acetyl-11-ketoboswellic-acid and Inflammation

Inflammation comprises the reaction of the body to injury, in which a series of changes of the terminal vascular bed, blood, and connective tissue tends to eliminate the injurious agent and to repair the damaged tissue. It is a complex process, which involves the release of diverse regulatory mediators. The current anti-inflammatory agents are challenged by multiple side effects and thus, new effective therapies are highly needed. The aim of this review is to summarize the described microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors or transcriptional suppressors from medicinal plants, which could be an ideal approach in the management of inflammatory disorders, but need further clinical trials in order to be ultimately validated.

Topics: Animals; Anti-Inflammatory Agents; Biological Products; Drug Discovery; Enzyme Inhibitors; Humans; Inflammation; Plants, Medicinal; Prostaglandin-E Synthases

Specialized pro-resolving mediators (SPM), primarily produced in innate immune cells, exert crucial bioactions for resolving inflammation. Among various lipoxygenases (LOX), 15-LOX-1 is key for SPM biosynthesis, but cellular activation principles of 15-LOX-1 are unexplored. It was shown that 3-O-acetyl-11-keto-β-boswellic acid (AKBA) shifts 5-LOX regiospecificity from 5- to 12-lipoxygenation products. Here, it is demonstrated that AKBA additionally activates cellular 15-LOX-1 via an allosteric site accomplishing robust SPM formation in innate immune cells, particularly in M2 macrophages. Compared to ionophore, AKBA-induced LOX activation is Ca

Topics: Allosteric Regulation; Animals; Arachidonate 15-Lipoxygenase; HEK293 Cells; Humans; Inflammation; Lipids; Lipoxygenase; Mice; Scavenger Receptors, Class E

Acetyl-11-keto-beta-boswellic acid (AKBA), a potent anti-inflammatory compound purified from Boswellia species, was investigated in a preclinical study for its potential in preventing and treating non-alcoholic fatty liver disease (NAFLD), the most common chronic inflammatory liver disorder. The study involved thirty-six male Wistar rats, equally divided into prevention and treatment groups. In the prevention group, rats were given a high fructose diet (HFrD) and treated with AKBA for 6 weeks, while in the treatment group, rats were fed HFrD for 6 weeks and then given a normal diet with AKBA for 2 weeks. At the end of the study, various parameters were analyzed including liver tissues and serum levels of insulin, leptin, adiponectin, monocyte chemoattractant protein-1 (MCP-1), transforming growth factor beta (TGF-β), interferon gamma (INF-ϒ), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). Additionally, the expression levels of genes related to the inflammasome complex and peroxisome proliferator-activated receptor gamma (PPAR-ϒ), as well as the levels of phosphorylated and non-phosphorylated AMP-activated protein kinase alpha-1 (AMPK-α1) protein, were measured. The results showed that AKBA improved NAFLD-related serum parameters and inflammatory markers and suppressed PPAR-ϒ and inflammasome complex-related genes involved in hepatic steatosis in both groups. Additionally, AKBA prevented the reduction of the active and inactive forms of AMPK-α1 in the prevention group, which is a cellular energy regulator that helps suppress NAFLD progression. In conclusion, AKBA has a beneficial effect on preventing and avoiding the progression of NAFLD by preserving lipid metabolism, improving hepatic steatosis, and suppressing liver inflammation.

Topics: AMP-Activated Protein Kinases; Animals; Diet; Fructose; Inflammasomes; Inflammation; Lipid Metabolism; Liver; Male; Non-alcoholic Fatty Liver Disease; Peroxisome Proliferator-Activated Receptors; Rats; Rats, Wistar

Multiple sclerosis (MS) is characterized by chronic autoimmune inflammation of central nervous system (CNS), i.e. brain and spinal cord. Autoimmune inflammation of the CNS and periphery causes demyelination of axons ultimately leading to clinical symptoms such as gait imbalance, lack of coordination and paraplegia. Innate immune cells such as dendritic cells and neutrophils play a critical role in the initiation and progression of MS through upregulation of oxidants. Two prominent pathways that play important role in regulation of oxidant-antioxidant balance are nuclear factor-erythroid factor 2-related factor 2(Nrf2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Nrf2-mediated upregulation of antioxidants counteracts NF-κB-mediated oxidant generation. Therefore, this study evaluated the effects of nutraceutical drug, acetyl-11-keto-β-boswellic acid (AKBA) in relapsing remitting model of experimental autoimmune encephelomyelitis (EAE). Efficacy of AKBA was explored on clinical symptoms, Nrf2, hemeoxygenase-1 (HO-1), NF-κB, inducible nitric oxide synthase (iNOS) in CNS and periphery of SJL/J mice. Our results show that expression of p-NF-κB and iNOS is elevated, whereas expression of Nrf2 and HO-1 is decreased in CD11c + DCs and CNS, which is linked with appearance of clinical symptoms in immunized SJL/J mice. Treatment of immunized SJL/J mice with AKBA causes improvement of clinical symptoms and downregulation of inflammatory markers in CD11c + DCs (p-NF-κB, iNOS, and nitrotyrosine), and CNS (p-NF-κB, iNOS, nitrotyrosine,lipid peroxides, and total antioxidant capacity). Treatment of immunized SJL/J mice with AKBA also causes rectification of Nrf2 signaling in CD11c + DCs, and CNS. These results propose AKBA ameliorates EAE disease progression through rectification of Nrf2 signaling and attenuation of NF-κB pathway in RR model of EAE. Therefore, nutraceutical compound, AKBA may be therapeutically useful in RRMS.

Topics: Animals; Antioxidants; Encephalomyelitis, Autoimmune, Experimental; Inflammation; Mice; Mice, Inbred Strains; NF-E2-Related Factor 2; NF-kappa B; Oxidants; Triterpenes

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.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Boswellia; Cell Hypoxia; Complement Activation; Complement Inactivating Agents; DNA Damage; Endothelial Cells; Glucose; Hypoxia-Ischemia, Brain; Inflammation; MAP Kinase Signaling System; Mice; Oxidative Stress; Oxygen; Plant Extracts; Plants, Medicinal; Reactive Oxygen Species; Triterpenes

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.

Topics: Animals; Apoptosis; Behavior, Animal; Brain; Cytokines; Dexamethasone; Inflammation; Lipopolysaccharides; Male; Mice; MicroRNAs; Neuroprotective Agents; Protein Carbonylation; Triterpenes

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.. 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.. 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.. 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.

Topics: Aminoquinolines; Animals; CD4-Positive T-Lymphocytes; Cell Differentiation; Cell Proliferation; Coculture Techniques; Cytokines; Dendritic Cells; Erythema; Imiquimod; Inflammation; Interleukin-12 Subunit p35; Interleukin-23 Subunit p19; Male; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Psoriasis; RNA, Messenger; Signal Transduction; Spleen; Toll-Like Receptor 7; Toll-Like Receptor 8; Triterpenes

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

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

There is significant number of evidences suggesting the anti-inflammatory properties of gum resin extracts of Boswellia serrata containing 3-O-acetyl-11-keto-β-boswellic acid (AKBA) and their promising potential as therapeutic interventions against inflammatory diseases such as osteoarthritis (OA). Unfortunately, the poor bioavailability of AKBA following oral administration might limit the anti-inflammatory efficacy of standardized Boswellia extract(s). To address this issue, we describe a novel composition called Aflapin, which contains B. serrata extract enriched in AKBA and non-volatile oil portion of B. serrata gum resin. Our observations show that the availability of AKBA in systemic circulation of experimental animals is increased by 51.78% in Aflapin-supplemented animals, in comparison with that of 30% AKBA standardized extract or BE-30 (5-Loxin(®)). Consistently, Aflapin confers better anti-inflammatory efficacy in Freund's Complete Adjuvant (FCA)-induced inflammation model of Sprague-Dawley rats. Interestingly, in comparison with BE-30, Aflapin(®) also provides significantly better protection from IL-1β-induced death of human primary chondrocytes and improves glycosaminoglycans production in human chondrocytes. In Tumor necrosis factor alpha (TNFα)-induced human synovial cells, the inhibitory potential of Aflapin (IC(50) 44.736 ng/ml) on matrix metalloproteinase-3 (MMP-3) production is 14.83% better than that of BE-30 (IC(50) 52.528 ng/ml). In summary, our observations collectively suggest that both the Boswellia products, BE-30 (5-Loxin(®)) and Aflapin, exhibit powerful anti-inflammatory efficacy and anti-arthritic potential. In particular, in comparison with BE-30, Aflapin provides more potential benefits in recovering articular cartilage damage or protection from proteolytic degradation due to inflammatory insult in arthritis such as osteoarthritis or rheumatoid arthritis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonate 5-Lipoxygenase; Biological Availability; Boswellia; Cell Culture Techniques; Cell Death; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Female; Foot; Freund's Adjuvant; Glycosaminoglycans; Hindlimb; Humans; Inflammation; Interleukin-1beta; Lipoxygenase Inhibitors; Male; Matrix Metalloproteinase 3; Osteoarthritis; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Rats, Wistar; Triterpenes; Tumor Necrosis Factor-alpha

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