Bisdemethoxycurcumin and Its Cyclized Pyrazole Analogue Differentially Disrupt Lipopolysaccharide Signalling in Human Monocyte-Derived Macrophages

Abstract

Several studies suggest that curcumin and related compounds possess antioxidant and anti-inflammatory properties including modulation of lipopolysaccharide- (LPS-) mediated signalling in macrophage cell models. We here investigated the effects of curcumin and the two structurally unrelated analogues GG6 and GG9 in primary human blood-derived macrophages as well as the signalling pathways involved. Macrophages differentiated from peripheral blood monocytes for 7 days were activated with LPS or selective Toll-like receptor agonists for 24 h. The effects of test compounds on cytokine production and immunophenotypes evaluated as CD80+/CCR2+ and CD206+/CD163+ subsets were examined by ELISA and flow cytometry. Signalling pathways were probed by Western blot. Curcumin (2.5–10 μM) failed to suppress LPS-induced inflammatory responses. While GG6 reduced LPS-induced IκB-α degradation and showed a trend towards reduced interleukin-1β release, GG9 prevented the increase in proinflammatory CD80+ macrophage subset, downregulation of the anti-inflammatory CD206+/CD163+ subset, increase in p38 phosphorylation, and increase in cell-bound and secreted interleukin-1β stimulated by LPS, at least in part through signalling pathways not involving Toll-like receptor 4 and nuclear factor-κB. Thus, the curcumin analogue GG9 attenuated the LPS-induced inflammatory response in human blood-derived macrophages and may therefore represent an attractive chemical template for macrophage pharmacological targeting.

Novel Curcumin-Diethyl Fumarate Hybrid as a Dualistic GSK-3β Inhibitor/Nrf2 Inducer for the Treatment of Parkinson’s Disease

“… 19 The capability of regulating the mediators and biological targets of the inflammation cascade contributes to this therapeutic effect. 20 In this respect, this natural compound, regarded as privileged structure, furnished the scaffold for the design of a large number of functionalized curcumin-based analogues endowed with significant antineurodegenerative activities, thus corroborating the enormous potential of this template in drug discovery. 21 …”

Pre- and Early Post-treatment With Arthrospira platensis (Spirulina) Extract Impedes Lipopolysaccharide-triggered Neuroinflammation in Microglia

“…In the attempt to define the underlying molecular mechanisms by which the extract of Spirulina modulated microglia inflammatory response, we evaluated the activation of the transcription factor NF-κB, which is required for the induction of several cytokines and inflammatory enzymes in microglia and other immune cells ( Zusso et al, 2017 ; Tedesco et al, 2018 ). To measure NF-κB activity, we monitored NF-κB p65 subunit movement from the cytoplasm to the nucleus.…”

Curcumin-1,2,3-Triazole Conjugation for Targeting the Cancer Apoptosis Machinery

“…Thus, derivatives properly designed based on PAIN-based synthons would perform as discriminating bioactive agents rather than reactive chemicals [15,16]. Extensive medicinal chemistry efforts have furnished support to this issue with the identification of a large variety of successful curcumin-related molecules, obtained upon appropriate modifications of its basic framework, also confirming the "privileged" character of this pharmacophore, intrinsically suitable for an efficient interaction with a various biologic targets [17][18][19][20][21]. A fine-tuning of curcumin covalent reactivity, by modulation of the target engagement rate, could represent a strategy through which avoiding the drawback of potential promiscuous reactions [22].…”