Polyenylpyrrole Derivatives Inhibit NLRP3 Inflammasome Activation and Inflammatory Mediator Expression by Reducing Reactive Oxygen Species Production and Mitogen-Activated Protein Kinase Activation

Abstract

Two polyenylpyrroles from a soil ascomycete Gymnoascus reessii were previously identified as hit compounds in screening for cytotoxicity against lung cancer cells. These compounds and various analogs, which have been previously synthesized and tested for anti-lung cancer cell activity, were tested for anti-inflammatory activity. After preliminary screening for cytotoxicity for RAW 264.7 murine macrophage cells, the non-toxic compounds were tested for anti-inflammatory activity using lipopolysaccharide (LPS)-activated RAW 264.7 cells. Compounds 1h, 1i, and 1n reduced LPS-induced nitric oxide (NO) production, with respective ED50 values of 15 ± 2, 16 ± 2, and 17 ± 2 µM. They also reduced expression of inducible NO synthase and interleukin-6 (IL-6) without affecting cyclooxygenase-2 expression. Compound 1h also reduced secretion of IL-6 and tumor necrosis factor-α by LPS-activated J774A.1 murine macrophage cells, primary mice peritoneal macrophages, and JAWSII murine bone marrow-derived dendritic cells and reduced NLRP3 inflammasome-mediated interleukin-1β (IL-1β) secretion by LPS + adenosine triphosphate-activated J774A.1 and JAWSII cells. The underlying mechanisms for the anti-inflammatory activity of compound 1h were found to be a decrease in LPS-induced reactive oxygen species (ROS) production, mitogen-activated protein kinase phosphorylation, and NF-κB activation and a decrease in ATP-induced ROS production and PKC-α phosphorylation. These results provide promising insights into the anti-inflammatory activity of these conjugated polyenes and a molecular rationale for future therapeutic intervention in inflammation-related diseases. They also show how compound 1h regulates inflammation and suggest it may be a new source for the development of anti-inflammatory agents to ameliorate inflammation- and NLRP3 inflammasome-related diseases.

Toll-like receptor 4-interacting SPA4 peptide suppresses the NLRP3 inflammasome in response to LPS and ATP stimuli

“…Therapeutic intervention at different steps of signaling, from priming to inflammasome activation, could also suppress IL-1b levels and an overall biologic response against infectious and inflammatory stimuli. Pharmacological agents Bay 11-7082, parthenolide, glyburide, cytokine release inhibitory drug 3, and pralnacasan (VX-740 and VX-765) have recently been reported to suppress inflammasome [22,[43][44][45][46][47]. The results presented here suggest that the TLR4-interacting SPA4 peptide reduces the inflammasome at the priming step in a noninfectious, LPS-and ATP-challenge model.…”

Synthetic 4-Hydroxy Auxarconjugatin B, a Novel Autophagy Inducer, Attenuates Gouty Inflammation by Inhibiting the NLRP3 Inflammasome

“…The auxarconjugatin B derivative 4-hydroxy auxarconjugatin B, or 6-((1E,3E,5E,7E)-8-(3-chloro-1H-pyrrol-2-yl)octa-1,3,5,7-tetraenyl)-4-hydroxy-2H-pyran-2-one (4-HAB, Figure 1A), is a novel, low-molecular-weight polyenylpyrrole agent [9]. Our previous data showed that 4-HAB exerts strong anti-inflammatory effects by inhibiting lipopolysaccharide (LPS)-induced inflammation in macrophages and dendritic cells [10]. However, little is known about the effects of 4-HAB on the NLRP3 inflammasome and the underlying molecular mechanism of these effects.…”

Negative regulators and their mechanisms in NLRP3 inflammasome activation and signaling

“…Isoliquiritigenin, a flavonoid derived from Glycyrrhiza uralensis , has an activity that suppresses NLRP3 inflammasome activation to inhibit diet‐induced obesity, insulin resistance and adipose tissue inflammation 67 . Polyenylpyrroles from soil ascomycete Gymnoascus reessii function as anti‐inflammatory agents to ameliorate NLRP3 inflammasome‐related diseases through ROS‐ and MAPK‐dependent pathways 68 …”