Background: Sepsis-associated encephalopathy (SAE) is characterized by diffuse brain dysfunction, long-term cognitive impairment, and increased morbidity and mortality. The current treatment for SAE is mainly symptomatic; the lack of specific treatment options and a poor understanding of the underlying mechanism of disease are responsible for poor patient outcomes. Fgr is a member of the Src family of tyrosine kinases and is involved in the innate immune response, hematologic cancer, diet-induced obesity, and hemorrhage-induced thalamic pain. This study investigated the protection provided by an Fgr kinase inhibitor in SAE and the underlying mechanism(s) of action.Methods: A cecal ligation and puncture (CLP)-induced mouse sepsis model was established. Mice were treated with or without an Fgr inhibitor and a PGC-1α inhibitor/activator. An open field test, a novel object recognition test, and an elevated plus maze were used to assess neurobehavioral changes in the mice. Western blotting and immunofluorescence were used to measure protein expression, and mRNA levels were measured using quantitative PCR (qPCR). An enzyme-linked immunosorbent assay was performed to quantify inflammatory cytokines. Mitochondrial membrane potential and morphology were measured by JC-1, electron microscopy, and the MitoTracker Deep Red probe. Oxidative stress and mitochondrial dysfunction were analyzed. In addition, the regulatory effect of Fgr on sirtuin 1 (SIRT1) was assessed.Results: CLP-induced sepsis increased the expression of Fgr in the hippocampal neurons. Pharmacological inhibition of Fgr attenuated CLP-induced neuroinflammation, the survival rate, cognitive and emotional dysfunction, oxidative stress, and mitochondrial dysfunction. Moreover, Fgr interacted with SIRT1 and reduced its activity and expression. In addition, activation of SIRT1/PGC-1α promoted the protective effects of the Fgr inhibitor on CLP-induced brain dysfunction, while inactivation of SIRT1/PGC-1α counteracted the benefits of the Fgr inhibitor.Conclusions: To our knowledge, this is the first report of Fgr kinase inhibition markedly ameliorating SAE through activation of the SIRT1/PGC-1α pathway, and this may be a promising therapeutic target for SAE.Graphical

General control non-derepressible 5 (GCN5) is ectopically expressed in different types of human cancer and association with the carcinogenesis, development, and poor prognosis of cancers. The present study was aimed to investigate the potential role and related mechanisms of GCN5 in IL-6–treated prostate cancer (PCa) cell. The results showed that an elevated GCN5 expression was stimulated by IL-6. Knockdown of GCN5 significantly inhibited IL-6–driven proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). Moreover, early growth response-1 (Egr-1) expression was elevated by IL-6 treatment and GCN5 siRNA down-regulated the expression of Egr-1. Furthermore, overexpression of Egr-1 attenuated the effects of GCN5 silence on cell proliferation, migration, invasion, and EMT in PCa. Besides, knockdown of GCN5 resulted in the down-regulation of p-Akt and up-regulation of PTEN, which was partly impeded by Egr-1 overexpression. The effects of GCN5 overexpression on cell proliferation and invasion were suppressed by LY294002, In conclusion, these data demonstrated the negative effect of up-regulated GCN5 in IL-6-induced metastasis and EMT in PCa cells through PI3K/PTEN/Akt signaling pathway down-regulating Egr-1 expression.

Prokineticin 2 (PK2) is a secreted protein and causes potent hyperalgesia in vivo, and is therefore considered to be a new pronociceptive mediator. However, the molecular targets responsible for the pronociceptive effects of PK2 are still poorly understood. Here, we have found that PK2 potentiates the activity of acid-sensing ion channels in the primary sensory neurons.

A collection of 515 rice landraces originating from Vietnam and China were screened for the reaction to brown planthopper (BPH) infestation. Most of the resistant landraces were indica types from Vietnam and the Guangxi province in China. An F(2) mapping population was created from the cross between a BPH resistant Vietnamese landrace Yagyaw and the susceptible cultivar Cpslo17. Four quantitative trait loci (QTL) contributing to BPH resistance were mapped on chromosomes 2, 4, 7 and 9, respectively. The individual QTL accounted 5.64% to 12.77% of the phenotypic variance, and three resistant alleles were harbored in the resistant landrace Yagyaw. Two QTL located on chromosomes 2 and 4 were identified with significant additive effects and are useful in breeding new rice inbred lines. One resistant allele was harbored by the susceptible parent Cpslo17. This gene is important in selecting rice inbred lines with stronger resistances to BPH.

Neuroinflammation is associated with the pathophysiology of depression. The molecular mechanism of depressive-like behavior caused by sepsis-associated encephalopathy (SAE) is incompletely understood. J147 (an analog of curcumin) has been reported to improve memory and has neuroprotective activity, but its biological function in the depressive-like behavior observed in SAE is not known. We investigated the effects of J147 on lipopolysaccharide (LPS)-induced neuroinflammatory, depressive-like behaviors, and the toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signal pathway in the mouse hippocampus and microglia (BV2 cells). The forced-swimming test (FST) and tail-suspension test (TST) were undertaken for assessment of depressive-like behaviors. Expression of the proinflammatory genes interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α were measured using RT-qPCR and ELISA. Microglia activation was detected using immunofluorescence staining. The TLR4/NF-κB signaling pathway was studied using western blotting and immunofluorescence staining. J147 pretreatment markedly downregulated expression of IL-6, IL-1β, and TNF-α, and the mean fluorescence intensity of ionized calcium-binding adapter protein-1 in microglia. J147 restrained LPS-induced nuclear translocation of nuclear factor-kappa B (NF-κB), inhibitor of nuclear factor kappa B (IκB) degradation, and TLR4 activation in microglia. J147 administration inhibited bodyweight loss, mortality, microglia activation, and depressive-like behaviors in LPS-treated mice. In conclusion, J147 ameliorated the sepsis-induced depressive-like behaviors induced by neuroinflammation through attenuating the TLR4/NF-κB signaling pathway in microglia.

Studies have suggested that microglial IL‐6 modulates inflammatory pain; however, the exact mechanism of action remains unclear. We therefore hypothesized that PKCε and MEG2 competitively bind to STAT3 and contribute to IL‐6‐mediated microglial hyperalgesia during inflammatory pain. Freund's complete adjuvant (FCA) and lipopolysaccharide (LPS) were used to induce hyperalgesia model mice and microglial inflammation. Mechanical allodynia was evaluated using von Frey tests in vivo. The interaction among PKCε, MEG2, and STAT3 was determined using ELISA and immunoprecipitation assay in vitro. The PKCε, MEG2, t‐STAT3, pSTAT3 ^Tyr705 , pSTAT3 ^Ser727 , IL‐6, GLUT3, and TREM2 were assessed by Western blot. IL‐6 promoter activity and IL‐6 concentration were examined using dual luciferase assays and ELISA. Overexpression of PKCε and MEG2 promoted and attenuated inflammatory pain, accompanied by an increase and decrease in IL‐6 expression, respectively. PKCε displayed a stronger binding ability to STAT3 when competing with MEG2. STAT3 ^Ser727 phosphorylation increased STAT3 interaction with both PKCε and MEG2. Moreover, LPS increased PKCε, MEG2, pSTAT3 ^Tyr705 , pSTAT3 ^Ser727 , IL‐6, and GLUT3 levels and decreased TREM2 during microglia inflammation. IL‐6 promoter activity was enhanced or inhibited by PKCε or MEG2 in the presence of STAT3 and LPS stimulation, respectively. In microglia, overexpression of PKCε and/or MEG2 resulted in the elevation of tSTAT3, pSTAT3 ^Tyr705 , pSTAT3 ^Ser727 , IL‐6, and TREM2, and the reduction of GLUT3. PKCε is more potent than MEG2 when competitively binding to STAT3, displaying dual modulatory effects of IL‐6 production, thus regulating the GLUT3 and TREM2 in microglia during inflammatory pain sensation.