Rutaecarpine derivative R3 attenuates atherosclerosis via inhibiting NLRP3 inflammasome‐related inflammation and modulating cholesterol transport

Abstract

Atherosclerosis is a chronic disease characterized by lipid deposition and inflammatory response. NOD‐, LRR‐ and pyrin domain‐containing protein 3 (NLRP3) inflammasome‐facilitated inflammatory responses are crucial in the pathogenesis of atherosclerosis, and thus new therapeutic approaches are emerging that target NLRP3 and inflammation. Here, we explored the anti‐atherosclerotic effect and mechanisms of a new rutaecarpine derivative, 5‐deoxy‐rutaecarpine (R3) in vitro and in vivo. R3 treatment attenuated atherosclerosis development and increased plaque stability in Apoe−/− mice fed a high‐fat diet, and decreased levels of inflammatory mediators, such as interleukin‐1β, in the serum of Apoe−/− mice and in oxidized low‐density lipoprotein (ox‐LDL)‐stimulated murine macrophages. R3 treatment inhibited NLRP3 inflammasome activation in the livers of Apoe−/− mice and ox‐LDL‐stimulated murine macrophages by inhibiting NF‐κB and MAPK pathways. Additionally, R3 significantly decreased total cholesterol in the serum and livers of Apoe−/− mice and promoted cholesterol efflux in murine macrophages through upregulating protein expression of ATP‐binding cassette subfamily A member 1 and scavenger receptor class B type I/human CD36 and lysosomal integral membrane protein‐II analogous‐1. Our results demonstrated that R3 prevented atherosclerotic progression via attenuating NLRP3 inflammasome‐related inflammation and modulating cholesterol transport.

Rutaecarpine Ameliorates Ethanol-Induced Gastric Mucosal Injury in Mice by Modulating Genes Related to Inflammation, Oxidative Stress and Apoptosis

“…It is undoubtedly an efficacious strategy for the treatment of GU to ameliorate the aberration of these inflammatory pathological factors. In fact, RUT has pronounced anti-inflammatory capabilities in a variety of disease models according to the reports (Li et al, 2019a;Li et al, 2019b;Luo et al, 2020), which also corroborates our results from the side.…”

“…However, the mechanism of ethanol damage to gastric mucosa is not completely clear. Previous studies have shown that it is related to the direct damage of gastric epithelial cells (Zhao et al, 2009) and mucus layer (da Silva et al, 2018), or the indirect damage such as the influence of gastric mucosal hemodynamics (Kawano and Tsuji, 2020), infiltration of leukocytes and ensued inflammatory (Li et al, 2017) and oxidative stress (Loguercio et al, 2009;Salaspuro, 2011) and apoptosis distortion (Arab et al, 2019). Thus, this present study focused on the forthputting of RUT to treat ethanol-induced gastric injury through antiinflammatory, anti-oxidation and anti-apoptosis.…”

Cellular Models and Assays to Study NLRP3 Inflammasome Biology

“…For example, J774A.1 cells have been used by Yaron and collaborators to demonstrate that K + efflux is upstream of Ca 2+ influx in the production of mtROS, thus beginning the cascade of events leading to NLRP3 inflammasome activation [ 75 ]. J774A.1 cells have been widely used to test the efficacy of potentially novel inhibitors of NLRP3 [ 53 , 76 , 77 , 78 ]. For instance, Hu et al nicely demonstrated that the antimicrobial cathelicidin peptide LL-37 inhibits LPS/ATP-mediated pyroptosis, thus providing new insights into modulation of sepsis [ 79 ].…”

Integrated Molecular Docking with Network Pharmacology to Reveal the Molecular Mechanism of Simiao Powder in the Treatment of Acute Gouty Arthritis

“…It potentially inhibits the production of inflammatory mediators by macrophages and lymphocytes [ 25 ]. Inhibition of NF- κ B and mitogen-activated protein kinase (MAPK) pathways in rutaecarpine-derivative R3 inhibits the NLRP3 inflammasome activation, which consequently lowers the expression of proinflammatory cytokine IL-1 β [ 26 , 27 ]. The pathogenesis of GA is highly associated with the inflammatory cascade induced by the activation of the inflammatory bodies of NLRP3 [ 2 ].…”