Anti-inflammatory Activity of Natural Geranylated Flavonoids: Cyclooxygenase and Lipoxygenase Inhibitory Properties and Proteomic Analysis.

Geranyl flavones have been studied as compounds that potentially can be developed as anti-inflammatory agents. A series of natural geranylated flavanones was isolated from Paulownia tomentosa fruits, and these compounds were studied for their anti-inflammatory activity and possible mechanism of action. Two new compounds were characterized [paulownione C (17) and tomentodiplacone O (20)], and all of the isolated derivatives were assayed for their ability to inhibit cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX). The compounds tested showed variable degrees of activity, with several of them showing activity comparable to or greater than the standards used in COX-1, COX-2, and 5-LOX assays. However, only the compound tomentodiplacone O (20) showed more selectivity against COX-2 versus COX-1 when compared with ibuprofen. The ability of the test compounds to interact with the above-mentioned enzymes was supported by docking studies, which revealed the possible incorporation of selected test substances into the active sites of these enzymes. Furthermore, one of the COX/LOX dual inhibitors, diplacone (14) (a major geranylated flavanone of P. tomentosa), was studied in vitro to obtain a proteomic overview of its effect on inflammation in LPS-treated THP-1 macrophages, supporting its previously observed anti-inflammatory activity and revealing the mechanism of its anti-inflammatory effect.

The Chemical Composition of Achillea wilhelmsii C. Koch and Its Desirable Effects on Hyperglycemia, Inflammatory Mediators and Hypercholesterolemia as Risk Factors for Cardiometabolic Disease.

This study was done to identify the content compounds of Achillea wilhelmsii (A. wilhelmsii) and to evaluate its hypoglycemic and anti-hypercholesterolemic activity and effect on inflammatory mediators. The extracts and fractions of A. wilhelmsii were thoroughly analyzed using high performance liquid chromatography (HPLC), and the total content of phenols and flavonoids was determined. The hypoglycemic activity was evaluated in vivo using alloxan-induced diabetic mice. The effect upon inflammatory mediators was evaluated in vitro using the human monocytic leukemia cell line (THP-1). The anti-hypercholesterolemic activity was evaluated in vitro using the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase assay kit. The water extract (WE)-treated group showed the highest reduction in the fasting blood glucose levels (FBGL). The chloroform fraction (CF) and ethyl acetate fraction (EAF) both showed a significant ability to reduce the secretion of tumor necrosis factor alpha (TNF-α). The EAF, however, also attenuated the levels of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). The CF showed the most significant 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) inhibition activity. The five main compounds in the CF were isolated and identified. Out of the five compounds in the CF, 1ß,10ß-epoxydesacetoxymatricarin (CP1) and leucodin (CP2) showed the highest anti-hypercholesterolemic potential. A molecular docking study provided corresponding results.

C-Geranylated Flavanones from Paulownia tomentosa Fruits as Potential Anti-inflammatory Compounds Acting via Inhibition of TNF-α Production.

Eleven new C-geranylated flavonoids, tomentodiplacones L, M, and N (1, 2, 10), tomentodiplacol B (3), 3',4'-O-dimethyl-5'-hydroxydiplacone (4), mimulones F, G, and H (5, 6, 7), paulowniones A (8) and B (9), tomentone (11), and 3',4',5'-trimethoxyflavanone (12), together with 11 known flavonoids (13-23), were isolated from fruits of Paulownia tomentosa. The structures of the compounds isolated were determined by spectroscopic data interpretation. The ability of compounds 1-23, together with the nonprenylated flavanones eriodictyol (24) and naringenin (25), to reduce the production of the pro-inflammatory cytokine TNF-α in THP-1 cells after bacterial lipopolysaccharide stimulation was evaluated using an in vitro screening test. The preliminary structure-activity relationships of these derivatives were also studied, and the correlation of their TNF-α inhibitory activity with their lipophilicity was investigated. The mechanism of action of compounds with significant antiphlogistic potential (4, 7, 10, 14, 22) was investigated. These compounds reduced both the secretion of TNF-α and the level of its corresponding mRNA. Compounds 4, 7, 10, 14, and 22 inhibited the nuclear translocation of NF-κB, which controls the expression of TNF-α, by blocking the degradation of IκB.

Evaluation of anti-inflammatory activity of prenylated substances isolated from Morus alba and Morus nigra.

Chromatographic separation of root extracts of Morus alba and M. nigra led to the identification of the 2-arylbenzofurans moracin C (1), mulberrofuran Y (2), and mulberrofuran H (3), and the prenylated flavonoids kuwanon E (4), kuwanon C (5), sanggenon H (6), cudraflavone B (7), and morusinol (8), and the Diels-Alder adducts soroceal (9), and sanggenon E (10). The cytotoxicity and their antiphlogistic activity, determined as the attenuation of the secretion of TNF-α and IL-1ß and the inhibition of NF-κB nuclear translocation in LPS-stimulated macrophages, were evaluated for compounds 1-10.

Antimicrobial and enzyme inhibitory activities of the constituents of Plectranthus madagascariensis (Pers.) Benth.

Plectranthus madagascariensis is used as a traditional medicine in Southern Africa. In search of compounds and activities supporting the medicinal use, the chemical profile of the methanolic extract was studied by high-performance liquid chromatography with diode array detection (HPLC-DAD). Four major constituents were isolated and identified as rosmarinic acid (1), 7ß,6ß-dihydroxyroyleanone (2), 7ß-acetoxy-6ß-hydroxyroyleanone (3) and coleon U quinone (4). The two abietane diterpenoids (2 and 3) were isolated for the first time from this species. Antimicrobial, cholinesterase and α-glucosidase inhibitory activities of these compounds were studied. The compounds exhibited inhibitory activity on α-glucosidase with IC50 values from 33 to 275 µM. Abietanes showed potent antibacterial activity against Staphylococcus aureus and Enterococcus faecalis.

Anti-MRSA activity of abietane diterpenes from Coleus blumei Benth.

Two heretofore uncharacterised abietane diterpenes, sincoetsin C (1) and 3-hydroxyspirocoleon 7-O-ß-D-glucoside (4), were isolated from a methanolic extract of Coleus blumei Benth. (Lamiaceae), along with the known compounds, scutellarioidone A (2) and spirocoleon 7-O-ß-D-glucoside (3) using chromatographic techniques. Their structures were determined by 1D and 2D nuclear magnetic resonance including HSQC, HMBC, COSY and NOESY experiments, mass spectrometry (HR-MS) and other spectroscopic methods (UV, IR). Their antibacterial activity against the reference strain of methicillin-resistant Staphylococcus aureus subsp. aureus CCM 4750 (MRSA) was evaluated using optical absorption to obtain quantitative information on their growth. All isolated compounds displayed anti-MRSA 4750 activity at the concentration of 512 µg/mL. Sincoetsin C (1) was the abietane diterpene most active against MRSA 4750, with a minimum inhibitory concentration of 128 µg/mL.

Parallel in vitro and in silico investigations into anti-inflammatory effects of non-prenylated stilbenoids.

Stilbenoids represent a large group of bioactive compounds, which occur in food and medicinal plants. Twenty-five stilbenoids were screened in vitro for their ability to inhibit COX-1, COX-2 and 5-LOX. Piceatannol and pinostilbene showed activity comparable to the zileuton and ibuprofen, respectively. The anti-inflammatory potential of stilbenoids was further evaluated using THP-1 human monocytic leukemia cell line. Tests of the cytotoxicity on the THP-1 and HCT116 cell lines showed very low toxic effects. The tested stilbenoids were evaluated for their ability to attenuate the LPS-stimulated activation of NF-κB/AP-1. Most of the tested substances reduced the activity of NF-κB/AP-1 and later attenuated the expression of TNF-α. The effects of selected stilbenoids were further investigated on inflammatory signaling pathways. Non-prenylated stilbenoids regulated attenuation of NF-ĸB/AP-1 activity upstream by inhibiting the phosphorylation of MAPKs. A docking study used to in silico analyze the tested compounds confirmed their interaction with NF-ĸB, COX-2 and 5-LOX.

Minor C-geranylated flavanones from Paulownia tomentosa fruits with MRSA antibacterial activity.

Exhaustive chromatographic separation of the chloroform portion of the ethanolic extract obtained from Paulownia tomentosa (Thunb). Steud. (Paulowniaceae) fruits has led to isolation of ten C-6 geranylated flavanones tomentodiplacone C-I and mimulone C-E, featured by 3'-methoxy and 4'-hydroxy or 4'-hydroxy substitution of the B-ring of the flavonoid, respectively. The structures of these compounds were determined by using mass spectrometry (including HRMS) and 1D and 2D NMR spectroscopy. The absolute configurations of the compounds at C-2 were determined using circular dichroism. The obtained compounds showed the presence of a geranyl moiety functionalized by a carbonyl, hydroxyl or methoxyl group, or by formation of tetrahydrofuran or fused-pyrane ring, respectively. All of the flavanones described were isolated for the first time from a natural source. The antibacterial activities of selected compounds isolated along with the previously isolated geranylated flavanones were evaluated against a common panel of microbes and MRSA strains. The selected isolated compounds were tested for their ability to affect eukaryotic translation initiation via dual-luciferase reporter assay (firefly and renilla).