Activation of Nrf2 by Esculetin Mitigates Inflammatory Responses through Suppression of NF-κB Signaling Cascade in RAW 264.7 Cells

Abstract

Inflammation is a major root of several diseases such as allergy, cancer, Alzheimer’s, and several others, and the present state of existing drugs provoked researchers to search for new treatment strategies. Plants are regarded to be unique sources of active compounds holding pharmacological properties, and they offer novel designs in the development of therapeutic agents. Therefore, this study aimed to explore the anti-inflammatory mechanism of esculetin in lipoteichoic acid (LTA)-induced macrophage cells (RAW 264.7). The relative expression of inducible nitric oxide synthase (iNOS), nitric oxide (NO) production and COX-2 expression were intensified in LTA-induced RAW cells. The phosphorylation status of mitogen-activated protein kinases (extracellular signal-regulated kinase (ERK)1/2, p38 MAPK, and c-Jun N-terminal kinase (JNK)) and nuclear factor kappa B (NF-κB) p65 were detected by using Western blot assay. The nuclear translocation of p65 was assessed by confocal microscopic image analysis. Esculetin significantly and concentration-dependently inhibited LTA-induced NO production and iNOS expression, but not COX-2 expression, in RAW cells. Esculetin was not effective in LTA-induced MAPK molecules (ERK, p38 and JNK). However, esculetin recovered LTA-induced IκBα degradation and NF-κB p65 phosphorylation. Moreover, esculetin at a higher concentration of 20 µM evidently inhibited the nuclear translocation of NF-κB p65. At the same high concentration, esculetin augmented Nrf2 expression and decreased DPPH radical generation in RAW 264.7 cells. This study exhibits the value of esculetin for the treatment of LTA-induced inflammation by targeting NF-κB signaling pathways via its antioxidant properties.

Identification of dynamic gene expression profiles during sequential vaccination with ChAdOx1/BNT162b2 using machine learning methods

“…NRF2 induces the expression of genes that promote specificity of macrophages such as the macrophage receptor, which is responsible for bacterial phagocytosis (Schaefer et al, 2022), and the cluster of differentiation gene 36 (CD36), which resists viral infection (Hillier et al, 2022). NRF2 Activation is involved in inflammatory cascade (Jayakumar et al, 2022), regulation of innate immune responses, and antiviral cytosolic DNA sensing. NRF2 inhibits pro-inflammatory signaling pathways such as TNF-α signaling and is involved in regulating the innate immune response during sepsis.…”

Keap1-Nrf2 Heterodimer: A Therapeutic Target to Ameliorate Sickle Cell Disease

“…Acacetin, a flavonoid, is another drug with antioxidative effects mediated by the phosphorylation of Nrf2 at Ser40 and the inhibition of Keap1 expression via the MsrA-Nrf2/Keap1 pathway [ 118 ]. Recent reports have also found esculetin to be a potent modulator of Nrf2 expression and downregulator of 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical generation in particular cells ( Table 1 ) [ 119 ]. Medicinal and therapeutic properties of various natural and synthetic small molecules including sulforaphane, curcumin, oltipraz and bardoxolone methyl have been investigated and found to be significantly involved in the expression of ARE-dependent cytoprotective genes [ 116 , 117 , 120 ].…”

Pharmacological and Therapeutic Applications of Esculetin

“…A study by Jayakumar et al found that esculetin reverse LTA-induced IkB degradation and NF-κB p65 phosphorylation. By increasing Nrf2 and scavenging DPPH radicals in RAW 264.7 cells at a concentration of 20 µM, esculetin inhibited the translocation of NF-κB p65 to the nucleus [ 69 ].…”