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Excessive activation of the TLR4 signalling pathway is critical for inflammation-associated disorders, while negative regulators play key roles in restraining TLR4 from over-activation. Naringenin is a citrus flavonoid with remarkable anti-inflammatory activity, but the mechanisms underlying its inhibition of LPS/TLR4 signalling are less clear. This study investigated the molecular targets and therapeutic effects of naringenin in vitro and in vivo. In LPS-stimulated murine macrophages, naringenin suppressed the expression of TNF-α, IL-6, TLR4, inducible NO synthase (iNOS), cyclo-oxygenase-2 (COX2) and NADPH oxidase-2 (NOX2). Naringenin also inhibited NF-κB and mitogen-activated protein kinase (MAPK) activation. However, it did not affect the IRF3 signalling pathway or interferon production, which upregulate activating transcription factor 3 (ATF3), an inducible negative regulator of TLR4 signalling. Naringenin was demonstrated to directly increase ATF3 expression. Inhibition of AMPK and its upstream calcium-dependent signalling reduced ATF3 expression and dampened the anti-inflammatory activity of naringenin. In murine endotoxaemia models, naringenin ameliorated pro-inflammatory reactions and improved survival. Furthermore, it induced AMPK activation in lung tissues, which was required for ATF3 upregulation and the enhanced anti-inflammatory activity. Overall, this study reveals a novel mechanism of naringenin through AMPK-ATF3-dependent negative regulation of the LPS/TLR4 signalling pathway, which thereby confers protection against murine endotoxaemia.

Bisphenol A (BPA), one of the most common environmental endocrine disruptors, has been recognized to have wide adverse effects on the brain development and behavior. These adversities are related to its ability to bind estrogen receptor (ER) with subsequent alteration of its expression in the target areas. However, very little is known about whether BPA exposure also affects ER phosphorylation and its translocation to nucleus during postnatal development, two critical steps for its function. Here, we found that during development from postnatal day 7 (P7) to P21, the alpha subtype of ER (ERα) in the hippocampus of male rats experienced remarkable alterations in terms of its expression, phosphorylation and translocation to nucleus. Exposure to low level of BPA had bidirectional, development-dependent effects on the expression of ERα mRNA and protein, but decreased ERα phosphorylation and impaired its translocation to nucleus throughout the period investigated. Treatment with low dose of ICI 182,780 (ICI), an ER antagonist to block the binding of ER with BPA, reversed the altered ERα following BPA exposure, highlighting critical involvement of ER. Moreover, ICI treatment rescued the hippocampus-dependent behavioral deficits in the adult rats experiencing early-life BPA exposure. Overall, our results indicate that BPA interferes with the ERα signaling in the developing hippocampus in an ER-dependent manner, which may underlie its adverse behavioral and cognitive outcomes in adult animals.

BackgroundBoth grain size and grain number are significant for rice yield. In the past decade, a number of genes related to grain size and grain number have been documented, however, the regulatory mechanisms underlying them remains ambiguous.ResultsWe identified a rice small grain (sg2) mutant in an EMS mutant library generated from an indica variety, Shuhui498. Using the MutMap gene mapping strategy, we identified two linkage regions on chromosome 7 and 8, respectively, consistent with the segregation ratios in the F2 population. We focused on the linkage region on chromosome 8, and named this locus as 08sg2. One of three SNPs identified in the linkage region was located in an exon of OsBAK1, leading to a nonsynonymous mutation in the kinase domain. The plant harboring the mutant version 08sg2 locus exhibited a decreased grain size, grain number and plant height. Cytological analysis indicated that 08SG2 regulated spikelet hull development by affecting cell proliferation. The grain size and number of knockout mutants of OsBAK1 in the japonica background were significantly decreased, but less so than in 08sg2, supporting the idea that the SNP in OsBAK1 was responsible for the 08sg2 phenotype, but that 08SG2/OsBAK1 function differently in indica and japonica backgrounds. 08sg2 was insensitive to 24-epiBL, and the expression of BR-related genes was obviously altered in 08sg2. The proportionally decreased grain length when 08sg2 and GS3 were combined indicate that 08SG2 and GS3 regulate grain length independently.ConclusionsOur work shows that 08SG2/OsBAK1 is important for rice yield in both indica and japonica backgrounds, by regulating grain size and grain number, and the function of 08SG2/OsBAK1 is obviously affected by genetic background. The amino acid substituted in 08sg2 is highly conserved among different species, supporting the idea that it is important for the molecular function of 08SG2/OsBAK1. Together, our work is helpful for fully understanding the function of 08SG2/OsBAK1.Electronic supplementary materialThe online version of this article (doi:10.1186/s12284-017-0165-2) contains supplementary material, which is available to authorized users.