RhoE promotes metastasis in gastric cancer through a mechanism dependent on enhanced expression of CXCR4.

RhoE, a novel member of the Rho protein family, is a key regulator of the cytoskeleton and cell migration. Our group has previously shown that RhoE as a direct target for HIF-1α and mediates hypoxia-induced epithelial to mesenchymal transition in gastric cancer cells. Therefore, we assumed that RhoE might play an important role in gastric cancer metastasis. In the present study, we have explored the role of RhoE expression in gastric cancer, cell invasion and metastasis, and the influence of RhoE on regulating the potential expression of down-stream genes. RhoE expression was elevated in gastric cancer tissues as compared with normal gastric tissues. We also found a close correlation between the histological grade and the diagnosis of the patient. Up-regulation of RhoE significantly enhanced the migratory and invasive abilities of gastric cancer cells both in vitro and in vivo. Moreover, down-regulation of RhoE diminished the metastatic potential of cancer cells. PCR array and subsequent transwell assay showed that the regulation of gastric cancer metastasis by RhoE was partially mediated by CXCR4. This observation suggested that CXCR4 might be a downstream effector for RhoE. In summary, our study identified RhoE as a novel prognostic biomarker and metastatic-promoting gene of gastric cancer

Bioinspired Peptide for Imaging Hg²⁺ Distribution in Living Cells and Zebrafish Based on Coordination-Mediated Supramolecular Assembling

Peptides with modular structure provide a tailorable platform for constructing responsive supramolecular assemblies, which are attractive as functional biomaterials and smart sensors. In this work, the feasibility of regulating small peptides assembly with molecular design and metal ion recognition was demonstrated. Tripeptides were designed and found to have diverse response and self-assembly behavior to Hg²⁺. The incorporation of an aggregation-induced emission fluorophore TPE enabled the visualization of Hg²⁺ recognition and the assembly phenomenon. A structural analogue (Pep<b>2</b>) to γ-glutathione was identified with high specificity and nanomolar response to Hg²⁺ both in buffer solution and living cells. Driven by the coordination force and noncovalent intramolecular stacking, assembling of twisted nanofibers from Pep<b>2</b>-TPE and Hg²⁺ were observed. Benefiting from its biocompatibility, fast and switchable fluorescence response, Pep<b>2</b>-TPE was applied for imaging and monitoring Hg²⁺ distribution in living cells and zebrafish. With good permeability to plasma membrane and tissues, Pep<b>2</b>-TPE indicated the preferential distribution of Hg²⁺ in cell nucleoli and brain of zebrafish, which is related with the deleterious effect of inorganic mercury in living biosystems

Spatiotemporal Trends of Heavy Metals in Indo-Pacific Humpback Dolphins (<i>Sousa chinensis</i>) from the Western Pearl River Estuary, China

We assessed the spatiotemporal trends of the concentrations of 11 heavy metals (HMs) in the liver and kidney of Indo-Pacific humpback dolphins (<i>Sousa chinensis</i>) from western Pearl River Estuary (PRE) during 2004–2015. The hepatic levels of Cr, As, and Cu in these dolphins were among the highest reported for cetaceans globally, and the levels of Zn, Cu, and Hg were sufficiently high to cause toxicological effects in some of the animals. Between same age-sex groups, dolphins from Lingdingyang were significantly more contaminated with Hg, Se, and V than those from the West-four region, while the opposite was true for Cd. Generalized additive mixed models showed that most metals had significant but dissimilar temporal trends over a 10-year period. The concentrations of Cu and Zn increased significantly in recent years, corresponding to the high input of these metals in the region. Body-length-adjusted Cd levels peaked in 2012, accompanied by the highest annual number of dolphin stranding events. In contrast to the significant decrease in HM levels in the dolphins in Hong Kong waters (the eastern reaches of the PRE), the elevated metal exposure in the western PRE raises serious concerns

Fluorescence Turn-On Chemosensor for Highly Selective and Sensitive Detection and Bioimaging of Al³⁺ in Living Cells Based on Ion-Induced Aggregation

Herein, a new fluorescence turn-on chemosensor 2-(4-(1,2,2-triphenylvinyl)­phenoxy)­acetic acid (TPE-COOH) specific for Al³⁺ was presented by combining the aggregation-induced-emission (AIE) effect of tertaphenylethylene and the complexation capability of carboxyl. The introduction of carboxylic group provides the probe with good water-solubility which is important for analyzing biological samples. The recognition toward Al³⁺ induced the molecular aggregation and activated the blue fluorescence of the TPE core. The high selectivity of the probe was demonstrated by discriminating Al³⁺ over a variety of metal ions in a complex mixture. A detection limit down to 21.6 nM was determined for Al³⁺ quantitation. Furthermore, benefiting from its good water solubility and biocompatibility, imaging detection and real-time monitoring of Al³⁺ in living HeLa cells were successfully achieved. The AIE effect of the probe enables high signal-to-noise ratio for bioimaging even without multiple washing steps. These superiorities make this probe a great potential for the functional study and analysis of Al³⁺ in complex biosystems

Prediction and evaluation of high-risk patients with primary biliary cholangitis receiving ursodeoxycholic acid therapy: an early criterion

Background and aimsCurrent treatment guidelines recommend ursodeoxycholic acid (UDCA) as the first-line treatment for new-diagnosed primary biliary cholangitis (PBC) patients. However, up to 40% patients are insensitive to UDCA monotherapy, and evaluation of UDCA response at 12&nbsp;months may result in long period of ineffective treatment. We aimed to develop a new criterion to reliably identify non-response patients much earlier.MethodsFive hundred sixty-nine patients with an average of 59&nbsp;months (Median: 53; IQR:32-79) follow-up periods were randomly divided into either the training (70%) or the validation cohort (30%). The efficiency of different combinations of total bilirubin (TBIL), alkaline phosphatase (ALP), and aspartate aminotransferase (AST) threshold values to predict outcomes was assessed at 1, 3 or 6&nbsp;month after the initiation of UDCA therapy. The endpoints were defined as adverse outcomes, including liver-related death, liver transplantation and complications of cirrhosis. Adverse outcome-free survival was compared using various published criteria and a proposed new criterion.ResultsA new criterion of evaluating UDCA responses at 1&nbsp;month was established as: ALP ≤ 2.5 × upper limit of normal (ULN) and AST ≤ 2 × ULN, and TBIL ≤ 1 × ULN (Xi'an criterion). The 5&nbsp;year adverse outcome-free survival rate of UDCA responders, defined by Xi'an criterion, was 97%, which was significantly higher than that of those non-responders (64%). An accurate distinguishing high-risk patients' capacity of Xi'an criterion was confirmed in both early and late-stage PBC.ConclusionsXi'an criterion has a similar or even higher ability to distinguish high-risk PBC patients than other published criteria. Xi'an criterion can facilitate early identification of patients requiring new therapeutic approaches

Expression of RhoE in gastric cancer tissues and cells, and its association with patient survival.

<p>(<b>A</b>), Immunohistochemical analysis of RhoE in tissues; (<b>a</b>), normal gastric epithelium; and (<b>b</b>) well-differentiated, (<b>c</b>) moderately differentiated or (<b>d</b>) poorly-differentiated gastric cancer tissue; (<b>e</b>) metastatic site in the lymph node. Brown coloration represents positive RhoE staining. (<b>B</b>), Kaplan- Meier post-operative survival curve as a function of RhoE expression. (<b>C</b>), Western blot analysis of RhoE expression in different gastric cell-lines. β-actin was used as the internal control. The relative expression levels of RhoE in gastric cancer cell-lines were presented as bar charts. * P <0.05.</p

RhoE promotes the migratory and invasive abilities of gastric cancer cells <i>in</i><i>vitro</i>.

<p>(<b>A</b>), RhoE was down-regulated in SGC7901-M cells after treatment with siRNA while RhoE expression was up-regulated in SGC7901-NM cells after treatment with lentivirus. RhoE protein levels were confirmed by Western blot analysis. (<b>B</b>), The migratory ability of the cells was evaluated by a wound-healing assay. The wound widths of each sample were measured at different time-points by phase-contrast microscopy (Olympus, Tokyo, Japan), and the closure ratio was calculated in accord with the following formula: Wound Closure (%) = (width 0 h) - width 24 h) / width 0 h. *P <0.05. These results were then compared to those of the control cells. (<b>C</b>), Tumor cell invasion activities were measured by transwell assay. Representative image fields of invasive cells on the membrane are shown. Data are represented as normalized cellular invasion (invasion index) relative to control cells. *P <0.05. The images shown are representative of three experiments.</p

Verification of the expression of downstream genes in different cell-lines by Western blot analysis of RhoE.

<p>(<b>A</b>) RhoE, CXCR4, VEGFA, CD82 and CTSK expression of SGC7901-M-control, SGC7901-M- siRhoE, SGC7901-NM-control, and SGC7901-NM-RhoE cell-lines. The expression of β-actin was used as internal control. The relative expression levels of CXCR4 were shown as bar charts. *P <0.05. Values represent the arithmetic mean and standard error of the mean (SEM) as determined from at least three experiments. (<b>B</b>) Immunohistochemical staining of RhoE and CXCR4 in 60 pairs of gastric cancer tissues. Three representative cases showed that CXCR4 expression was well-correlated with that of RhoE.</p