Dietary Flavone Baicalein Combinate with Genipin Attenuates Inflammation Stimulated by Lipopolysaccharide in RAW264.7 Cells or Pseudomonas aeruginosa in Mice via Regulating the Expression and Phosphorylation of AKT.

Man Zhang,Gang Bai,Lin Niu,Fukui Shen,Lili Ye,Chuanjing Cheng,Yuanyuan Hou

doi:10.3390/nu13124462

Abstract

Mounting evidence has shown that single-targeted therapy might be inadequate to achieve satisfactory effects. Thus, drug combinations are gaining attention as they can regulate multiple targets to obtain more beneficial effects. Heat shock protein 90 (HSP90) is a molecular chaperone that assists the protein assembly and folding of client proteins and maintains their stability. Interfering with the interaction between HSP90 and its client proteins by inhibiting the latter’s activity may offer a new approach toward combination therapy. The HSP90 client protein AKT plays an important role in the inflammatory response syndrome caused by infections. In this study, the dietary flavone baicalein was identified as a novel inhibitor of HSP90 that targeted the N-terminal ATP binding pocket of HSP90 and hindered the chaperone cycle, resulting in AKT degradation. Combining baicalein with genipin, which was extracted from Gardenia jasminoides, could inhibit the pleckstrin homology domain of AKT, significantly increasing the anti-inflammatory effects both in vitro and in vivo. This synergistic effect was attributed to the reduction in AKT expression and phosphorylation. Thus, elucidating the mechanism underlying this effect will provide a new avenue for the clinical application and development of synergistic anti-inflammatory drugs.

Highlights

Cytokine storm refers to the rapid and mass production of multiple cytokines in the body fluids post a microbial infection [1]
We identified the potential target proteins of BAI in RAW264.7 cells by target fishing using BAI-probe-modified functionalized magnetic microspheres (BAI-MMs) (Figure 1A)
We integrated the data on the anti-inflammatory protein targets of BAI, obtained by virtual docking on PharmMapper, with the inflammation associated proteins obtained from the GeneCards database in a Venn diagram (Figure 1B)

Summary

Introduction

Cytokine storm (inflammatory storm) refers to the rapid and mass production of multiple cytokines in the body fluids post a microbial infection [1]. If a patient develops cytokine-storm-like complications, antiviral therapy alone is insufficient as a treatment, and anti-inflammatory medicine becomes necessary [4]. Many studies have shown that inflammation is an essential immune response associated with the development of many diseases, including cancer and diabetes and those related to the cardiovascular system [6]. Various inflammation-related signal transduction pathways were identified, including the Keap1–Nrf, TLR4–NF-κB, PI3K–AKT, JAK–STAT3, and MAPK pathways [7,8,9,10]. The anti-inflammatory response mediated by the PI3K–AKT signaling pathway plays a critical role in cells [11]. Glycyrrhizic acid exhibits significant anti-inflammatory effects by affecting the signal transduction in the PI3K–AKT signaling pathway and reducing cytokine production [13]. AKT is a key node of the PI3K/AKT signaling pathway and is a potential drug target for inflammatory regulation [16]

Methods

Results

Discussion

Conclusion