Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice. We first reported an S140G mutation of KCNQ1, an alpha subunit of potassium channels, in one Chinese kindred with AF. However, the molecular defects and cellular mechanisms in most patients with AF remain to be identified. We evaluated 28 unrelated Chinese kindreds with AF and sequenced eight genes of potassium channels (KCNQ1, HERG, KCNE1, KCNE2, KCNE3, KCNE4, KCNE5, and KCNJ2). An arginine-to-cysteine mutation at position 27 (R27C) of KCNE2, the beta subunit of the KCNQ1-KCNE2 channel responsible for a background potassium current, was found in 2 of the 28 probands. The mutation was present in all affected members in the two kindreds and was absent in 462 healthy unrelated Chinese subjects. Similar to KCNQ1 S140G, the mutation had a gain-of-function effect on the KCNQ1-KCNE2 channel; unlike long QT syndrome-associated KCNE2 mutations, it did not alter HERG-KCNE2 current. The mutation did not alter the functions of the HCN channel family either. Thus, KCNE2 R27C is a gain-of-function mutation associated with the initiation and/or maintenance of AF.

Recent data have redefined the concept of inflammation as a critical component of tumor progression. However, there has been little development on cases where inflammation on or near a wound and a tumor exist simultaneously. Therefore, this pilot study aims to observe the impact of a wound on a tumor, to build a new mouse tumor model with a manufactured surgical wound representing acute inflammation, and to evaluate the relationship between acute inflammation or wound healing and the process of tumor growth. We focus on the two phases that are present when acute inflammation influences tumor. In the early phase, inhibitory effects are present. The process that produces these effects is the functional reaction of IFN-gamma secretions from a wound inflammation. In the latter phase, the inhibited tumor is made resistant to IFN-gamma through the release of TGF-beta to balance the inflammatory factor effect on the tumor cells. A pair of cytokines IFN-gamma/TGF-beta established a new balance to protect the tumor from the interference effect of the inflammation. The tumor was made resistant to IFN-gamma through the release of TGF-beta to balance the inflammatory effect on the tumor cells. This balance mechanism that occurred in the tumor cells increased proliferation and invasion. In vitro and in vivo experiments have confirmed a new view of clinical surgery that will provide more detailed information on the evaluation of tumors after surgery. This study also provides a better understanding of the relationship between tumor and inflammation, as well as tumor cell attacks on inflammatory factors.

Periodontitis is one of the most widespread infectious diseases in humans. It is the main cause of tooth loss and associated with a number of systemic diseases. Until now, there is no appropriate method for functional periodontal tissue regeneration. Here, we establish a novel approach of using allogeneic periodontal ligament stem cells (PDLSCs) sheet to curing periodontitis in a miniature pig periodontitis model. Significant periodontal tissue regeneration was achieved in both the autologous and the allogeneic PDLSCs transplantation group at 12 weeks post-PDLSCs transplantation. Based on clinical assessments, computed tomography (CT) scanning, and histological examination, there was no marked difference between the autologous and allogeneic PDLSCs transplantation groups. In addition, lack of immunological rejections in the animals that received the allogeneic PDLSCs transplantation was observed. Interestingly, we found that human PDLSCs fail to express human leukocyte antigen (HLA)-II DR and costimulatory molecules. PDLSCs were not able to elicit T-cell proliferation and inhibit T-cell proliferation when stimulated with mismatched major histocompatibility complex molecules. Furthermore, we found that prostaglandin E2 (PGE2) plays a crucial role in PDLSCs-mediated immunomodulation and periodontal tissue regeneration in vitro and in vivo. Our study demonstrated that PDLSCs possess low immunogenicity and marked immunosuppression via PGE2-induced T-cell anergy. We developed a standard technological procedure of using allogeneic PDLSCs to cure periodontitis in swine.

Stem cells from human exfoliated deciduous teeth (SHED) have been identified as a population of postnatal stem cells capable of differentiating into osteogenic and odontogenic cells, adipogenic cells, and neural cells. Herein we have characterized mesenchymal stem cell properties of SHED in comparison to human bone marrow mesenchymal stem cells (BMMSCs).

Recent genome-wide association studies (GWAS) revealed that a 9p21.3 locus was associated with type 2 diabetes. In this study, we carried out a large-scale case-control study in the GeneID Chinese Han population to 1) further replicate the association of 9p21.3 type 2 diabetes GWAS single nucleotide polymorphisms (SNPs) and 2) assess the association of these SNPs with coronary artery disease.

No abstract available

Chinese thuja (Platycladus orientalis) has a wide but fragmented distribution in China. It is an important conifer tree in reforestation and plays important roles in ecological restoration in the arid mountains of northern China. Based on high-resolution environmental data for current and future scenarios, we modeled the present and future suitable habitat for P. orientalis, evaluated the importance of environmental factors in shaping the species' distribution, and identified regions of high risk under climate change scenarios. The niche models showed that P. orientalis has suitable habitat of ca. 4.2×106 km2 across most of eastern China and identified annual temperature, monthly minimum and maximum ultraviolet-B radiation and wet-day frequency as the critical factors shaping habitat availability for P. orientalis. Under the low concentration greenhouse gas emissions scenario, the range of the species may increase as global warming intensifies; however, under the higher concentrations of emissions scenario, we predicted a slight expansion followed by contraction in distribution. Overall, the range shift to higher latitudes and elevations would become gradually more significant. The information gained from this study should be an useful reference for implementing long-term conservation and management strategies for the species.

Recent reports showed that functional control of HIV-1 infection for a prolonged time is possible by early antiretroviral therapy (ART); however, its underlying mechanism needs to be studied with a suitable animal model. Recently, humanized-BLT (bone marrow, liver, and thymus) mouse (hu-BLT) was shown to be an excellent model for studying HIV-1 infection. We thus tested the feasibility of studying functional control of HIV-1 infection using hu-BLT mice.

HIV-1 depletes CD4+ T cells in the blood, lymphatic tissues, gut and lungs. Here we investigated the relationship between depletion and infection of CD4+ T cells in the lung parenchyma. The lungs of 38 Indian rhesus macaques in early to later stages of SIVmac251 infection were examined, and the numbers of CD4+ T cells and macrophages plus the frequency of SIV RNA+ cells were quantified. We showed that SIV infected macrophages in the lung parenchyma, but only in small numbers except in the setting of interstitial inflammation where large numbers of SIV RNA+ macrophages were detected. However, even in this setting, the number of macrophages was not decreased. By contrast, there were few infected CD4+ T cells in lung parenchyma, but CD4+ T cells were nonetheless depleted by unknown mechanisms. The CD4+ T cells in lung parenchyma were depleted even though they were not productively infected, whereas SIV can infect large numbers of macrophages in the setting of interstitial inflammation without depleting them. These observations point to the need for future investigations into mechanisms of CD4+ T cell depletion at this mucosal site, and into mechanisms by which macrophage populations are maintained despite high levels of infection. The large numbers of SIV RNA+ macrophages in lungs in the setting of interstitial inflammation indicates that lung macrophages can be an important source for SIV persistent infection.

The dried roots of Scutellaria baicalensis Georgi, is known in traditional Chinese medicine as Huang Qin (H. qin), and it has been officially and traditionally used in treatment of various diseases such as hepatitis in China. Baicalein (BA), a flavonoid originally isolated from H. qin, has shown a wide range of biological activities. This study was to evaluate whether baicalein, can reduce the intestinal mucosal cell apoptosis caused by cirrhotic endotoxemia and its possible mechanisms.

The voltage-gated Na(+) channel Nav 1.5 is essential for action potential (AP) formation and electrophysiological homoeostasis in the heart. The ubiquitin-proteasome system (UPS) is a major degradative system for intracellular proteins including ion channels. The ubiquitin protein ligase E3 component N-recognin (UBR) family is a part of the UPS; however, their roles in regulating cardiac Nav 1.5 channels remain elusive. Here, we found that all of the UBR members were expressed in cardiomyocytes. Individual knockdown of UBR3 or UBR6, but not of other UBR members, significantly increased Nav 1.5 protein levels in neonatal rat ventricular myocytes, and this effect was verified in HEK293T cells expressing Nav 1.5 channels. The UBR3/6-dependent regulation of Nav 1.5 channels was not transcriptionally mediated, and pharmacological inhibition of protein biosynthesis failed to counteract the increase in Nav 1.5 protein caused by UBR3/6 reduction, suggesting a degradative modulation of UBR3/6 on Nav 1.5. Furthermore, the effects of UBR3/6 knockdown on Nav 1.5 proteins were abolished under the inhibition of proteasome activity, and UBR3/6 knockdown reduced Nav 1.5 ubiquitylation. The double UBR3-UBR6 knockdown resulted in comparable increases in Nav 1.5 proteins to that observed for single knockdown of either UBR3 or UBR6. Electrophysiological recordings showed that UBR3/6 reduction-mediated increase in Nav 1.5 protein enhanced the opening of Nav 1.5 channels and thereby the amplitude of the AP. Thus, our findings indicate that UBR3/6 regulate cardiomyocyte Nav 1.5 channel protein levels via the ubiquitin-proteasome pathway. It is likely that UBR3/6 have the potential to be a therapeutic target for cardiac arrhythmias.

Microsatellite markers were developed in Veratrum maackii (Melanthiaceae) to assess the pattern of population genetic structures across the species' distribution.

Solid dispersions are a useful approach to improve the dissolution rate and bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). The aim of this study was to improve the physicochemical properties and bioavailability of a poorly water-soluble aprepitant by preparation of solid dispersions. The solid dispersions were characterized by dissolution, FTIR, XRPD, DSC, SEM and pharmacokinetic studies in rats. The dissolution rate of the aprepitant was significantly increased by solid dispersions, and XRD, DSC, and SEM analysis indicated that the aprepitant existed in an amorphous form within the solid dispersions. The result of dissolution study showed that the dissolution rate of SDs was nearly five-fold faster than aprepitant. FTIR spectrometry suggested the presence of intermolecular hydrogen bonds between the aprepitant and polymer. Pharmacokinetic studies in rats indicated that the degree drug absorption was comparable with that of Emend®. Aprepitant exists in an amorphous state in solid dispersions and the solid dispersions can markedly improve the dissolution and oral bioavailability of the aprepitant. The AUC0-t of the SDs was 2.4-fold that of the aprepitant. In addition, the method and its associated techniques are very easy to carry out.

MicroRNAs (miRNAs) are a class of small non-coding RNAs, whose expression levels vary in different cell types and tissues. Emerging evidence indicates that tissue-specific and -enriched miRNAs are closely associated with cellular development and stress responses in their tissues. MiR-25 has been documented to be abundant in cardiomyocytes, but its function in the heart remains unknown. Here, we report that miR-25 can protect cardiomyocytes against oxidative damage by down-regulating mitochondrial calcium uniporter (MCU). MiR-25 was markedly elevated in response to oxidative stimulation in cardiomyocytes. Further overexpression of miR-25 protected cardiomyocytes against oxidative damage by inactivating the mitochondrial apoptosis pathway. MCU was identified as a potential target of miR-25 by bioinformatical analysis. MCU mRNA level was reversely correlated with miR-25 under the exposure of H2O2, and MCU protein level was largely decreased by miR-25 overexpression. The luciferase reporter assay confirmed that miR-25 bound directly to the 3' untranslated region (UTR) of MCU mRNA. MiR-25 significantly decreased H2O2-induced elevation of mitochondrial Ca2+ concentration, which is likely to be the result of decreased activity of MCU. We conclude that miR-25 targets MCU to protect cardiomyocytes against oxidative damages. This finding provides novel insights into the involvement of miRNAs in oxidative stress in cardiomyocytes.

Brain-derived neurotrophic factor (BDNF) is associated with coronary artery diseases. However, its role and mechanism in myocardial infarction (MI) is not fully understood.

In this study, the complete mitochondrial genome of Macropodus opercularis was sequenced using Illumina-based de novo transcriptome technology and annotated using bioinformatic tools. The circular mitochondrial genome was 16,496bp in length and contained two ribosomal RNAs, 13 protein-coding genes, 22 transfer RNA genes, and the control region. The gene composition and order were similar to suborder Anabantoidei. Phylogenetic analyses using concatenated amino acid and nucleotide sequences of the 13 protein-coding genes with two different methods (Neighbor-joining and Bayesian analysis) both highly supported the close relationship of M. opercularis to M. ocellatus, consistent with previous classifications based on morphological and molecular studies. Furthermore, family Channidae and Parachanna insignis were clustered in the same clade. Our results supported the inclusion of family Channidae in suborder Channoidei. The complete mitochondrial genome of M. opercularis will provide genetic markers for better understanding species identification, population genetics and phylogeographics of freshwater fishes.

Dried stem bark from Albizia julibrissin (AJ) is a highly valued Traditional Chinese Medicine, which has been shown to suppress tumor growth and angiogenesis. Total saponins from AJ (TSAJ) are one of the most bioactive components of AJ extract. The present study evaluated the anti‑tumor and anti‑angiogenic effects of TSAJ in vitro and in vivo. The anti‑angiogenic activity of TSAJ was investigated by measuring the effects on vascular endothelial growth factor (VEGF)‑induced proliferation, migration and tube formation of Ea.hy926 endothelial cells in vitro. The expression levels of proteins associated with VEGF‑induced angiogenesis were determined by western blotting. Furthermore, in vivo Matrigel™ plug and H22 hepatoma tumor models were used to verify the anti‑angiogenic effects of TSAJ. The present study demonstrated that TSAJ significantly inhibited VEGF‑mediated endothelial cell proliferation, migration and tube formation of Ea.hy926 cells in vitro. The anti‑angiogenic effects of TSAJ were modulated by suppression of phosphorylated‑(p‑) focal adhesion kinase, p‑Akt, and p‑extracellular signal‑regulated kinase in the VEGF/VEGF receptor 2 (R2) signaling pathway. Furthermore, oral administration of TSAJ significantly inhibited tumor growth and tumor‑induced angiogenesis, as well as the formation of functional vessels, in the Matrigel™ plug model. These results suggest that TSAJ may be a potential anti‑angiogenic agent that targets the VEGF/VEGFR2 signaling pathway, and inhibits tumor‑induced angiogenesis.

Activated hepatic stellate cells are the main source of excessive collagen deposition in liver fibrosis. Here we report the inhibitory effects of the combinational treatment of two natural products, astragalus polysaccharide (APS) and β-elemene (ELE) on the activation of human liver hepatic stellate cell line LX-2 cells.

Phosphatase of regenerating liver-3 (PRL-3) is believed to be associated with cell motility, invasion, and metastasis. Our previous work found that PRL-3 is highly overexpressed in gastric cancer (GC) tissue with peritoneal metastasis and directly involved in the pathogenesis of GC peritoneal metastasis. Moreover, we further found that the down-regulation of endogenous miR-495 expression plays a causative role in over expression of PRL-3 in GC peritoneal metastasis. However, the molecular regulation mechanisms by which endogenous miR-495 expression is down-regulated and PRL-3 promotes GC peritoneal metastasis remain to be clearly elucidated. Some studies have shown that the promoter methylation is closely related to the miRNA gene expression. Therefore, in present study, based on our previous findings, we will analysis whether DNA methylation is a major cause of the down-expression of endogenous miR-495, which results in PRL-3 overexpression in GC peritoneal metastasis. Methylation specific PCR (MSP) and sodium bisulfite sequencing method (BSP) detected miR-495 gene promoter methylation status. We treated GC cell lines with 5-Aza-2'-deoxycytidine (5-Aza-dC) to make the gene promoter methylation inactivation. By treating with 5-Aza-dC the migration and invasion of GC cells were significantly inhibited. And the miR-495 was overexpressing, corresponds to the mRNA and protein levels of PRL-3 were reduced, the ability of invasion and metastasis was inhibited. This study suggest that miR-495 have tumor suppressor properties and are partially silenced by DNA hypermethylation in GC, will provide new strategies for prevention and treatment of GC peritoneal metastasis.

Although pterostilbene (PTE) has been shown to have potent antitumor activities against various cancer types, the molecular mechanisms of these activities remain unclear. In this study, we investigated the antitumor activity of PTE against human lung adenocarcinoma in vitro and in vivo and explored the role of the Notch1 signaling pathway in this process. PTE treatment resulted in a dose- and time-dependent decrease in the viability of A549 cells. Additionally, PTE exhibited strong antitumor activity, as evidenced not only by a reduced mitochondrial membrane potential (MMP) and a decreased intracellular glutathione content but also by increases in the apoptotic index and the level of reactive oxygen species (ROS). Furthermore, PTE treatment induced the activation of the Notch1 Intracellular Domain (NICD) protein and activated Hes1. DAPT (a gamma secretase inhibitor) and Notch1 siRNA prevented the induction of NICD and Hes1 activation by PTE treatment and sensitized the cells to PTE treatment. The down-regulation of Notch signaling also prevented the activation of pro-survival pathways (most notably the PI3K/Akt pathway) after PTE treatment. In summary, lung adenocarcinoma cells may enhance Notch1 activation as a protective mechanism in response to PTE treatment. Combining a gamma secretase inhibitor with PTE treatment may represent a novel approach for treating lung adenocarcinoma by inhibiting the survival pathways of cancer cells.