SENP1-mediated NEMO de-SUMOylation inhibits intermittent hypoxia induced inflammatory response of microglia in vitro

Among the seven small ubiquitin-like modifier (SUMO)-specific proteases (SENPs), our previous work showed that SENP1 suppressed nuclear factor kappa B (NF-κB) activation and alleviates the inflammatory response in microglia. However, the mechanism is still largely unknown. In this study, western blot analysis and enzyme-linked immunosorbent assay were utilized for evaluating the extent of NF-κB activation and expression of proinflammatory cytokines. qPCR and western blot analysis were performed to detect SENP1 expression. Coimmunoprecipitation followed by western blot analysis was applied to measure the changes in SUMOylation of NF-κB essential modulator (NEMO) and P65 in microglia with or without overexpression of SENP1. As the results, we found that intermittent hypoxia (IH) triggered the activation of NF-κB and upregulated the expression levels of tumor necrosis factor-α and interleukin-6. Interestingly, our data indicated that the SUMOylation of NEMO was enhanced by IH while SUMOylation of P65 was not affected. Further, our data showed that overexpression of SENP1 could decrease the extent of NF-κB activation and inhibit the inflammatory response of microglia through regulating the SUMOylation of NEMO. Collectively, this study presents the first report of the SENP1-controlled de-SUMOylation process of NEMO and its critical role in regulating NF-κB activation and proinflammatory cytokines secretion in microglia cells. This study would benefit for clarifying the role of SENP1 in IH-induced activation of microglia, thus providing potential therapeutic targets for obstructive sleep apnea treatment.     

Novel orally active morpholine N-arylsulfonamides γ-secretase inhibitors with low CYP 3A4 liability

A new class of 2,6-disubstituted morpholine N-arylsulfonamide γ-secretase inhibitors was designed based on the introduction of a morpholine core in lieu or piperidine in our lead series. This resulted in compounds with improved CYP 3A4 profiles. Several analogs that were active at lowering Aβ levels in Tg CRND8 mice upon oral administration were identified.     

NOD1 modulates decidual stromal cell function to maintain pregnancy in the early trimester

We sought to explore the functions and modulated factors of NOD1 in normal decidual stromal cells (DSCs) derived from the first trimester pregnancy and whether existed different expression of NOD1 between normal and unexplained recurrent pregnancy loss (URPL) in DSCs. Twenty‐six patients with normal pregnancies that required abortion and 12 URPL patients at first trimester were enrolled for the study. As a result, we found lower levels of NOD1 in the DSCs derived from URPL compared with those from normal early trimester pregnancy. Furthermore, increased NOD1 expression in the normal DSCs induced apoptosis and increased monocyte chemotactic protein‐1 (MCP‐1) and IL‐1β (interleukin 1 beta) secretion but decreased their invasion capacity. In addition, several cytokines such as IL‐1β, tumour necrosis factor‐alpha (TNF‐α), interferon‐gamma (IFN‐γ), and interleukin‐17 (IL‐17) were present at the maternal‐fetal interface in RPL and were found to regulate NOD1 expression in primary DSCs. Our study indicates that RPL may be associated with NOD1 aberrant expression in DSCs, which plays a significant role in maintaining pregnancy via infection control and regulation of immune responses that might affect the pregnancy outcome. We expect that our results will bring more comprehensively understanding about the connection between NOD1 and RPL for researchers.     

Synthesis of L-Sangivamycin and Toyocamycin Analogues and Their Inhibitory Activities of SER/THR Protein Kinases

Abstract

Novel _l-sangivamycin and toyocamycin analogues were synthesized and evaluated for Cdc2 protein kinase activity. Among the compounds tested, _l-xylose derivative and _l-arabinose derivative exhibited potent inhibitory activity against Cdc2 protein kinase with IC₅₀ values of 3.7 and 1.6 μM, respectively.     

Ecology of Hantaan virus at Twin Bridges Training Area,Gyeonggi Province,Republic of Korea, 2005–2007

The Twin Bridges Training Area (TBTA) in the Republic of Korea consists of dirt roads, barren training areas, and forested hillsides adjacent to linear and broad expanses of tall grasses, herbaceous, and scrub vegetation. Of the six species of small mammals, the striped field mouse, Apodemus agrarius, was the most frequently captured (96.1%). Apodemus agrarius capture rates varied from 17.7 to 33.2% during three trapping periods. Gravid females were observed during November‐December 2006 (8.4%) and March 2007 (5.1%). In 2005, the overall seroprevalence of Hantaan virus (HTNV) was high (34.4%) and lower during surveys in 2006 (14.2%) and 2007 (13.8%). Seroprevalence was directly correlated with weight increase of A. agrarius.     

Computational Analysis of Functional Single Nucleotide Polymorphisms Associated with the CYP11B2 Gene

Single nucleotide polymorphisms (SNPs) are the most common type of genetic variations in humans and play a major role in the genetics of human phenotype variation and the genetic basis of human complex diseases. Recently, there is considerable interest in understanding the possible role of the CYP11B2 gene with corticosterone methyl oxidase deficiency, primary aldosteronism, and cardio-cerebro-vascular diseases. Hence, the elucidation of the function and molecular dynamic behavior of CYP11B2 mutations is crucial in current genomics. In this study, we investigated the pathogenic effect of 51 nsSNPs and 26 UTR SNPs in the CYP11B2 gene through computational platforms. Using a combination of SIFT, PolyPhen, I-Mutant Suite, and ConSurf server, four nsSNPs (F487V, V129M, T498A, and V403E) were identified to potentially affect the structure, function, and activity of the CYP11B2 protein. Furthermore, molecular dynamics simulation and structure analyses also confirmed the impact of these nsSNPs on the stability and secondary properties of the CYP11B2 protein. Additionally, utilizing the UTRscan, MirSNP, PolymiRTS and miRNASNP, three SNPs in the 3′UTR region were predicted to exhibit a pattern change in the upstream open reading frames (uORF), and eight microRNA binding sites were found to be highly affected due to 3′UTR SNPs. This cataloguing of deleterious SNPs is essential for narrowing down the number of CYP11B2 mutations to be screened in genetic association studies and for a better understanding of the functional and structural aspects of the CYP11B2 protein.     

MicroRNA-206 has a bright application prospect in the diagnosis of cases with oral cancer

Previous studies have shown that microRNA-206 (miR-206) exhibits anti-tumour properties in various tumours. Nevertheless, diagnostic significance of miR-206 in oral cancer is still poorly known. Our research was carried out to explore the performance of miR-206 in the diagnosis of oral cancer. Quantitative real-time polymerase chain reaction (qRT-PCR) method was adopted to measure the level of miR-206 in serum specimens from oral cancer cases and control individuals. Chi-square test was performed to analyse the correlation between miR-206 level and clinicopathological parameters of the cases. Receiver operating characteristic (ROC) curve was constituted to assess diagnostic accuracy of miR-206 in oral cancer. Serum miR-206 level in oral cancer patients was significantly lower than that in control individuals (P < .001). miR-206 expression was obviously related to T classification (P = .033), TNM stage (P = .008) and lymph node metastasis (P = .028). The area under the curve (AUC) of the ROC curve was 0.846 (95% CI = 0.797-0.896, P < .001) with a specificity of 72.7% and a sensitivity of 81.2%. It revealed that miR-206 might be a non-invasive indicator in differentiating oral cancer cases from control individuals. Down-regulation of miR-206 is related to the development of oral cancer. Serum miR-206 might be an effective indicator for early detection of oral cancer.     

A Preliminary Molecular Phylogeny of Planthoppers (Hemiptera: Fulgoroidea) Based on Nuclear and Mitochondrial DNA Sequences

The planthopper superfamily Fulgoroidea (Insecta: Hemiptera) is one of the most dominant groups of phytophagous insects. It comprises about 20 families, containing a total of 9000 species worldwide. Despite several recent studies, the phylogeny of Fulgoroidea is not yet satisfactorily resolved and the phylogenetic positions of several key families, especially Cixiidae, Delphacidae, Tettigometridae, Nogodinidae, Acanaloniidae and Issidae, are contentious. Here, we expand upon recent phylogenetic work using additional nuclear (18S and 28S) and novel mitochondrial (16S and cytb) markers. Maximum likelihood and Bayesian analyses yielded robust phylogenetic trees. In these topologies, a group containing Cixiidae and Delphacidae is recovered as the sister group to the remaining taxa. Tettigometridae is placed in a more nested position and is grouped with Caliscelidae. Sister relationships are found between Flatidae and Ricaniidae, and between Dictyopharidae and Fulgoridae. Nogodinidae and Issidae are confirmed to be non-monophyletic families. For major nodes of interest, divergence date estimates are generally older than those from the fossil record.