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Phorbaketal A, Isolated from the Marine Sponge Phorbas sp., Exerts Its Anti-Inflammatory Effects via NF-κB Inhibition and Heme Oxygenase-1 Activation in Lipopolysaccharide-Stimulated Macrophages.

Seo YJ, Lee KT, Rho JR, Choi JH - Mar Drugs (2015)

Bottom Line: We found that phorbaketal A significantly inhibited the LPS-induced production of nitric oxide (NO), but not prostaglandin E₂, in RAW 264.7 cells.In addition, phorbaketal A reduced the LPS-induced production of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and monocyte chemotactic protein-1.These data suggest that phorbaketal A, isolated from the marine sponge Phorbas sp., inhibits the production of inflammatory mediators via down-regulation of the NF-κB pathway and up-regulation of the HO-1 pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Life & Nanopharmaceutical Sciences, Kyung Hee University, Seoul 130-701, Korea. syg9108@khu.ac.kr.

ABSTRACT
Marine sponges harbor a range of biologically active compounds. Phorbaketal A is a tricyclic sesterterpenoid isolated from the marine sponge Phorbas sp.; however, little is known about its biological activities and associated molecular mechanisms. In this study, we examined the anti-inflammatory effects and underlying molecular mechanism of phorbaketal A in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. We found that phorbaketal A significantly inhibited the LPS-induced production of nitric oxide (NO), but not prostaglandin E₂, in RAW 264.7 cells. Further, phorbaketal A suppressed the expression of inducible NO synthase at both the mRNA and protein levels. In addition, phorbaketal A reduced the LPS-induced production of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and monocyte chemotactic protein-1. Treatment with phorbaketal A inhibited the transcriptional activity of nuclear factor-kappaB (NF-κB), a crucial signaling molecule in inflammation. Moreover, phorbaketal A up-regulated the expression of heme oxygenase-1 (HO-1) in LPS-stimulated RAW 264.7 cells. These data suggest that phorbaketal A, isolated from the marine sponge Phorbas sp., inhibits the production of inflammatory mediators via down-regulation of the NF-κB pathway and up-regulation of the HO-1 pathway.

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Effects of phorbaketal A on the activation of nuclear factor-kappaB (NF-κB) in LPS-stimulated RAW 264.7 cells. Cells were transiently transfected with pNF-κB-Luc vector, and then pretreated with different concentrations of phorbaketal A (2.5, 5, and 10 μM) for 1 h followed by LPS (1 μg/mL) stimulation for 2 h. Then luciferase activities were determined using a Promega luciferase assay system. Data are presented as the means ± SD of three independent experiments. Statistical analysis was carried out using the one-way ANOVA followed by the Tukey’s test. #p < 0.05 vs. CTRL group. * p < 0.05 vs. LPS-stimulated group.
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marinedrugs-13-07005-f004: Effects of phorbaketal A on the activation of nuclear factor-kappaB (NF-κB) in LPS-stimulated RAW 264.7 cells. Cells were transiently transfected with pNF-κB-Luc vector, and then pretreated with different concentrations of phorbaketal A (2.5, 5, and 10 μM) for 1 h followed by LPS (1 μg/mL) stimulation for 2 h. Then luciferase activities were determined using a Promega luciferase assay system. Data are presented as the means ± SD of three independent experiments. Statistical analysis was carried out using the one-way ANOVA followed by the Tukey’s test. #p < 0.05 vs. CTRL group. * p < 0.05 vs. LPS-stimulated group.

Mentions: NF-κB is a key transcription factor in immune and inflammatory responses. It plays a major role in inflammatory processes by regulating the expression of pro-inflammatory genes, including those encoding iNOS, TNF-α, IL-1β, and IL-6 [33,34,35]. When NF-κB is stimulated with inflammatory agents such as LPS, activated NF-κB dimers (of which p50/p65 is the most common heterodimer) translocate to the nucleus and interact with target DNA recognition sites to activate the transcription of diverse pro-inflammatory genes [36,37]. To test whether the anti-inflammatory effects of phorbaketal A are associated with the inhibition of NF-κB activation in RAW 264.7 cells, the transcriptional activity of NF-κB was evaluated using a luciferase assay. As shown in Figure 4, phorbaketal A significantly suppressed the LPS-induced transcriptional activity of NF-κB in LPS-stimulated macrophages. These results suggest that phorbaketal A inhibits the expression of pro-inflammatory genes, including those encoding iNOS, TNF-α, IL-1β, IL-6, and MCP-1, via negative regulation of the NF-κB pathway.


Phorbaketal A, Isolated from the Marine Sponge Phorbas sp., Exerts Its Anti-Inflammatory Effects via NF-κB Inhibition and Heme Oxygenase-1 Activation in Lipopolysaccharide-Stimulated Macrophages.

Seo YJ, Lee KT, Rho JR, Choi JH - Mar Drugs (2015)

Effects of phorbaketal A on the activation of nuclear factor-kappaB (NF-κB) in LPS-stimulated RAW 264.7 cells. Cells were transiently transfected with pNF-κB-Luc vector, and then pretreated with different concentrations of phorbaketal A (2.5, 5, and 10 μM) for 1 h followed by LPS (1 μg/mL) stimulation for 2 h. Then luciferase activities were determined using a Promega luciferase assay system. Data are presented as the means ± SD of three independent experiments. Statistical analysis was carried out using the one-way ANOVA followed by the Tukey’s test. #p < 0.05 vs. CTRL group. * p < 0.05 vs. LPS-stimulated group.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4663563&req=5

marinedrugs-13-07005-f004: Effects of phorbaketal A on the activation of nuclear factor-kappaB (NF-κB) in LPS-stimulated RAW 264.7 cells. Cells were transiently transfected with pNF-κB-Luc vector, and then pretreated with different concentrations of phorbaketal A (2.5, 5, and 10 μM) for 1 h followed by LPS (1 μg/mL) stimulation for 2 h. Then luciferase activities were determined using a Promega luciferase assay system. Data are presented as the means ± SD of three independent experiments. Statistical analysis was carried out using the one-way ANOVA followed by the Tukey’s test. #p < 0.05 vs. CTRL group. * p < 0.05 vs. LPS-stimulated group.
Mentions: NF-κB is a key transcription factor in immune and inflammatory responses. It plays a major role in inflammatory processes by regulating the expression of pro-inflammatory genes, including those encoding iNOS, TNF-α, IL-1β, and IL-6 [33,34,35]. When NF-κB is stimulated with inflammatory agents such as LPS, activated NF-κB dimers (of which p50/p65 is the most common heterodimer) translocate to the nucleus and interact with target DNA recognition sites to activate the transcription of diverse pro-inflammatory genes [36,37]. To test whether the anti-inflammatory effects of phorbaketal A are associated with the inhibition of NF-κB activation in RAW 264.7 cells, the transcriptional activity of NF-κB was evaluated using a luciferase assay. As shown in Figure 4, phorbaketal A significantly suppressed the LPS-induced transcriptional activity of NF-κB in LPS-stimulated macrophages. These results suggest that phorbaketal A inhibits the expression of pro-inflammatory genes, including those encoding iNOS, TNF-α, IL-1β, IL-6, and MCP-1, via negative regulation of the NF-κB pathway.

Bottom Line: We found that phorbaketal A significantly inhibited the LPS-induced production of nitric oxide (NO), but not prostaglandin E₂, in RAW 264.7 cells.In addition, phorbaketal A reduced the LPS-induced production of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and monocyte chemotactic protein-1.These data suggest that phorbaketal A, isolated from the marine sponge Phorbas sp., inhibits the production of inflammatory mediators via down-regulation of the NF-κB pathway and up-regulation of the HO-1 pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Life & Nanopharmaceutical Sciences, Kyung Hee University, Seoul 130-701, Korea. syg9108@khu.ac.kr.

ABSTRACT
Marine sponges harbor a range of biologically active compounds. Phorbaketal A is a tricyclic sesterterpenoid isolated from the marine sponge Phorbas sp.; however, little is known about its biological activities and associated molecular mechanisms. In this study, we examined the anti-inflammatory effects and underlying molecular mechanism of phorbaketal A in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. We found that phorbaketal A significantly inhibited the LPS-induced production of nitric oxide (NO), but not prostaglandin E₂, in RAW 264.7 cells. Further, phorbaketal A suppressed the expression of inducible NO synthase at both the mRNA and protein levels. In addition, phorbaketal A reduced the LPS-induced production of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and monocyte chemotactic protein-1. Treatment with phorbaketal A inhibited the transcriptional activity of nuclear factor-kappaB (NF-κB), a crucial signaling molecule in inflammation. Moreover, phorbaketal A up-regulated the expression of heme oxygenase-1 (HO-1) in LPS-stimulated RAW 264.7 cells. These data suggest that phorbaketal A, isolated from the marine sponge Phorbas sp., inhibits the production of inflammatory mediators via down-regulation of the NF-κB pathway and up-regulation of the HO-1 pathway.

Show MeSH
Related in: MedlinePlus