Dual Effect of Soloxolone Methyl on LPS-Induced Inflammation In Vitro and In Vivo

Abstract

Plant-extracted triterpenoids belong to a class of bioactive compounds with pleotropic functions, including antioxidant, anti-cancer, and anti-inflammatory effects. In this work, we investigated the anti-inflammatory and anti-oxidative activities of a semisynthetic derivative of 18βH-glycyrrhetinic acid (18βH-GA), soloxolone methyl (methyl 2-cyano-3,12-dioxo-18βH-olean-9(11),1(2)-dien-30-oate, or SM) in vitro on lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and in vivo in models of acute inflammation: LPS-induced endotoxemia and carrageenan-induced peritonitis. SM used at non-cytotoxic concentrations was found to attenuate the production of reactive oxygen species and nitric oxide (II) and increase the level of reduced glutathione production by LPS-stimulated RAW264.7 cells. Moreover, SM strongly suppressed the phagocytic and migration activity of activated macrophages. These effects were found to be associated with the stimulation of heme oxigenase-1 (HO-1) expression, as well as with the inhibition of nuclear factor-κB (NF-κB) and Akt phosphorylation. Surprisingly, it was found that SM significantly enhanced LPS-induced expression of the pro-inflammatory cytokines interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) in RAW264.7 cells via activation of the c-Jun/Toll-like receptor 4 (TLR4) signaling axis. In vivo pre-exposure treatment with SM effectively inhibited the development of carrageenan-induced acute inflammation in the peritoneal cavity, but it did not improve LPS-induced inflammation in the endotoxemia model.

Cyano Enone-Bearing Triterpenoid Soloxolone Methyl Inhibits Epithelial-Mesenchymal Transition of Human Lung Adenocarcinoma Cells In Vitro and Metastasis of Murine Melanoma In Vivo

“…The remaining compounds either showed a lower level of bioactivity compared to SM (pi-153) or were unable to affect motility of tumor cells at all (TM, pi-156). The obtained results are in line with published data: recently, we found that SM at identical concentration (0.5 µM) effectively inhibited migration of RAW264.7 macrophages [ 64 ]; furthermore, SM’s structural analog CDDO-Me and its derivatives significantly reduced motility of both malignant [ 65 , 66 , 67 , 68 , 69 ] and non-malignant [ 70 , 71 , 72 ] cells at submicromolar concentrations (0.05–1 µM). Revealed differences in the level of inhibitory activity of investigated compounds against tumor cell motility are consistent with the level of their cytotoxicity.…”

Potential anti-inflammatory activity of walnut protein derived peptide leucine-proline-phenylalanine in lipopolysaccharides-irritated RAW264.7 cells

“…Thus, the amino acid composition of peptides might be critical for the anti-inflammatory property. Macrophages could be activated by LPS to increase phagocytic potential (Markov et al, 2020). As shown in Figure 1C, LPF suppressed the increment of phagocytic ability caused by LPS.…”

Anti-inflammatory and anti-nociceptive effects of Cinnamon and Clove essential oils nanogels: an in vivo study

“…Pro-inflammatory agents, including carrageenan, can affect vascular permeability and blood cells migration through modulated nitric oxide (NO) secretion [ 46 , 47 ]. On the other hand, the production of pro-inflammatory mediators is stimulated by inducing nitric synthase (iNOS) and cyclooxygenase-2 (COX-2) (50, 51).…”