 0.001). Enriched formulation induced lower ER-alpha expression in CRC (P < 0.001) and higher ER-beta expression in LGD (P < 0.001) being associated to higher epithelial turnover (BrdU; P<0.001) in normal mucosa and increased apoptosis in LGD and CRC (P < 0.001 for both). Our results are promising for a successful anti-inflammatory and chemopreventive effect of enriched formulation in CRC arising from inflamed tissue.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Azoxymethane; Chemoprevention; Colitis; Colon; Colonoscopy; Colorectal Neoplasms; Curcumin; Cytokines; Dextran Sulfate; Disease Models, Animal; Food, Fortified; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Polysaccharides; Real-Time Polymerase Chain Reaction; Receptors, Estrogen; Silymarin; Triterpenes

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.

Topics: Administration, Intravenous; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Cells, Cultured; Chitosan; Disease Models, Animal; Glucose; Glutathione Peroxidase; Infarction, Middle Cerebral Artery; Interleukin-1beta; L-Lactate Dehydrogenase; Nanoparticles; Neurons; Neuroprotection; Neuroprotective Agents; Oxygen; Rats, Sprague-Dawley; Superoxide Dismutase; Tissue Distribution; Triterpenes; Tumor Necrosis Factor-alpha

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Boswellia; Carrageenan; Cellulose; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Disease Models, Animal; Drug Carriers; Female; Indomethacin; Inflammation; Microscopy, Electron, Scanning; Phytotherapy; Plants, Medicinal; Polyethylene Glycols; Rats, Wistar; Resins, Plant; Solubility; Solvents; Spectrophotometry, Ultraviolet; Stomach Ulcer; Triterpenes

Retinal diseases characterized by pathologic retinal angiogenesis are the leading causes of blindness worldwide. Although therapies directed toward vascular endothelial growth factor (VEGF) represent a significant step forward in the treatment of proliferative retinopathies, further improvements are needed. In the last few years, an intense research activity has focused around the use of herbal and traditional natural medicines as an alternative for slowing down the progression of proliferative retinopathies. In the present study, we investigated the antiangiogenic effects of acetyl-11-keto-β-boswellic acid (AKBA), one of the active principles derived from the plant Boswellia serrata, used in Ayurvedic systems of medicine. We studied the antiangiogenic properties of AKBA using the mouse model of oxygen-induced retinopathy (OIR), which mimics the neovascular response seen in human retinopathy of prematurity. We first evaluated the effects of subcutaneously administered AKBA on the expression/activity of proteins which are known to play a role in the OIR model. In the retina, AKBA increased expression and activity of Src homology region 2 domain-containing phosphatase 1 and reduced the phosphorylation of the transcription factor signal transducer and activator of transcription 3 (STAT3) as well as VEGF expression and VEGF receptor (VEGFR)-2 phosphorylation. Likely as a result of these effects, AKBA significantly reduced retinal neovascularization in OIR mice without affecting retinal cell survival and retinal function. Using retinal explants cultured in hypoxia and an activator of STAT3 phosphorylation, we showed that the AKBA-induced inhibition of VEGFR-2 phosphorylation is likely to be mediated by a mechanism depending on an SHP-1/STAT3/VEGF axis. In the OIR model, neovascularization results from the activation of retinal endothelial cells, therefore we evaluated whether AKBA affected the angiogenic response of human retinal microvascular endothelial cells (HRMECs). We observed that AKBA reduced proliferation, migration and tube formation in HRMECs stimulated with exogenous VEGF, while it reduced migration and tube formation in untreated HRMECs. Taken together, our results demonstrate the antiangiogenic effects of AKBA in a model of pathologic neovascularization, providing a rationale for further investigation of AKBA as a promising therapeutic agent to reduce the impact of proliferative retinopathies.

Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Cell Proliferation; Cell Survival; Disease Models, Animal; Electroretinography; Endothelial Cells; Female; Male; Mice; Mice, Inbred C57BL; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Retinal Neovascularization; Triterpenes; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Acetyl-11-keto-beta-BA (AKBA), a component of the gum resin of Boswellia serrata, has been recognized as a promising agent for the prevention of intestinal tumorigenesis. Aspirin, a non-steroidal anti-inflammatory drug (NSAID), has also been considered to have the activity against intestinal tumorigenesis. However, the prevention of colonic cancer is insufficient and no definitive recommendation has been made for clinic use. Herein, we compared the efficacy of AKBA with that of aspirin in an adenomatous polyposis coli intestinal neoplasia consecutive weeks. Mice were sacrificed by anesthetizing. The whole intestine was removed from each mouse. The number, size and histopathology of intestinal adenomatous polyps were examined under microscopy. The adenomatous polyps were removed for further analysis by the assays of western blotting and immunohistochemical staining. AKBA significantly prevented the formation of intestinal adenomatous polyps without toxicity to mice. Statistical analysis indicated that AKBA's activity both in the prevention of small intestinal and colonic polyps was more potently than aspirin. Histopathologic examination revealed that AKBA's effect, that is the reduction of polyp size and degree of dysplasia, was more prominent in larger sized polyps, especially those originating in colon. These effects of AKBA were associated with its role in the induction of apoptosis in carcinomas. The assays of western blotting and immunohistochemistry staining indicated that the efficacy of AKBA might arise from its activity in the modulation of the Wnt/β-catenin pathway and NF-κB/COX-2 pathway in adenomatous polyps. Conclusion, AKBA by oral application prevented intestinal tumorigenesis more potential than aspirin.

Topics: Adenocarcinoma; Adenomatous Polyposis Coli; Administration, Oral; Animals; Anti-Inflammatory Agents; Anticarcinogenic Agents; Apoptosis; Aspirin; beta Catenin; Cell Transformation, Neoplastic; Colonic Polyps; Cyclooxygenase 2; Disease Models, Animal; Genes, APC; Inflammation Mediators; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; NF-kappa B; Time Factors; Triterpenes; Tumor Burden; Wnt Signaling Pathway

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.

Topics: Animals; Antioxidant Response Elements; Apoptosis; Brain Ischemia; Cell Hypoxia; Cerebral Cortex; Disease Models, Animal; Gene Expression Regulation; Glucose; Heme Oxygenase-1; Male; Neurons; Neuroprotective Agents; NF-E2-Related Factor 2; Oxygen; Primary Cell Culture; Rats; Rats, Sprague-Dawley; RNA, Small Interfering; Signal Transduction; Stroke; Triterpenes

Numerous cancer therapeutics were originally identified from natural products used in traditional medicine. One such agent is acetyl-11-keto-beta-boswellic acid (AKBA), derived from the gum resin of the Boswellia serrata known as Salai guggal or Indian frankincense. Traditionally, it has been used in Ayurvedic medicine to treat proinflammatory conditions. In this report, we hypothesized that AKBA can affect the growth and metastasis of colorectal cancer (CRC) in orthotopically implanted tumors in nude mice. We found that the oral administration of AKBA (50-200 mg/kg) dose-dependently inhibited the growth of CRC tumors in mice, resulting in decrease in tumor volumes than those seen in vehicle-treated mice without significant decreases in body weight. In addition, we observed that AKBA was highly effective in suppressing ascites and distant metastasis to the liver, lungs and spleen in orthotopically implanted tumors in nude mice. When examined for the mechanism, we found that markers of tumor proliferation index Ki-67 and the microvessel density cluster of differentiation (CD31) were significantly downregulated by AKBA treatment. We also found that AKBA significantly suppressed nuclear factor-κB (NF-κB) activation in the tumor tissue and expression of proinflammatory (cyclooxygenase-2), tumor survival (bcl-2, bcl-xL, inhibitor of apoptosis (IAP-1) and survivin), proliferative (cyclin D1), invasive (intercellular adhesion molecule 1 and matrix metalloproteinase-9) and angiogenic C-X-C (CXC) receptor 4 and vascular endothelial growth factor) biomarkers. When examined for serum and tissue levels of AKBA, a dose-dependent increase in the levels of the drug was detected, indicating its bioavailability. Thus, our findings suggest that this boswellic acid analog can inhibit the growth and metastasis of human CRC in vivo through downregulation of cancer-associated biomarkers.

Topics: Animals; Biomarkers, Tumor; Boswellia; Cell Proliferation; Colorectal Neoplasms; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Inflammation; Male; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Neovascularization, Pathologic; Triterpenes; Xenograft Model Antitumor Assays

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.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Drug Delivery Systems; Humans; Inflammation Mediators; Mice; Mice, Mutant Strains; NF-kappa B; Psoriasis; Triterpenes

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.. 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.. 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.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Boswellia; Cells, Cultured; Disease Models, Animal; Inflammation; Lipopolysaccharides; Mice; Mice, Knockout; NF-kappa B; Plant Extracts; Triterpenes

Basic fibroblast growth factor (bFGF), a metastatic growth factor is known to be one of the promoting factors in the tumor induced angiogenesis. The antiangiogenic activity of acetyl 11-keto beta-boswellic acid was screened against bFGF-induced angiogenesis using in-vivo Matrigel Plug Assay. Histological & colorimetric examination confirmed that numerous blood vessels were present in Matrigel+bFGF group in comparison to Matrigel alone treated mice. Acetyl 11-keto beta-boswellic acids (10 mg/kg/d) inhibited the Matrigel+bFGF-induced angiogenesis significantly (P<0.01) in contrast to anti-inflammatory agent indomethacin (10 mg/kg/d) and alkylating agent cyclophosphamide (10 mg/kg/d).

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Alkylating; Collagen; Cyclooxygenase Inhibitors; Cyclophosphamide; Disease Models, Animal; Drug Combinations; Fibroblast Growth Factor 2; Indomethacin; Laminin; Male; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Proteoglycans; Reproducibility of Results; Subcutaneous Tissue; Triterpenes

The gum resin extract from Boswellia serrata (H15), an herbal product, was recently shown to have positive therapeutic effects in inflammatory bowel disease (IBD). However, the mechanisms and constituents responsible for these effects are poorly understood. This study examined the effect of the Boswellia extract and its single constituent acetyl-11-keto-beta-boswellic acid (AKBA) on leukocyte-endothelial cell interactions in an experimental model of IBD. Ileitis was induced by two subcutaneous injections of indomethacin (7.5 mg/kg) in Sprague-Dawley rats 24 h apart. Rats also received oral treatment with the Boswellia extract (H15) or AKBA at two different doses (low and high) equivalent to recommendations in human disease over 2 days. Controls received only the carriers NaHCO3 (subcutaneously) and tylose (orally). Effects of treatment were assessed by intravital microscopy in ileal submucosal venules for changes in the number of rolling and adherent leukocytes and by macroscopic and histological scoring. Increased leukocyte-endothelial cell adhesive interactions and severe tissue injury accompanied indomethacin-induced ileitis. Treatment with the Boswellia extract or AKBA resulted in a dose-dependent decrease in rolling (up to 90%) and adherent (up to 98%) leukocytes. High-dose Boswellia extract as well as both low- and high-dose AKBA significantly attenuated tissue injury scores. Oral therapy with the Boswellia extract or AKBA significantly reduces macroscopic and microcirculatory inflammatory features normally associated with indomethacin administration, indicating that the anti-inflammatory actions of the Boswellia extract in IBD may be due in part to boswellic acids such as AKBA.

Topics: Animals; Disease Models, Animal; Follow-Up Studies; Ileitis; Inflammatory Bowel Diseases; Male; Plant Extracts; Plants, Medicinal; Probability; Rats; Rats, Sprague-Dawley; Reference Values; Resins, Plant; Sensitivity and Specificity; Treatment Outcome; Triterpenes