pinosylvin and Inflammation

Stilbenoid compounds have been described to have anti-inflammatory properties in animal models. To study how stilbenoid compounds affect inflammatory signaling. We found that DSS induces severe changes in the bacteriome of the. Taken together, we show that the stilbenoids PS and PSMME have anti-inflammatory properties

Topics: Animals; Ankyrins; Anti-Inflammatory Agents; Drosophila; Drosophila melanogaster; Inflammation; Intestines; NF-kappa B; Stilbenes

Pinosylvin is a natural stilbenoid found particularly in Scots pine. Stilbenoids are a group of phenolic compounds identified as protective agents against pathogens for many plants. Stilbenoids also possess health-promoting properties in humans; for instance, they are anti-inflammatory through their suppressing action on proinflammatory M1-type macrophage activation. Macrophages respond to environmental changes by polarizing towards proinflammatory M1 phenotype in infection and inflammatory diseases, or towards anti-inflammatory M2 phenotype, mediating resolution of inflammation and repair. In the present study, we investigated the effects of pinosylvin on M2-type macrophage activation, aiming to test the hypothesis that pinosylvin could polarize macrophages from M1 to M2 phenotype to support resolution of inflammation. We used lipopolysaccharide (LPS) to induce M1 phenotype and interleukin-4 (IL-4) to induce M2 phenotype in J774 murine and U937 human macrophages, and we measured expression of M1 and M2-markers. Interestingly, along with inhibiting the expression of M1-type markers, pinosylvin had an enhancing effect on the M2-type activation, shown as an increased expression of arginase-1 (Arg-1) and mannose receptor C type 1 (MRC1) in murine macrophages, and C-C motif chemokine ligands 17 and 26 (CCL17 and CCL26) in human macrophages. In IL-4-treated macrophages, pinosylvin enhanced PPAR-γ expression but had no effect on STAT6 phosphorylation. The results show, for the first time, that pinosylvin shifts macrophage polarization from the pro-inflammatory M1 phenotype towards M2 phenotype, supporting resolution of inflammation and repair.

Topics: Animals; Anti-Inflammatory Agents; Cell Polarity; Humans; Inflammation; Interleukin-4; Lipopolysaccharides; Macrophage Activation; Macrophages; Mice; Phenotype; Pinus sylvestris; Plant Extracts; RNA, Messenger; Signal Transduction; Stilbenes; U937 Cells

Stilbenoids are a group of polyphenolic compounds found in plants, trees, berries, and nuts. Stilbenoids have been shown to serve an antimicrobial and antifungal function in plants. There is also evidence that as a part of the human diet, stilbenoids play an important role as antioxidants and may have anti-inflammatory effects. The PI3K/Akt pathway is a well-characterized signaling pathway controlling cellular functions involved in growth and cell cycle and in metabolism. There is also increasing evidence to show the involvement of this pathway in the regulation of inflammatory responses. In the present study, an attempt was made to investigate the anti-inflammatory properties of the naturally occurring stilbenoids pinosylvin (1), monomethylpinosylvin (2), resveratrol (3), pterostilbene (4), piceatannol (5), and rhapontigenin (6). Glycosylated derivatives of piceatannol and rhapontigenin, namely, astringin (7) and rhaponticin (8), respectively, were also investigated. In addition to the natural stilbenoids, pinosylvin derivatives (9-13) were synthesized and subjected to the testing of their effects on the PI3K/Akt pathway in inflammatory conditions. The investigated natural stilbenoids (except the glycosylated derivatives) were found to down-regulate Akt phosphorylation, which is a well-acknowledged marker for PI3K activity. It was also found that all of the studied natural stilbenoids had anti-inflammatory effects in vitro. The three most potent stilbenoids, piceatannol, pinosylvin, and pterostilbene, were selected for in vivo testing and were found to suppress inflammatory edema and to down-regulate the production of inflammatory mediators IL6 and MCP1 in carrageenan-induced paw inflammation in mice. When compared to the commercial PI3K inhibitor LY294002, the anti-inflammatory effects appeared to be quite similar. The results reveal hitherto unknown anti-inflammatory effects of natural stilbenoids and suggest that those effects may be mediated via inhibition of the PI3K/Akt pathway.

Topics: Animals; Anti-Inflammatory Agents; Biological Products; Cell Line; Chemokine CCL2; Down-Regulation; Inflammation; Inflammation Mediators; Interleukin-6; Macrophages; Male; Mice; Mice, Inbred C57BL; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction

Topics: Acute Disease; Animals; Calcium; Calcium Channels; HEK293 Cells; Humans; Inflammation; Inhibitory Concentration 50; Isothiocyanates; Male; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Stilbenes; Transient Receptor Potential Channels; TRPA1 Cation Channel

Oxidative stress (OS) is important in the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA) and its experimental model--adjuvant arthritis (AA). Antioxidants are scarcely studied in autoimmunity, and future analyses are needed to assess its effects in ameliorating these diseases. Although there are studies about antioxidants effects on the course of RA, their role in combination therapy has not yet been studied in detail, especially on extra-articular manifestations of AA. During the 28-d administration of pinosylvin (PIN) in monotherapy and in combination with methotrexate (MTX) to AA rats, we evaluated the impact of the treatment on selected parameters. The experiment included: healthy controls, untreated AA, AA administered 50 mg/kg b.w. of PIN daily p.o., AA administered 0.4 mg/kg b.w. of MTX twice weekly p.o. and AA treated with a combination of PIN+MTX. AA was monitored using: hind paw volume, C-reactive protein, monocyte chemotactic protein-1 (MCP-1), thiobarbituric acid reactive substances (TBARS) and F2-isoprostanes in plasma, γ-glutamyltransferase activity in spleen, activity of lipoxygenase (LOX) in lung, heme oxygenase-1 (HO-1) and nuclear factor kappa B (NF-κB) in liver and lung. PIN monotherapy significantly improved the activation of NF-κB in liver and lung, HO-1 expression and activity of LOX in the lung, MCP-1 levels in plasma (on 14th d) and plasmatic levels of F2-isoprostanes. An important contribution of PIN to MTX effect was the reduction of OS (an increase of HO-1 expression in lung and reduction of plasmatic TBARS) and decrease of LOX activity in the lung.

Topics: Animals; Antirheumatic Agents; Arthritis, Experimental; Biomarkers; C-Reactive Protein; Chemokine CCL2; Drug Synergism; Drug Therapy, Combination; F2-Isoprostanes; gamma-Glutamyltransferase; Heme Oxygenase-1; Hindlimb; Inflammation; Lipoxygenase; Liver; Lung; Male; Methotrexate; NF-kappa B; Oxidative Stress; Rats; Rats, Inbred Lew; Spleen; Stilbenes; Thiobarbituric Acid Reactive Substances

Scots pine (Pinus sylvestris) is known to be rich in phenolic compounds, which may have anti-inflammatory properties. The present study investigated the anti-inflammatory effects of a knot extract from P. sylvestris and two stilbenes, pinosylvin and monomethylpinosylvin, isolated from the extract. Inflammation is characterized by increased release of pro-inflammatory and regulatory mediators including nitric oxide (NO) produced by the inducible nitric oxide synthase (iNOS) pathway. The knot extract (EC50 values of 3 and 3 μg/mL) as well as two of its constituents, pinosylvin (EC50 values of 13 and 15 μM) and monomethylpinosylvin (EC50 values of 8 and 12 μM), reduced NO production and iNOS expression in activated macrophages. They also inhibited the production of inflammatory cytokines IL-6 and MCP-1. More importantly, pinosylvin and monomethylpinosylvin exerted a clear anti-inflammatory effect (80% inhibition at the dose of 100 mg/kg) in the standard in vivo model, carrageenan-induced paw inflammation in the mouse, with the effect being comparable to that of a known iNOS inhibitor L-NIL. The results reveal that the Scots pine stilbenes pinosylvin and monomethylpinosylvin are potential anti-inflammatory compounds.

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Cell Line; Chemokine CCL2; Gene Expression; HEK293 Cells; Humans; Inflammation; Interleukin-6; Macrophages; Mice; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Pinus sylvestris; Plant Extracts; Stilbenes; Wood