<div>Abstract<p>Actin cytoskeleton dynamic rearrangement is required for tumor cell metastasis and is a key characteristic of <i>Helicobacter pylori</i> (<i>H. pylori</i>)-infected host cells. Actin cytoskeleton modulation is coordinated by multiple actin-binding proteins (ABP). Through Kyoto encyclopedia of gene and genomes database, GEPIA website, and real-time PCR data, we found that <i>H. pylori</i> infection significantly induced L-plastin, a key ABP, in gastric cancer cells. We further explored the regulation and function of L-plastin in <i>H. pylori</i>–associated gastric cancer and found that, mechanistically, <i>H. pylori</i> infection induced gastric cancer cells to express L-plastin via <i>cagA</i>-activated ERK signaling pathway to mediate SP1 binding to L-plastin promoter. Moreover, this increased L-plastin promoted gastric cancer cell proliferation and migration <i>in vitro</i> and facilitated the growth and metastasis of gastric cancer <i>in vivo</i>. Finally, we detected the expression pattern of L-plastin in gastric cancer tissues, and found that L-plastin was increased in gastric cancer tissues and that this increase of L-plastin positively correlated with <i>cagA</i><sup>+</sup> <i>H. pylori</i> infection status. Overall, our results elucidate a novel mechanism of L-plastin expression induced by <i>H. pylori</i>, and a new function of L-plastin–facilitated growth and metastasis of gastric cancer, and thereby implicating L-plastin as a potential therapeutic target against gastric cancer.</p>Implications:<p>Our results elucidate a novel mechanism of L-plastin expression induced by <i>H. pylori</i> in gastric cancer, and a new function of L-plastin–facilitated gastric cancer growth and metastasis, implicating L-plastin as a potential therapeutic target against gastric cancer.</p></div>
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Exploring the effect of bile salts on the properties of emulsion carriers containing hydrophobic bioactive compounds is particularly critical to understanding the stability and bioavailability of these hydrophobic bioactive compounds in the digestive process. In this study, the effects of bile salts on the stability and digestive characteristics of the ursolic acid (UA) self-stabilized water-in-oil (W/O) emulsion were investigated via static and dynamic (with or without enzyme) in vitro simulated digestive systems. The results showed that under the static system, the basic conditions had less interference, while the bile salts had a significant effect on the appearance and microstructure of the emulsion. The primary mechanism of emulsion instability is hydrophobic binding and depletion flocculation. Under the dynamic condition, it was found that the low concentrations of bile salts can promote the release amount and the rate of free fatty acids via displacement, while high concentrations of bile salts inhibit the decomposition of lipid, which may be related to the secondary coverage formed at the interface by the bile salts. These findings provide a theoretical basis for understanding the digestive behavior of the UA emulsion and its interaction with bile salts, which are conducive to developing and designing new emulsions to improve the bioaccessibility of UA.
Rapamune® (oral rapamycin/sirolimus) administration is plagued by poor bioavailability, extensive fecal elimination, and wide biodistribution. Thus, this pleotropic mTOR inhibitor has a narrow therapeutic window, numerous side effects and provides inadequate transplantation protection. Parental formulation was not possible due to rapamycin's hydrophobicity (log P 4.3). Here, we demonstrate that subcutaneous rapamycin delivery via poly(ethylene glycol)-b-poly(propylene sulfide)(PEG-b-PPS) polymersome (PS) nanocarriers modulates cellular biodistribution of rapamycin to change its immunosuppressive mechanism for enhanced efficacy while minimizing side effects (Fig. 1).Subcutaneously administered rapamycin-loaded polymersomes (rPS) avoid fecal elimination and allow for sustained delivery of rapamycin to immune cell rich organs, especially the axillary lymph nodes. While oral rapamycin inhibits naïve T cell proliferation directly, rPS instead modulated Ly-6Clow monocytes and tolerogenic semi-mature dendritic cells, with immunosuppression mediated by CD8+ Tregs and rare CD4+ CD8+ double-positive T cells. As PEG-b-PPS PS are uniquely non-inflammatory, background immunostimulation from the vehicle was avoided, allowing immunomodulation to be primarily attributed to rapamycin's cellular biodistribution. Repurposing mTOR inhibition significantly improved maintenance of normoglycemia in a clinically relevant, MHC-mismatched, allogeneic, intraportal (liver) islet transplantation model (Fig. 2a,b). Importantly, rPS treatment does not alter serum albumin:globulin ratios (Fig. 2c).These results demonstrate the ability of engineered nanocarriers to repurpose drugs for alternate routes of administration by rationally controlling cellular biodistribution.
Abstract Palladium‐catalyzed amination of 7‐bromo‐4‐methyl‐2,1,3‐benzothiadiazole ( 7 ) with benzophenone imine as an ammonia equivalent is described as a new, safe and practical alternative to nitration for the synthesis of 7‐amino‐4‐methyl‐2,1,3‐benzothiadiazole ( 1 ) in high yield. This methodology was successfully scaled‐up in the pilot plant on 14.0‐kg scale of 7 and was also utilized for the synthesis of 7‐amino‐4,6‐dimethyl‐2,1,3‐ben‐zothiadiazole ( 12 ) by the amination of 7‐bromo‐4,6‐dimethyl‐2,1,3‐benzothiadiazole ( 10 ).
Self-constructed stable delivery system for hydrophobic bioactives are the promising strategy to solve their low solubility and poor bioavailability problems. This work aims to form a super stable W/O Pickering emulsion to increase the bioaccessibility of betulin. Microscopy, confocal laser scanning microscopy and rheology indicated that the stabilizing mechanism is attributed to betulin crystals on the emulsion interface and the crystals in the continuous phase, enabling excellent freeze/thaw and thermal stability. The Pickering emulsion significantly increased betulin bioaccessibility (22.4%) compared to betulin alone (0.2%) and betulin-oil physical mixture (7.9%). A higher level of betulin had smaller emulsion particle size, which may own a greater surface area, leading to higher release of FFA and thus contributing to the release and solubilization of betulin from the Pickering system and the formation of micelles. This study demonstrates Pickering emulsions solely stabilized by phytochemical betulin serve as an innovative way to improve its bioaccessibility.
Objective
To investigate the effect of miR-184 on proliferation of neural stem cells (NSCs) and its mechanisms in mice.
Methods
The pHBLV-U6-GFP-miR-184 over-expression plasmid and pHBLV-U6-GFP-miR-184 inhibitor plasmid were used to construct recombinant lentivirus. And the NSCs derived from subventricular zone of E14d CD1 mouse were confirmed by immunofluorescence assay. There were four groups that contain a miR-184 overexpression group, a miR-184 inhibitor group and two control groups. The NSCs which infected with lentiviral vectors were selected for puromycin resistance for 5-7 days, and then surviving cells were cultivated to three generations. The expression level of miR-184 was detected by real time-quantitative PCR (RT-qPCR). And the target genes of miR-184 were predicted through TargetScan, IRTarBase and MiRanda, and were confirmed by Western blotting and RT-qPCR. The cells in the four groups were cultured under proliferating conditions incorporated bromodeoxyuridine (BrdU) in cell proliferation analyses. The protein expressions of Hes1 and Hes5, the target proteins of Notch signaling pathways, and their mRNA expressions were detected by Western blotting and RT-qPCR.
Results
There were 90% of cells in each group expressing both Nestin and Sox2. The miR-184 level in the miR-184 overexpression group was 67.63±7.53 times of that of the control group, with significant difference (P<0.05). The percent of BrdU+/DAPI+ of the miR-184 overexpression group was 1.47±0.05 times of that in the control group, with significant difference (P<0.05); and the percent of BrdU+/DAPI+ of the miR-184 inhibitor group was 0.84±0.03 times of that in the inhibitor control group, with significant difference (P<0.05). Numbl was a target gene of miR-184 indicated by IRTarBase and MiRanda. The miR-184 could inhibit Numbl protein expression; the Numbl protein expression level in the miR-184 overexpression group was 0.73±0.07 times of that in the control group, and the Numbl protein expression level in the miR-184 inhibitor group was 1.30±0.05 times of that in the control group, with significant difference (P<0.05); but miR-184 did not change the Numbl mRNA level. The miR-184 could activate Notch signaling pathway through inhibiting the Numbl protein expression, and increase the Hes1 and Hes5 protein and mRNA expression levels (P<0.05).
Conclusion
The miR-184 promotes the NSCs proliferation through inhibiting the Numbl protein translation and further activating the Notch signaling pathway.
Key words:
Micro-184; Neural stem cell; Numbl protein; Notch signaling pathway; Hes1 protein; Hes5 protein
Anoikis resistance is the prerequisite of cancer cells metastasis. Elucidation of the mechanism of anoikis resistance remains a significant challenge. We reported here a model to mimic anoikis resistant process of hepatoma cells in vitro. Experimental results indicated cell to cell aggregation could mediate anoikis resistance of BEL7402 hepatoma cells. Further investigation of these aggregations indicated the biological properties changed greatly after the hepatoma cells lost their anchorage. Aggregation forming process could be separated into three distinct phases according to their biological characteristics, comprising of premature phase, mature phase and postmature phase. Mature phase aggregations have the premium state of cell viability and may mimic the metastatic cells in the circulating system. Biological properties of these three phases aggregations were studied in details including morphological alteration, cell viability and microarray expression profiles. It indicated there was a great upregulation of adhesion molecules during the process of aggregation formation and the cell to cell contact in the aggregation may be mediated independent of calcium involved adhesion pathway. This model might shed light on the anoikis resistance mechanism of hepatoma cells and help to develop new therapies that may target the anoikis resistant hepatoma cells in the metastasis process.
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