No abstract

Individual variation in the addiction liability of amphetamines has a heritable genetic component. We previously identified Hnrnph1 (heterogeneous nuclear ribonucleoprotein H1) as a quantitative trait gene underlying decreased methamphetamine-induced locomotor activity in mice. Here, we showed that mice (both females and males) with a heterozygous mutation in the first coding exon of Hnrnph1 (H1 ϩ/Ϫ) showed reduced methamphetamine reinforcement and intake and dose-dependent changes in methamphetamine reward as measured via conditioned place preference. Furthermore, H1 ϩ/Ϫ mice showed a robust decrease in methamphetamine-induced dopamine release in the NAc with no change in baseline extracellular dopamine, striatal whole-tissue dopamine, dopamine transporter protein, dopamine uptake, or striatal methamphetamine and amphetamine metabolite levels. Immunohistochemical and immunoblot staining of midbrain dopaminergic neurons and their forebrain projections for TH did not reveal any major changes in staining intensity, cell number, or forebrain puncta counts. Surprisingly, there was a twofold increase in hnRNP H protein in the striatal synaptosome of H1 ϩ/Ϫ mice with no change in whole-tissue levels. To gain insight into the mechanisms linking increased synaptic hnRNP H with decreased methamphetamine-induced dopamine release and behaviors, synaptosomal proteomic analysis identified an increased baseline abundance of several mitochondrial complex I and V proteins that rapidly decreased at 30 min after methamphetamine administration in H1 ϩ/Ϫ mice. In contrast, the much lower level of basal synaptosomal mitochondrial proteins in WT mice showed a rapid increase. We conclude that H1 ϩ/Ϫ decreases methamphetamine-induced dopamine release, reward, and reinforcement and induces dynamic changes in basal and methamphetamine-induced synaptic mitochondrial function.

No abstract

Necrosis is a hallmark of glioblastoma (GBM) and is responsible for poor prognosis and resistance to conventional therapies. However, the molecular mechanisms underlying necrotic microenvironment-induced malignancy of GBM have not been elucidated. Here, we report that transglutaminase 2 (TGM2) is upregulated in the perinecrotic region of GBM and triggered mesenchymal (MES) transdifferentiation of glioma stem cells (GSC) by regulating master transcription factors (TF), such as C/EBPβ, TAZ, and STAT3. TGM2 expression was induced by macrophages/microglia-derived cytokines via NF-κB activation and further degraded DNA damage-inducible transcript 3 (GADD153) to induce C/EBPβ expression, resulting in expression of the MES transcriptome. Downregulation of TGM2 decreased sphere-forming ability, tumor size, and radioresistance and survival in a xenograft mouse model through a loss of the MES signature. A TGM2-specific inhibitor GK921 blocked MES transdifferentiation and showed significant therapeutic efficacy in mouse models of GSC. Moreover, TGM2 expression was significantly increased in recurrent MES patients and inversely correlated with patient prognosis. Collectively, our results indicate that TGM2 is a key molecular switch of necrosis-induced MES transdifferentiation and an important therapeutic target for MES GBM. .

The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailed molecular mechanisms underlying the relationship between these two cell types remain unclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger protein that is essential for early mammalian development, plays critical roles in GSC maintenance and M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL, encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicity of GSCs through production of prostaglandin E 2 (PGE 2), which stimulates β-catenin activation of GSC and M2-like TAM polarization. We identify M2-like signature downregulated by which MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mouse xenograft model by blocking PGE 2 production. Taken together, our results suggest that blocking the interplay between GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially novel therapeutic option for GBM patients.

Ischemia-reperfusion injury (IRI) is a major complication in liver transplantation (LT) and it is closely related to the recovery of grafts' function. Researches has verified that both innate and adaptive immune system are involved in the development of IRI and Kupffer cell (KC), the resident macrophages in the liver, play a pivotal role both in triggering and sustaining the sterile inflammation. Damage-associated molecular patterns (DAMPs), released by the initial dead cell because of the ischemia insult, firstly activate the KC through pattern recognition receptors (PRRs) such as toll-like receptors. Activated KCs is the dominant players in the IRI as it can secret various pro-inflammatory cytokines to exacerbate the injury and recruit other types of immune cells from the circulation. On the other hand, KCs can also serve in a contrary way to ameliorate IRI by upregulating the anti-inflammatory factors. Moreover, new standpoint has been put forward that KCs and macrophages from the circulation may function in different way to influence the inflammation. Managements towards KCs are expected to be the effective way to improve the IRI.

Background. This study is aimed at investigating the changes in relevant pathways and the differential expression of related gene expression after ischemic stroke (IS) at the single-cell level using multiple weighted gene coexpression network analysis (WGCNA) and single-cell analysis. Methods. The transcriptome expression datasets of IS samples and single-cell RNA sequencing (scRNA-seq) profiles of cerebrovascular tissues were obtained by searching the Gene Expression Omnibus (GEO) database. First, gene pathway scoring was calculated via gene set variation analysis (GSVA) and was imported into multiple WGCNA to acquire key pathways and pathway-related hub genes. Furthermore, SCENIC was used to identify transcription factors (TFs) regulating these core genes using scRNA-seq data. Finally, the pseudotemporal trajectory analysis was used to analyse the role of these TFs on various cell types under hypoxic and normoxic conditions. Results. The scores of 186 KEGG pathways were obtained via GSVA using microarray expression profiles of 40 specimens. WGCNA of the KEGG pathways revealed the two following pathways: calcium signaling pathway and neuroactive ligand-receptor interaction pathways. Subsequently, WGCNA of the gene expression matrix of the samples revealed the calcium signaling pathway-related genes (AC079305.10, BCL10, BCL2A1, BRE-AS1, DYNLL2, EREG, and PTGS2) that were identified as core genes via correlation analysis. Furthermore, SCENIC and pseudotemporal analysis revealed JUN, IRF9, ETV5, and PPARA score gene-related TFs. Jun was found to be associated with hypoxia in endothelial cells, whereas Irf9 and Etv5 were identified as astrocyte-specific TFs associated with oxygen concentration in the mouse cerebral cortex. Conclusions. Calcium signaling pathway-related genes (AC079305.10, BCL10, BCL2A1, BRE-AS1, DYNLL2, EREG, and PTGS2) and TFs (JUN, IRF9, ETV5, and PPARA) were identified to play a key role in IS. This study provides a new perspective and basis for investigating the pathogenesis of IS and developing new therapeutic approaches.

The dominant amount of antifouling D-PSBMA with a minor amount of bactericidal D-PQAs facilitate the synergistic anti-biofilm effect.