Natural product; pentacyclic triterpenoid; PI3K/AKT
Boswellic acid targets multiple pathways involved in inflammation and cancer. It is a non-redox inhibitor of 5-lipoxygenase (5-LOX), an enzyme involved in leukotriene biosynthesis. It inhibits the production of pro-inflammatory cytokines by inhibiting cyclooxygenase 2 (COX2). It also targets NO, PGE2, Nrf2, HO-1, and ROS. α-Boswellic acid has gastroprotective properties by decreasing oxidative stress and activating the Nrf2/HO-1 pathway. It also increases Survivin and Reelin expression and decreases production of reactive oxygen species (ROS) and levels of hyperphosphorylated Tau.

In this study, researchers investigated the effects of α-boswellic acid (ABA) as one of the major component of Boswellia serrata resin on primary fetal human astrocytes under a stress paradigm as a possible model for AD through study on Reelin cascade. For this aim, we used streptozotocin (STZ), in which from an outlook generates Alzheimer's hallmarks in astrocytes, and assayed Reelin expression, Tau and Akt phosphorylation as well as reactive oxygen species (ROS) generation and apoptosis in the presences of ABA. Our results indicated that while STZ (100 µM) down-regulated the expression of Reelin, ABA (25 µM) up-regulated its expression (p < 0.01) for 24 h. ABA efficiently reduced hyperphosphorylated Tau (Ser404) in STZ-treated astrocytes (p < 0.01). Furthermore, STZ-induced apoptosis by increasing cleaved caspase three (p < 0.01) and ROS generation (p < 0.01), a further pathological hallmark of Tauopathy. On the other hand, ABA decreased ROS generation and promoted proliferation of astrocytes through elevating Survivin expression (p < 0.01). These results showed that ABA could be considered as a potent therapeutic agent for prevention and decreasing the progression of Alzheimer's hallmarks in astrocytes; however, more in vivo studies would be needed[3].
In vitro, boswellic acid inhibits viral replication and has anti-inflammatory properties. It inhibits the production of pro-inflammatory cytokines by inhibiting COX2. It increases Survivin and Reelin expression and decreases production of reactive oxygen species (ROS) and levels of hyperphosphorylated Tau. α-Boswellic acid has gastroprotective properties by decreasing oxidative stress and activating the Nrf2/HO-1 pathway. These activities demonstrate its potential for the treatment of inflammatory, neurodegenerative, and neoplastic diseases.

Boswellic acids, triterpenoids derived from the genus Boswellia (Burseraceae), are known for their anti-inflammatory and anti-tumor efficacy. Atopic dermatitis is a chronic, non-infectious inflammatory skin disease. However, the effects of α-boswellic acid on atopic dermatitis have not been studied. Therefore, in this study we examined the expression level of pro-inflammatory cytokines, histopathological analysis, and physiological data from BALB/c mice with atopic-like dermatitis induced by 2,4-dinitrochlorobenzene and TNF-α/IFN-γ-stimulated HaCaT cells to better understand the agent's anti-atopic dermatitis efficacy. First, we found that α-boswellic reduced the epidermal thickening, mast cell numbers, and dermal infiltration of 2,4-dinitrochlorobenzene-induced atopic-like dermatitis in BALB/c mice. Furthermore, we also found that α-boswellic acid can restore transepidermal water loss and skin reddening in mice. In human keratinocytes inflamed by TNF-α/IFN-γ, α-boswellic acid inhibited MAP kinase activation and showed a reduction in NF-κB nuclear translocation. Finally, α-boswellic acid can reduce the expression level of cytokines (IL-1β, IL-6, and IL-8) following the stimulation of TNF-α/IFN-γ in HaCaT cells. Taken together, our study suggests that α-boswellic acids are a potential component for the development of anti-atopic dermatitis drugs[1].

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The results showed that α-BA reduced injuries associated with the administration of ethanol, gastric juice acidity and the formation of MDA and increased CAT activity and SOD activity and the level of NO and PGE-2 in a dose-depended manner. The expression of both Nrf2 and HO-1 was significantly increased in the group treated with 200 mg/kg α-BA, which suggested that activation of the Nrf2/HO-1 pathway might be critical in α-BA's prevention of gastric ulcers. Conclusions: These findings demonstrate that α-BA decreases oxidative stress and that the Nrf2/HO-1 pathway might play a role in the gastroprotective action of α-BA in ethanol-induced gastric injury in rats.[2]
In vivo, α-boswellic acid prevents and decreases the progression of Alzheimer's hallmarks. It has anti-inflammatory effects in mice. It has gastroprotective properties. The compound's anti-inflammatory, antioxidant, and neuroprotective activities suggest potential therapeutic applications in Alzheimer's disease, inflammatory bowel disease, arthritis, and cancer. Its effects on Survivin and Reelin expression indicate a role in neuronal plasticity and survival.

The in vitro activity of boswellic acid is assessed using various biochemical and cell-based assays. For 5-lipoxygenase inhibition, the enzyme is incubated with arachidonic acid substrate and varying concentrations of boswellic acid, and leukotriene production is measured by ELISA or HPLC. For anti-inflammatory activity, macrophages are stimulated with LPS and treated with boswellic acid, and cytokine production (TNF-α, IL-6, IL-1β) is measured by ELISA. The expression of COX2, iNOS, and other inflammatory mediators is analyzed by Western blotting or qPCR. Antioxidant activity is assessed by measuring ROS production using DCFH-DA fluorescence.

MTT Assay[1]
The cell suspension (1 × 105 cells/mL) was cultured in 24-well plates for 24 h. Cells were pretreated with or without α-boswellic acid (1–50 μM) for 1 h, then MTT solution was added and incubated for 4 h. Finally, 200 μL of DMSO was added to each well, and 180 μL was pipetted into 96 wells for absorbance measurement. Absorbance was measured at 550 nm using Tecan’s Sunrise absorbance microplate reader.
For cellular assays, macrophages (RAW 264.7), neuronal cell lines (SH-SY5Y, PC12), or cancer cell lines are cultured in appropriate media. Cells are treated with various concentrations of boswellic acid (typically 1-100 µM) for 24-72 hours. Cell viability is assessed using MTT or CellTiter-Glo assays. Cytokine production is measured by ELISA. ROS production is measured using DCFH-DA fluorescence. The expression of target proteins (e.g., Survivin, Reelin, Tau, Nrf2, HO-1) is analyzed by Western blotting or qPCR. Apoptosis is evaluated by flow cytometry using Annexin V/PI staining.

First, the effect of α-boswellic acid on AD was assessed on DNBC-induced mice. DNBC-induced AD was developed according to a previously reported method. The dorsal hairs of the mice were briefly shaved and then 100 μL and 20 μL of 1% DNCB in ethanol were applied to sensitive dorsal and ear skin for 7 days. Then, from Day 8 to Day 15, 0.5% DNCB solution was re-challenged every three days. The schematic diagram of the animal experiment is shown in Figure 6. Mice were randomly divided into 5 groups, including the normal control group, AD model group (DNCB solution sensitization challenge), α-boswellic acid group (3 and 10 mg/kg), and positive control group dexamethasone (0.5 mg/kg). α-Boswellic acid or dexamethasone was injected intraperitoneally every 3 days from Day 5 to Day 15. On Day 15 before sacrifice, the lesions on the back skin of the mice were photographed, including the erythema, edema, crusting, and exfoliation. The dorsal skin was isolated, the skin tissue port was fixed in 4% paraformaldehyde for histological analysis, and the remaining skin tissue was immediately frozen in liquid nitrogen and then stored at −80 °C for subsequent studies.[1]

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The gastroprotection of α-BA was assessed with ethanol-induced gastric lesions model, by histopathological assessment and measuring gastric juice acidity (pH), gastric wall mucus (GWM), prostaglandins E2 (PGE-2), membrane lipids peroxidation (MDA), superoxide dismutase (SOD) activity, catalase (CAT) activity and amount of nitric oxide (NO). The gastroprotective effects of α-BA through the nuclear factor erythroid-2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) anti-oxidative pathway were presented and measured by immunohistochemistry and Western blot.[2]
In vivo, boswellic acid is typically administered orally to animal models. In Alzheimer's disease models, the compound is administered at doses ranging from 10-100 mg/kg daily for several weeks, and cognitive function is assessed using behavioral tests (e.g., Morris water maze). Amyloid plaque load and Tau phosphorylation are assessed by immunohistochemistry and Western blotting. In inflammatory models (e.g., DSS-induced colitis, carrageenan-induced paw edema), the compound is administered before or after induction of inflammation, and inflammatory markers are measured.

Boswellic acid has a molecular weight of 456.70 g/mol and a molecular formula of C30H48O3. It is soluble in DMSO at 10 mM. The compound should be stored at -20°C under desiccated conditions. Specific pharmacokinetic parameters such as bioavailability, half-life, and volume of distribution are not detailed in the provided search results. The compound's lipophilic nature may limit its oral bioavailability, but it is still effective at therapeutic doses.

Specific toxicity data for boswellic acid is not available in the provided search results. As a natural product with a long history of use in traditional medicine, it is generally considered to have low toxicity. The compound is generally well-tolerated in animal studies at therapeutic doses. Comprehensive toxicological studies are required to establish its full safety profile. The compound should be handled with standard laboratory safety precautions.

[1]. Evaluation of the Anti-Atopic Dermatitis Effects of α-Boswellic Acid on Tnf-α/Ifn-γ-Stimulated HaCat Cells and DNCB-Induced BALB/c Mice. Int J Mol Sci. 2022 Aug 30;23(17):9863.

[2]. Alpha-boswellic acid protects against ethanol-induced gastric injury in rats: involvement of nuclear factor erythroid-2-related factor 2/heme oxygenase-1 pathway. J Pharm Pharmacol. 2016 Apr;68(4):514-22.

[3]. The Effects of Alpha Boswellic Acid on Reelin Expression and Tau Phosphorylation in Human Astrocytes. Neuromolecular Med. 2017 Mar;19(1):136-146.

α-Boswellic acid is a triterpenoid compound. It has been reported to exist in Boswellia sacra, Cyclocarya paliurus, and other organisms with relevant data.
Boswellic acid is a natural product derived from Boswellia serrata gum resin, which has been used in traditional medicine for centuries for its anti-inflammatory properties. It is the major bioactive constituent of Boswellia extracts and has been studied for its potential therapeutic applications in inflammatory diseases, arthritis, asthma, inflammatory bowel disease, and cancer. Boswellic acid is not approved as a pharmaceutical drug but is available as a dietary supplement ingredient. Its multiple mechanisms of action make it a compound of significant research interest.

C30H48O3

456.7003

456.36

C, 78.90; H, 10.59; O, 10.51

471-66-9

637234

White to off-white solid powder

1.1±0.1 g/cm3

552.7±50.0 °C at 760 mmHg

302.1±26.6 °C

0.0±3.4 mmHg at 25°C

1.557

Boswellia sacra, Cyclocarya paliurus, etc.

9.43

2

3

1

33

889

9

C[C@@]12CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@H]([C@]5(C)C(=O)O)O)C)C)[C@@H]1CC(CC2)(C)C)C

BZXULBWGROURAF-IKNLXHIFSA-N

InChI=1S/C30H48O3/c1-25(2)14-15-26(3)16-17-28(5)19(20(26)18-25)8-9-21-27(4)12-11-23(31)30(7,24(32)33)22(27)10-13-29(21,28)6/h8,20-23,31H,9-18H2,1-7H3,(H,32,33)/t20-,21+,22+,23+,26+,27+,28+,29+,30+/m0/s1

(3R,4R,4aR,6aR,6bS,8aR,12aR,14aR,14bR)-3-hydroxy-4,6a,6b,8a,11,11,14b-heptamethyl-1,2,3,4a,5,6,7,8,9,10,12,12a,14,14a-tetradecahydropicene-4-carboxylic acid

alpha-Boswellic acid; 471-66-9; CHEMBL395428; a-Boswellic acid; (3R,4R,4aR,6aR,6bS,8aR,12aR,14aR,14bR)-3-hydroxy-4,6a,6b,8a,11,11,14b-heptamethyl-1,2,3,4a,5,6,7,8,9,10,12,12a,14,14a-tetradecahydropicene-4-carboxylic acid; (4R)-3alpha-Hydroxyolean-12-en-24-oic acid; -Boswellic acid; Boswellic acid, alpha;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~25 mg/mL (~54.74 mM)

Solubility in Formulation 1: 2.5 mg/mL (5.47 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (5.47 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.47 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)