Biochanin a Enhances the Defense Against Salmonella enterica Infection Through AMPK/ULK1/mTOR-Mediated Autophagy and Extracellular Traps and Reversing SPI-1-Dependent Macrophage (MΦ) M2 Polarization

Abstract

A novel treatment regimen for bacterial infections is the pharmacological enhancement of the host's immune defenses. We demonstrated that biochanin A (BCA), an isoflavone constituent in some plants, could enhance both intra- and extracellular bactericidal activity of host cells. First, BCA could induce a complete autophagic response in nonphagocytic cells (HeLa) or macrophages (MΦ) via the AMPK/ULK1/mTOR pathway and Beclin-1-dependent manner, and BCA enhanced the killing of invading Salmonella by autophagy through reinforcing ubiquitinated adapter protein (LRSAM1, NDP52 and p62)-mediated recognition of intracellular bacteria and through the formation of autophagolysosomes. Second, we demonstrated that BCA could enhance the release of MΦ extracellular traps (METs) to remove extracellular Salmonella also via the AMPK/ULK1/mTOR pathway, not through reactive oxygen species (ROS) pathway. Furtherly, in a Salmonella-infected mouse model, BCA treatment increased intra- and extracellular bactericidal activity through the strengthening autophagy and MET production, respectively, in peritoneal MΦ, liver and spleen tissue. Additionally, our findings showed that BCA downregulated SPI-1 (Salmonella pathogenicity island 1) expression during Salmonella infection in vitro and in vivo to reverse the MΦ M2 polarization, which was different from the MΦ M1 phenotype caused by most of bacteria infection. Together, these findings suggest that BCA has an immunomodulatory effect on Salmonella-infected host cells and enhances their bactericidal activity in vitro and in vivo through autophagy, extracellular traps and regulation of MΦ polarization.

Roquin-1 Regulates Macrophage Immune Response and Participates in Hepatic Ischemia–Reperfusion Injury

“…3D, Supplemental Table II). Combined with previous research results (21,22), we inferred that the target of Roquin-1 was AMPKa (Supplemental Fig. 2E), and Roquin-1 regulate AMPKa/mTOR singling pathway to modulate the polarization of mø.…”

Salmonella Interacts With Autophagy to Offense or Defense

“…Ammanathan et al (2019) found that Acacetin (5,7dihydroxy-4-methoxyflavone), a potent xenophagy inducer, could enhance the host response against intracellular Salmonella. Moreover, biochanin A (BCA), a polyphenolic compound found in certain species of plants, has been proven to target Salmonella infection through AMPK/ULK1/mTOR-mediated autophagy, extracellular traps, and the reversal of SPI-1dependent macrophage M2 polarization (Zhao et al, 2018). In addition, Huang (2016) found that 1,25-dihydroxyvitamin D3 may promote the autophagic removal of intracellular Salmonella and modulate inflammatory responses to prevent the host from the adverse effects of excessive inflammation.…”

Perspectives Regarding the Role of Biochanin A in Humans

“…Subsequently, studies investigating the anticancer activity of BCA were carried out in different cancer cell lines, followed by animal models. Many types of tumors could be inhibited by BCA, such as lung cancer (Lee et al, 1991), prostate cancer (Peterson and Barnes, 1993; Sun et al, 1998), gastrointestinal tract cancer (Yanagihara et al, 1993), pancreatic cancer (Bhardwaj et al, 2014), breast cancer (Balabhadrapathruni et al, 2000; Sehdev et al, 2009), osteosarcoma (Hsu et al, 2018; Zhao et al, 2018), malignant melanoma (Xiao et al, 2017), and tumors of the central nervous system (Sehm et al, 2014). However, the ability of BCA to inhibit the growth of some types of cancer cells was weaker than that of GEN (Peterson and Barnes, 1991), but the anticancer usage of BCA might be broader because of its targeting of anticancer activity, especially in malignant brain tumors (Sehm et al, 2014).…”

“…Reactive oxygen species (ROS) and COX-2 are important proinflammatory factors that can stimulate transcription factors to increase inflammatory mediator expression. BCA scavenges ROS and increases SOD activity (Xue et al, 2017; Zhao et al, 2018). BCA significantly reduces the synthesis of prostaglandin E2 and/or thromboxane B2 by inhibiting COX-2 expression (Lam et al, 2004; Lim et al, 2013).…”