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A new anthranilic acid derivative (1) was isolated from a Philippine sponge, Oscarella stillans (Bergquist and Kelly). The structure of compound 1, named oscarellin, was determined as 2-amino-3-(3'-aminopropoxy)benzoic acid from spectroscopic data and confirmed by synthesis. We examined the immunomodulating effect of compound 1 and its mechanism in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Our data indicated that the expression of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 were significantly reduced by the pretreatment of 1 (0.1-10 μM) for 2 h. In addition, compound 1 suppressed activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun NH-termimal kinase (JNK), but not p38 mitogen-activated protein kinase (MAPK) in LPS-stimulated RAW 264.7 cells. Compound 1 abrogated LPS-induced nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) activities, whereas the induction of activating transcription factor-3 (ATF-3) was increased. Taken together, our results suggest that compound 1 attenuates pro-inflammatory cytokines via the suppression of JNK, ERK, AP-1, and NF-κB and the activation of the ATF-3 signaling pathway.

Lobaric acid (LA) is a constituent of the lichen Stereocaulon alpinum. LA has multiple biological activities, including antibacterial and antioxidant ones. The purpose of this study was to investigate the effect of LA and its mechanism on lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Macrophages were pretreated with different concentrations of LA (0.2 – 20 µM), followed by LPS stimulation. LA treatment of LPS stimulated macrophages decreased their nitric oxide production and the expression of cyclooxygenase-2 and prostaglandin E2. LA also significantly reduced the production of tumor necrosis factor-α and interleukin (IL)-6 by inhibiting the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB). Additionally, LA inhibited the production of IL-1β and IL-18, as well as caspase-1 maturation, by inhibition of NLRP3 inflammasome activation in LPS/ATP-stimulated cells. These results strongly suggest that LA could inhibit inflammation by downregulating NF-κB/MAPK pathways and NLRP3 inflammasome activation in activated macrophages. These results reveal a new therapeutic approach to modulate inflammatory diseases linked to deregulated inflammasome activities.

Introduction: Advanced glycation end products (AGEs) and receptor of advanced glycation end products (RAGE) mediate renal function during diabetic and non-diabetic nephropathy development. Methylglyoxal-lysine dimer (MOLD), a typical toxic advanced glycation end product (TAGE), contributes to inflammatory responses during renal diseases. This study determines the effect of MOLD on inflammatory responses in mouse mesangial cells. Methods and Results: The murine mesangial cell line SV40 MES 13 is used to assess nuclear factor-kappa B (NF-B) expression, reactive oxygen species (ROS) production, and mitochondria labeling. The interaction model between RAGE and MOLD is also determined. MOLD treatment of mesangial cells markedly increases RAGE expression and the linkage with V-type Ig domain of RAGE. MOLD induces ROS production and mitochondrial dysfunction. MOLD activates phosphatidylinositol 3-kinase-protein kinase B (PI3KB) and NF-B signaling pathways. It is confirmed that these changes are reversed when ROS is suppressed. These effects may be regulated through mitogen-activated protein kinases and pro-inflammatory cytokines in circulatory inflammation responses. Conclusion: MOLD plays a major role in nephropathy via ROS production and mitochondrial dysfunction through direct association with RAGE. Further, the NF-kB and PI3K/AKT signaling pathways triggered by ROS mediate the inflammatory response to exacerbate MOLD-induced damages in inflammation-related diabetic and non-diabetic renal diseases.