ABSTRACT
In recent decades, the interest in natural products with immunomodulatory properties has increased due to their therapeutic potential. These products have a wider range of pharmacological activities and demonstrate lower toxicity levels when compared to their synthetic counterparts. Therefore, this study aimed to investigate the immunomodulatory effects of sesquiterpenoids (SQs) and sesquiterpenoid dimers (SQDs) isolated from Dysoxylum parasiticum (Osbeck) Kosterm. stem bark on human and murine cells, particularly focusing on toll-like receptor 4 (TLR4). Utilizing the secreted alkaline phosphatase (SEAP) assay on engineered human and murine TLR4 of HEK-Blue cells, antagonist TLR4 compounds were identified, including SQs 6, 9, and 10, as well as SQDs 17 and 22. The results showed that 10-hydroxyl-15-oxo-α-cadinol (9) had a potent ability to reduce TLR4 activation induced by LPS stimulation, with minimal toxicity observed in both human and murine cells. The SEAP assay also revealed diverse immune regulatory effects for the same ligand. For instance, SQs 12, 14, and 16 transitioned from antagonism on human to murine TLR4. The SQs (4, 7, 11, and 15) and SQDs (18-20) offered partial antagonist effect exclusively on murine TLR4. Furthermore, these selected SQs and SQDs were assessed for their influence on the production of proinflammatory cytokines TNF-α, IL-1α, IL-1ß, and IL-6 of the NF-κB signaling pathway in human and murine macrophage cell lines, showing a dose-dependent manner. Additionally, a brief discussion on the structure-activity relationship was presented.
Subject(s)
Plant Bark , Sesquiterpenes , Toll-Like Receptor 4 , Toll-Like Receptor 4/metabolism , Humans , Animals , Plant Bark/chemistry , Mice , Sesquiterpenes/pharmacology , Sesquiterpenes/chemistry , HEK293 Cells , Meliaceae/chemistry , Plant Extracts/pharmacology , Plant Extracts/chemistry , Immunologic Factors/pharmacology , Immunologic Factors/chemistry , Immunologic Factors/isolation & purification , Cytokines/metabolism , RAW 264.7 Cells , Immunomodulating Agents/pharmacology , Immunomodulating Agents/chemistry , Lipopolysaccharides/pharmacologyABSTRACT
Seven previously undescribed preurianin-type limonoids, namely paraxylines A-G, and three known analogs were isolated from stem bark of Dysoxylum parasiticum. The structures, including absolute configurations, were established through spectroscopic analyses, quantum chemical calculations using the density functional theory method, as well as the DP4+ algorithm. Paraxylines A-G were identified as the first preurianin-type with full substitution at C, D-rings, leading to the highly oxygenated seco-limonoids skeleton. The secreted alkaline phosphate assay against an engineered human and murine TLR4 of HEK-Blue cells was performed to evaluate the immune regulating effects. Among them, paraxyline B was found to be a remarkable TLR4 agonist whereas two analogs (toonapubesins A and B) were found to antagonise lipopolysaccharide stimulation of the TLR4 pathway. Paraxylines A and C-E acted either as agonists or antagonists depending on the origin of the TLR4 receptor (human or mouse). The effect of these selected compounds on the expression of pro-inflammatory cytokines TNF-α, IL-1α, IL-1ß, and IL-6 of the NF-κB signaling pathway were examined in macrophage cell lines, revealing dose-dependent effects. Additionally, paraxylines A, C, D, and G also presented modest cytotoxic activity against MCF-7 and HeLa cell lines with IC50 values ranging from 23.1 to 43.5 µM.
Subject(s)
Antineoplastic Agents, Phytogenic , Antineoplastic Agents , Limonins , Meliaceae , Humans , Animals , Mice , Limonins/pharmacology , Limonins/chemistry , Toll-Like Receptor 4 , HeLa Cells , Plant Bark/chemistry , Molecular Structure , Antineoplastic Agents, Phytogenic/chemistry , Meliaceae/chemistryABSTRACT
Chisocheton plants from the family Meliaceae have traditionally been used to treat several diseases; however, scientific evidence is limited. The most abundant chemical constituents of this plant are the limonoids, which are known for their various biological activities, including anti-inflammatory effects. However, the anti-inflammatory effects and underlying mechanisms of action of the constituents of Chisocheton plants have not been fully explored. In this report, we evaluated the anti-inflammatory activity of 17 limonoid compounds from Chisocheton plant primarily by measuring their inhibitory effects on the production of pro-inflammatory cytokines, including TNF-α, IL-6, IL-1ß, and MCP-1, in LPS-stimulated THP-1 cells using an ELISA assay. Compounds 3, 5, 9, and 14-17 exhibited significant activity in inhibiting the evaluated pro-inflammatory markers, with IC50 values less than 20 µM and a high selectivity index (SI) range. Compounds 3, 5, 9, and 15 significantly suppressed the expression of phosphorylated p38 MAPK in THP-1 cells stimulated with LPS. These findings support the use of limonoids from Chisocheton plants as promising candidates for anti-inflammatory therapy.
ABSTRACT
Two new azadirone-type limonoids, namely lasiocarpine A (1) and lasiocarpine B (2) were isolated from the fruit of Chisocheton lasiocarpus along with three known limonoids (3-5). UV, IR, one- and two- dimensional NMR, and mass spectrometry were used to determine the chemical structure of the isolated compounds. Furthermore, their cytotoxic activity against breast cancer cell line MCF-7 was evaluated using PrestoBlue reagent. From these compounds, lasiocarpine A (1) showed the strongest activity with an IC50 value of 43.38 µM.
Subject(s)
Antineoplastic Agents , Limonins , Meliaceae , Meliaceae/chemistry , Fruit/chemistry , Limonins/pharmacology , Limonins/chemistry , Magnetic Resonance Spectroscopy , Molecular StructureABSTRACT
Chisocarpene A (1) is a new tirucallane-type triterpenoid together with odoratone (2) and 24-methylenecycloartanol (3), isolated from the stem bark of Chisocheton lasiocarpus. The chemical structures of compounds 1-3 were elucidated through a detailed analysis of their spectroscopic data (IR, MS, 1 D, and 2 D NMR). The isolated compounds were evaluated for cytotoxic activity against the MCF-7 breast cancer cell line using a resazurin-based assay. Compound 1 showed the most potent activity (IC50 26.56 ± 1.01 µM) and was two-fold more active than the positive control.
ABSTRACT
The natural limonoids distributed mainly in the Meliaceae and Rutaceae plants are known for their unique and complex structure with high degree oxidation and cyclic rearrangement. However, these compounds exhibit a broad range of biological activities such as insecticidal, antibacterial, antifungal, antimalarial, antioxidant, anticancer, antiviral, and anti-inflammatory. There is still limited report about the biological activity of the anti-inflammatory effect of limonoids isolated from plants. Therefore, this study aimed to examine the effect of intact, deformed and rearranged limonoids as anti-inflammatory agents. The majority of anti-inflammatory investigations were evaluated by in vitro and in vivo assays of the isolated pure compounds and their derivatives. For the in vitro study, intact and C-ring seco limonoids showed a potent inhibitory effect against NO production. The in vivo analysis of Intact, C-seco, and AD-seco limonoids showed a potent effect based on the inhibition of pro-inflammatory cytokines expression, indicating their potency as anti-inflammatory agents.
