Activation of PPARγ by a Natural Flavonoid Modulator, Apigenin Ameliorates Obesity-Related Inflammation Via Regulation of Macrophage Polarization.

PPARγ has emerged as a master regulator of macrophage polarization and is the molecular target of the thiazolidinedione drugs. Here we show that apigenin binds and activates PPARγ by acting as a modulator. Activation of PPARγ by apigenin blocks p65 translocation into nuclei through inhibition of p65/PPARγ complex translocation into nuclei, thereby decreasing NF-κB activation and favoringM2 macrophage polarization. In HFD and ob/ob mice, apigenin significantly reverses M1 macrophage into M2 and reduces the infiltration of inflammatory cells in liver and adipose tissues, as well as decreases the levels of pro-inflammatory cytokines, thereby alleviating inflammation. Strikingly, apigenin reduces liver and muscular steatosis, decreases the levels of ALT, AST, TC and TG, improving glucose resistance obviously. Unlike rosiglitazone, apigenin does not cause significant weight gain, osteoporosis et al. Our findings identify apigenin as a modulator of PPARγ and a potential lead compound for treatment of metabolic disorders.

Identification of human liver mitochondrial aldehyde dehydrogenase as a potential target for microcystin-LR.

Microcystins (MCs) are hepatotoxins produced by a variety of freshwater cyanobacteria. The toxicity of these hepatotoxins is a severe health issue for both humans and livestock; MCs have been implicated in the development of liver cancer, necrosis, and even deadly intrahepatic bleeding. Microcystin-LR (MC-LR) is the MC variant most commonly encountered in a contaminated aquatic system. Thus far, MC-LR has only been shown to target the serine/threonine protein phosphatases 1 and 2A (PP1 and PP2A) and it is still unknown whether MC-LR can bind and inhibit any other protein targets inside the cell. To find potential MC-LR targets, we screened a phage display library for peptide ligands that specifically recognize MC-LR. Using these peptide sequences as guides, we performed a series of bioinformatics analyses revealing that MC-LR binds human liver aldehyde dehydrogenase 2 (ALDH2) at residues 447-451. We confirmed MC-LR binding of ALDH2 via automated docking computation, which yielded results matching our experimental and bioinformatics analyses. ALDH2 dysfunction may lead to aldehyde-induced reactive oxygen species (ROS) generation and, in turn, apoptosis. Therefore, ALDH2 could potentially be a target of MC-LR associated with the process of ROS-induced apoptosis. Our current study presents a new approach to the study of interactions of biological molecules by combining phage display technology with computational methods.