Identification of a novel small-molecule Keap1–Nrf2 PPI inhibitor with cytoprotective effects on LPS-induced cardiomyopathy

A new Keap1–Nrf2 protein–protein interaction (PPI) inhibitor ZJ01 was identified from our compound library by fluorescence polarization assay, surface plasmon resonance, molecular docking and molecular dynamics simulation. ZJ01 could in vitro trigger Nrf2 nuclear translocation, subsequently resulting in increased mRNA levels of Nrf2 target genes HO-1 and NQO1. Meanwhile, ZJ01 suppressed LPS-induced production of ROS and the mRNA levels of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 in H9c2 cardiac cells. Moreover, in an in vivo mouse model of septic cardiomyopathy induced by intraperitoneal injection of lipopolysaccharide, ZJ01 demonstrated a cytoprotective effect, upregulated Nrf2 protein nuclear accumulation, and remarkably suppressed the abovementioned cytokine levels in cardiomyocytes. The results presented herein provided a novel chemotype for the development of direct Keap1–Nrf2 PPI inhibitors and suggested that compound ZJ01 is a promising drug lead for septic cardiomyopathy treatment.

ZJ01 was identified as a new Keap1–Nrf2 PPI inhibitor and drug lead for septic cardiomyopathy treatment by in vitro and in vivo experiments.     

Dietary supplementation with soybean lecithin increases pulmonary PAF bioactivity in asthmatic rats

The prevalence of asthma has risen over the last few decades, and some studies correlate this with the greater consumption of polyunsaturated fatty acids (PUFAs). Dietary PUFAs are known to increase the susceptibility of biological structures to lipid peroxidation, a process by which platelet-activating factor (PAF)-like lipids can be generated. These lipids functionally mimic the bioactivity of PAF, a potent proinflammatory mediator that exerts several deleterious effects on asthma. Thus, this work aimed to investigate if dietary supplementation with soybean lecithin (SL), a source of PUFAs, increases lipid peroxidation and PAF bioactivity in lungs of asthmatic Wistar rats. Animals were separated into groups: control, supplemented, asthmatic, asthmatic supplemented with SL (2 g/kg body weight), asthmatic supplemented with SL (2 g/kg body weight) and dl-α-tocopheryl acetate (100 mg/kg body weight). Asthmatic inflammation increased pulmonary lipid peroxidation, PAF bioactivity, alveolar–capillary barrier permeability and production of nitric oxide. In asthmatics, dietary supplementation with SL promoted an increase in pulmonary lipid peroxidation and PAF bioactivity, and an increase in the permeability of the alveolar–capillary barrier. Moreover, the treatment of asthmatic rats with dl-α-tocopheryl acetate inhibited the lipid peroxidation and decreased the PAF bioactivity. Therefore, the increase in pulmonary PAF bioactivity in asthmatic individuals elicited by the dietary supplementation with SL probably involves the generation of PAF-like lipids. This finding suggests that PAF-like lipids may account for the deleterious effects of dietary PUFAs on asthma.     

How Do Real Indians Fish? Neoliberal Multiculturalism and Contested Indigeneities in the Colorado Delta

ABSTRACT   There has been a growing interest in anthropology regarding how certain political conditions set the stage for "articulations" between indigenous movements and environmental actors and discourses. However, relatively little attention has been paid to how these same conditions can suppress demands for indigenous rights. In this article, I argue that the pairing of neoliberalism and multiculturalism in contemporary Mexico has created political fields in which ethnic difference has been foregrounded as a way of denying certain rights to marginalized groups. Drawing on ethnographic fieldwork conducted in northern Mexico, I analyze how the arguments of a group of Cucapá for fishing rights in the Colorado Delta have been constrained within these political circumstances. I argue that cultural difference has been leveraged by the Mexican federal government and local NGOs to prevent the redistribution of environmental resources among vulnerable groups such as the Cucapá.     

Design and synthesis of pregnenolone/2-cyanoacryloyl conjugates with dual NF-κB inhibitory and anti-proliferative activities

Twenty-five novel pregnenolone/2-cyanoacryloyl conjugates (6–30) were designed and prepared, with the aim of developing novel anticancer drugs with dual NF-κB inhibitory and anti-proliferative activities. Compounds 22 and 27–30 showed inhibition against TNF-α-induced NF-κB activation in luciferase assay, which was confirmed by Western blotting. Among them, compound 30 showed potent NF-κB inhibitory activity (IC₅₀ = 2.5 μM) and anti-proliferative against MCF-7, A549, H157, and HL-60 cell lines (IC₅₀ = 6.5–36.2 μM). The present study indicated that pregnenolone/2-cyanoacryloyl conjugate I can server as a novel scaffold for developing NF-κB inhibitors and anti-proliferative agents in cancer chemotherapy.