Polyphenols from the Peels of Punica granatum L. and Their Bioactivity of Suppressing Lipopolysaccharide-Stimulated Inflammatory Cytokines and Mediators in RAW 264.7 Cells via Activating p38 MAPK and NF-κB Signaling Pathways

Abstract

Punica granatum L. (Punicaceae) is a popular fruit all over the world. Owning to its enriched polyphenols, P. granatum has been widely used in treating inflammation-related diseases, such as cardiovascular diseases and cancer. Twenty polyphenols, containing nine unreported ones, named punicagranins A–I (1–9), along with eleven known isolates (10–20), were obtained from the peels. Their detailed structures were elucidated based on UV, IR, NMR, MS, optical rotation, ECD analyses and chemical evidence. The potential anti-inflammatory activities of all polyphenols were examined on a lipopolysaccharide (LPS)-induced inflammatory macrophages model, which indicated that enhancing nitric oxide (NO) production in response to inflammation stimulated in RAW 264.7 cells was controlled by compounds 1, 3, 5–8, 10, 11, 14 and 16–20 in a concentration-dependent manner. The investigation of structure–activity relationships for tannins 6–8 and 12–20 suggested that HHDP, flavogallonyl and/or gallagyl were key groups for NO production inhibitory activity. Western blotting indicated that compounds 6–8 could down-regulate the phosphorylation levels of proteins p38 MAPK, IKKα/β, IκBα and NF-κB p65 as well as inhibit the levels of inflammation-related cytokines and mediators, such as IL-6, TNF-α, iNOS and COX-2, at the concentration of 30 μM. In conclusion, polyphenols are proposed to be the potential anti-inflammatory active ingredients in P. granatum peels, and their molecular mechanism is likely related to the regulation of the p38 MAPK and NF-κB signaling pathways.

Arteannuin-B and (3-chlorophenyl)-2-spiroisoxazoline derivative exhibit anti-inflammatory effect in LPS-activated RAW 264.7 macrophages and Balb/c mice induced pro-inflammatory responses via down-regulation of NF-κB/P38 MAPK Signalling.

“…L-NAME and Dexamethasone (10 µM) were used as positive controls, and suppressed the LPS induced levels of nitric oxide from 80.38 µM to 45.61 µM and 44.5 µM, respectively. While as 1 suppresses the release of NO to 23.29 µM at 10 μM, 36.26 at 5 µM, 48.65 at 1 µM; JR-9, on the other hand, suppresses the same to 16.43 µM at 10 µM, 31.62 at 5 µM, 40.97 at 1 µM proving JR-9 to be the better nitric oxide inhibitor as compared to 1 [27].…”

Effect of traditional Chinese medicine in osteosarcoma: Cross-interference of signaling pathways and potential therapeutic targets

“…[65] However, when cells receive various external stimuli, receptors on the cell membrane translocate into the cytoplasm, and iκB is phosphorylated by binding to the iκB kinase complex, so as to activate the NF-κB signaling pathway, at which time NF-κB moves into the nucleus and induces transcription of related genes. [66] Moreover, activated NF-κB signaling pathway can also induce biological reactions in related factors, such as IL-6, tumor necrosis factor-α (TNF-α), chemokines, inflammatory mediators nitric oxide (NO), prostaglandin E2, inducible cyclooxygenase-2, adhesion factors, inflammatory enzymes, immune receptors, apoptotic genes, proliferation-regulating genes, signal transduction genes, anti-oxidative stress-related genes, [67] so as to further amplify the inflammatory response. [68] And the long-standing inflammatory reactions will mutate tumor suppressor genes in normal cells, eventually promote tumor formation.…”

Pomegranates bioactive metabolites and biological activities: an updated review

“…Cells via Activating p38 MAPK and NF-κB Signaling Pathways. (30) It was reported that the Plant flower extracts were tested for their anti-inflammatory effects by determining the ability to inhibit the activity of lipoxygenase and proteinase. They are characterized by the ability to inhibit lipoxygenase at a level above 80% and proteinase at the level of about 55%.…”