Tea O-methylated catechins, especially (−)-epigallocatechin 3-O-(3-O-methyl)gallate (EGCG3″Me), have been attracting much attention as a result of their positive health effects. The transcription regulators of O-methylated catechin biosynthesis remain elusive. In this study, the expression pattern of genes related to O-methylated catechin biosynthesis, including CsLAR, CsANS, CsDFR, CsANR, and CCoAOMT, in three tea cultivars with different contents of EGCG3″Me was investigated. Two WRKY transcription factors (TFs), designated as CsWRKY31 and CsWRKY48, belonging to groups IIb and IIc of the WRKY family, respectively, were further identified. CsWRKY31 and CsWRKY48 were nuclear-localized proteins and possessed transcriptional repression ability. Furthermore, expression of CsWRKY31 and CsWRKY48 showed negative correlation with CsLAR, CsDFR, and CCoAOMT during EGCG3″Me accumulation in tea leaves. More importantly, W-box (C/ T)TGAC(T/C) elements were located in the promoter of CsLAR, CsDFR, and CCoAOMT, and further assays revealed that CsWRKY31 and CsWRKY48 were capable of repressing the transcription of CsLAR, CsDFR, and CCoAOMT via the attachment of their promoters to the W-box elements. Collectively, our findings identify two novel negative regulators of O-methylated catechin biosynthesis in tea plants, which might provide a potential strategy to breed high-quality tea cultivar.

SCM-198 is an alkaloid found only in Herba leonuri and it has been reported to possess considerable neuroprotective effects in animal models of ischemic stroke, Parkinson’s disease and Alzheimer’s disease (AD). In this study, we demonstrated for the first time that 3-month oral SCM-198 treatment could significantly improve both recognition and spatial memory, inhibit microgliosis and promote neuronal survival in amyloid-β protein precursor and presenilin-1(AβPP/PS1) double-transgenic mice without affecting amyloid-β (Aβ) burden. In addition, decreases in cAMP-response element-binding protein (CREB) phosphorylation, brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) phosphorylation were attenuated by SCM-198 both in vivo and in primary cortical neurons, which could be blocked by protein kinase A (PKA) inhibitors, suggesting the involvement of upstream PKA in enhancing the BDNF/TrkB/CREB signaling by SCM-198. Our results indicate that SCM-198, a drug that could promote neuronal survival and enhance BDNF/TrkB/CREB signaling, has beneficial effects on behavioral and biochemical alterations without affecting Aβ burden in AβPP/PS1 mice and might become a potential drug candidate for AD treatment in the future.

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Parainfluenza virus infection is a common respiratory illness in children. Although lncRNAs are novel regulators of virus-induced innate immunity, a systemic attempt to characterize the differential expression of lncRNAs upon parainfluenza virus infection is lacking. In this report, we identify 207 lncRNAs and 166 mRNAs differentially expressed in SeV-infected HEK293T cells by microarray. The functional annotation analysis reveals that differentially regulated transcripts are predominantly involved in the host antiviral response pathway. The lncRNAs with the potential to regulate SeV-induced antiviral response are identified by building the lncRNA-mRNA coexpression network. Furthermore, silencing lncRNA ENST00000565297 results in reduced type I IFN signaling upon SeV infection. These catalogs may facilitate future analysis of the functions of lncRNAs in innate immunity and related diseases.

The thalamus and central dopamine signaling have been shown to play important roles in high-level cognitive processes including impulsivity. However, little is known about the role of dopamine receptors in the thalamus in decisional impulsivity. In the present study, rats were tested using a delay discounting task and divided into three groups: high impulsivity (HI), medium impulsivity (MI), and low impulsivity (LI). Subsequent in vivo voxel-based magnetic resonance imaging revealed that the HI rats displayed a markedly reduced density of gray matter in the lateral thalamus compared with the LI rats. In the MI rats, the dopamine D1 receptor antagonist SCH23390 or the D2 receptor antagonist eticlopride was microinjected into the lateral thalamus. SCH23390 significantly decreased their choice of a large, delayed reward and increased their omission of lever presses. In contrast, eticlopride increased the choice of a large, delayed reward but had no effect on the omissions. Together, our results indicate that the lateral thalamus is involved in decisional impulsivity, and dopamine D1 and D2 receptors in the lateral thalamus have distinct effects on decisional impulsive behaviors in rats. These results provide a new insight into the dopamine signaling in the lateral thalamus in decisional impulsivity.

Non-coding RNAs represent a class of important regulators in immune response. Previously, LINC02605 was identified as a candidate regulator in innate immune response by lncRNA microarray assays. In this study, we systematically analyzed the functions and the acting mechanisms of LINC02605 in antiviral innate immune response. LINC02605 was up-regulated by RNA virus, DNA virus, and type I IFNs in NF-κB and Jak-stat dependent manner. Overexpression of LINC02605 promotes RNA virus-induced type I interferon production and inhibited viral replication. Consistently, knockdown of LINC02605 resulted in reduced antiviral immune response and increased viral replication. Mechanistically, LINC02605 released the inhibition of hsa-miR-107 on the expression of phosphatase and tensin homolog (PTEN). By microRNA mimics and inhibitors, hsa-miR-107 was demonstrated to not only inhibit PTEN’s expression but also negatively regulate the antiviral immune response. Knockdown of LINC02605 led to the reduction of PTEN expression both in mRNA and protein levels. Overexpression of LINC02605 had an opposite impact. Moreover, LINC02605 attenuated the serine 97 phosphorylation level of interferon regulatory factor 3 (IRF3) by promoting PTEN expression. Nucleoplasmic fragmentation assay showed that knocking down LINC02605 inhibited the nuclear translocation of IRF3, rendering the host cells more susceptible to viral invasion, while overexpression showed opposite effects. Therefore, LINC02605 is an induced lncRNA by viral infection and plays a positive feedback in antiviral immune response through modulating the nuclear translocation of IRF3.

Human UBL4A/GdX, encoding an ubiquitin-like protein, was shown in this study to be upregulated by viral infection and IFN stimulation. Then the functions of UBL4A in antiviral immune response were characterized. Overexpression of UBL4A promoted RNA virus-induced ISRE or IFN-b or NF-kB activation, leading to enhanced type I IFN transcription and reduced virus replication. Consistently, knockdown of UBL4A resulted in reduced type I IFN transcription and enhanced virus replication. Additionally, overexpression of UBL4A promoted virus-induced phosphorylation of TBK1, IRF3, and IKKa/b. Knockdown of UBL4A inhibited virus-induced phosphorylation of TBK1, IRF3, and IKKa/b. Coimmunoprecipitation showed that UBL4A interacted with TRAF6, and this interaction was enhanced upon viral infection. Ubiquitination assays showed that UBL4A promoted the K63-linked ubiquitination of TRAF6. Therefore, we reveal a novel positive feedback regulation of UBL4A in innate immune response combating virus invasion by enhancing the K63-linked ubiquitination of TRAF6.