Nuclear Factor Erythroid 2 Related Factor 2 Activator JC-5411 Inhibits Atherosclerosis Through Suppression of Inflammation and Regulation of Lipid Metabolism

Abstract

Phenethyl isothiocyanate is widely present in cruciferous vegetables with multiple biological effects. Here we reported the antiatherogenic effects and the underlying mechanisms of JC-5411 (Phenethyl isothiocyanate formulation) in vitro and in vivo. Luciferase reporter assay showed that JC-5411 increased the activity of nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant response element (ARE). JC-5411 treatment significantly increased the protein expression of Nrf2 and its downstream target gene hemeoxygenase 1 (HO-1) in liver of apolipoprotein E deficient (ApoE−/−) mice. Importantly, JC-5411 treatment significantly reduced atherosclerotic plaque area in both en face aorta and aortic sinus when compared with model group in WD induced ApoE−/− mice. JC-5411 obviously decreased proinflammatory factors’ levels in serum of ApoE−/− mice, LPS stimulated macrophages and TNFα induced endothelial cells, respectively. JC-5411 significantly decreased the levels of total cholesterol (TC) and triglyceride (TG) in both serum and liver of ApoE−/− mice and hyperlipidemic golden hamsters. Mechanism studies showed that JC-5411 exerted anti-inflammatory effect through activating Nrf2 signaling and inhibiting NF-κB and NLRP3 inflammasome pathway. JC-5411 exerted regulating lipid metabolism effect through increasing cholesterol transfer proteins (ABCA1 and LDLR) expression, regulating fatty acids synthesis related genes (p-ACC, SCD1 and FAS), and increasing fatty acids β-oxidation (CPT1A) in vivo. Furthermore, JC-5411 treatment had a favorable antioxidant effect in ApoE−/− mice by increasing the antioxidant related genes expression. Taken together, we conclude that JC-5411 as a Nrf2 activator has anti-inflammatory, rebalancing lipid metabolism, and antioxidant effects, which makes it as a potential therapeutic agent against atherosclerosis.

Direct Inhibition of GSDMD by PEITC Reduces Hepatocyte Pyroptosis and Alleviates Acute Liver Injury in Mice

“…PEITC has also been reported to significantly increase the activities of Nrf2 and a series of antioxidant enzymes in fibroblasts (21). Mechanistic studies showed that the anti-inflammatory effect of PEITC was driven, at least in part, by inhibiting the NLRP3 inflammasome pathway, as indicated by the downregulation of NLRP3, TXNIP, caspase-1, and IL-1b (34,35). Our results also showed that PEITC can inhibit the expression of NLRP3 and the cleavage of CASP1 (upstream of GSDMD) both in vivo and in vitro (Figures 3, 4A, B, 5G, 6B, C).…”

Effects of frog skin peptide temporin-1CEa and its analogs on ox-LDL induced macrophage-derived foam cells

“…AS is a chronic cardiovascular disease that endangers human health and a multifactorial disease that is influenced by multiple environmental and genetic factors ( Jiang et al, 2020 ). In the early stage of AS, LDL across the vascular endothelium by passive transport or receptor-mediated transcytosis and retained in the arterial wall.…”

Activation of the High Mobility Group Box 1/Receptor for Advanced Glycation Endproducts /NOD‐like Receptor Family Pyrin Domain‐Containing 3 Axis Under Chronic Intermittent Hypoxia Induction Promotes the Progression of Atherosclerosis in ApoE −/− Mice

“…For instance, inhibition of the NLRP3 inflammasome pathway by JC‐5411 could prevent pro‐inflammation in atherosclerosis, thereby producing a therapeutic effect. 44 Specific suppression of NLRP3 could play a protective role against atherosclerosis associated with diabetes. 45 Additionally, inactivation of NLRP3 inflammasome because of Tan IIA treatment could ameliorate atherosclerosis in ApoE −/− mice fed with a high‐fat diet.…”