Weak up-regulation of serum response factor in gastric ulcers in patients with co-morbidities is associated with increased risk of recurrent bleeding

<p>Abstract</p> <p>Background</p> <p>Serum response factor (SRF) is crucial for gastric ulcer healing process. The study determined if gastric ulcer tissues up-regulate SRF and if such up-regulation correlated with co-morbidities and the risk of recurrent bleeding.</p> <p>Methods</p> <p>Ulcer and non-ulcer tissues were obtained from 142 patients with active gastric ulcers for SRF expression assessed by immunohistochemistry. Based on the degree of SRF expression between these two tissue types, SRF up-regulation was classified as strong, intermediate, and weak patterns. The patients were followed-up to determine if SRF up-regulation correlated to recurrent bleeding.</p> <p>Results</p> <p>Gastric ulcer tissues had higher SRF expression than non-ulcer tissues (<it>p </it>< 0.05). Patients with strong SRF up-regulation had lower rates of stigmata of recent hemorrhage (SRH) on the ulcer base than the others (<it>p </it>< 0.05). Multivariate logistic regression confirmed that co-morbidities and weak SRF up-regulation were two independent factors of recurrent gastric ulcer bleeding (<it>p </it>< 0.05). Combining both factors, there was an 8.29-fold (95% CI, 1.31~52.62; <it>p </it>= 0.03) higher risk of recurrent gastric ulcer bleeding.</p> <p>Conclusions</p> <p>SRF expression is higher in gastric ulcer tissues than in non-ulcer tissues. Weak SRF up-regulation, combined with the presence of co-morbidities, increase the risk of the recurrent gastric ulcer bleeding.</p

14-3-3σ Regulates β-Catenin-Mediated Mouse Embryonic Stem Cell Proliferation by Sequestering GSK-3β

[[abstract]]Background: Pluripotent embryonic stem cells are considered to be an unlimited cell source for tissue regeneration and cell-based therapy. Investigating the molecular mechanism underlying the regulation of embryonic stem cell expansion is thus important. 14-3-3 proteins are implicated in controlling cell division, signaling transduction and survival by interacting with various regulatory proteins. However, the function of 14-3-3 in embryonic stem cell proliferation remains unclear. Methodology and Principal Findings: In this study, we show that all seven 14-3-3 isoforms were detected in mouse embryonic stem cells. Retinoid acid suppressed selectively the expression of 14-3-3σ isoform. Knockdown of 14-3-3σ with siRNA reduced embryonic stem cell proliferation, while only 14-3-3σ transfection increased cell growth and partially rescued retinoid acid-induced growth arrest. Since the growth-enhancing action of 14-3-3σ was abrogated by β-catenin knockdown, we investigated the influence of 14-3-3σ overexpression on β-catenin/GSK-3β. 14-3-3σ bound GSK-3β and increased GSK-3β phosphorylation in a PI-3K/Akt-dependent manner. It disrupted β-catenin binding by the multiprotein destruction complex. 14-3-3σ overexpression attenuated β-catenin phosphorylation and rescued the decline of β-catenin induced by retinoid acid. Furthermore, 14-3-3σ enhanced Wnt3a-induced β-catenin level and GSK-3β phosphorylation. DKK, an inhibitor of Wnt signaling, abolished Wnt3a-induced effect but did not interfere GSK-3β/14-3-3σ binding. Significance:Our findings show for the first time that 14-3-3σ plays an important role in regulating mouse embryonic stem cell proliferation by binding and sequestering phosphorylated GSK-3β and enhancing Wnt-signaled GSK-3β inactivation. 14-3-3σ is a novel target for embryonic stem cell expansion

Synergistic Effects of the Combinational Use of Escitalopram Oxalate and 5-Fluorouracil on the Inhibition of Gastric Cancer SNU-1 Cells

Owing to its high recurrence rate, gastric cancer (GC) is the leading cause of tumor-related deaths worldwide. Besides surgical treatment, chemotherapy is the most commonly used treatment against GC. However, the adverse events associated with chemotherapy use limit its effectiveness in GC treatment. In this study, we investigated the effects of using combinations of low-dose 5-fluorouracil (5-FU; 0.001 and 0.01 mM) with different concentrations of escitalopram oxalate (0.01, 0.02, 0.06, and 0.2 mM) to evaluate whether the assessed combination would have synergistic effects on SNU-1 cell survival. 5-FU (0.01 mM) + escitalopram oxalate (0.02 mM) and 5-FU (0.01 mM) + escitalopram oxalate (0.06 mM) administered over 24 h showed synergistic effects on the inhibition of SNU-1 cell proliferation. Moreover, 5-FU (0.001 mM) + escitalopram oxalate (0.02 or 0.06 mM) and 5-FU (0.01 mM) + escitalopram oxalate (0.02, 0.06, or 0.2 mM) administered over 48 h showed synergistic effects on the inhibition of SNU-1 cell proliferation. Compared with controls, SNU-1 cells treated with 5-FU (0.01 mM) + escitalopram oxalate (0.02 mM) exhibited significantly increased levels of annexin V staining, reactive oxygen species, cleaved poly (ADP-ribose) polymerase, and caspase-3 proteins. Furthermore, 5-FU (12 mg/kg) + escitalopram oxalate (12.5 mg/kg) significantly attenuated xenograft SNU-1 cell proliferation in nude mice. Our study is the first to report the synergistic effects of the combinational use of low-dose 5-FU and escitalopram oxalate on inhibiting SNU-1 cell proliferation. These findings may be indicative of an alternative option for GC treatment

One-Pot Asymmetric Synthesis of Seven-Membered Carbocycles Cyclohepta[<i>b</i>]indoles via a Sequential Organocatalytic Michael/Double Friedel–Crafts Alkylation Reaction

A new method has been developed for the enantioselective synthesis of highly functionalized cyclohepta[<i>b</i>]indoles with high enantioselectivity (up to 96% <i>ee</i>). The process combines an enantioselective organocatalytic Michael addition and a highly efficient double Friedel–Crafts reaction sequence in one pot with good yields and stereoselectivity. The structures and absolute configurations of the products were confirmed by X-ray analysis

One-Pot Asymmetric Synthesis of Seven-Membered Carbocycles Cyclohepta[<i>b</i>]indoles via a Sequential Organocatalytic Michael/Double Friedel–Crafts Alkylation Reaction

A new method has been developed for the enantioselective synthesis of highly functionalized cyclohepta[<i>b</i>]indoles with high enantioselectivity (up to 96% <i>ee</i>). The process combines an enantioselective organocatalytic Michael addition and a highly efficient double Friedel–Crafts reaction sequence in one pot with good yields and stereoselectivity. The structures and absolute configurations of the products were confirmed by X-ray analysis

One-Pot Asymmetric Synthesis of Seven-Membered Carbocycles Cyclohepta[<i>b</i>]indoles via a Sequential Organocatalytic Michael/Double Friedel–Crafts Alkylation Reaction

A new method has been developed for the enantioselective synthesis of highly functionalized cyclohepta[<i>b</i>]indoles with high enantioselectivity (up to 96% <i>ee</i>). The process combines an enantioselective organocatalytic Michael addition and a highly efficient double Friedel–Crafts reaction sequence in one pot with good yields and stereoselectivity. The structures and absolute configurations of the products were confirmed by X-ray analysis

One-Pot Asymmetric Synthesis of Seven-Membered Carbocycles Cyclohepta[<i>b</i>]indoles via a Sequential Organocatalytic Michael/Double Friedel–Crafts Alkylation Reaction

A new method has been developed for the enantioselective synthesis of highly functionalized cyclohepta[<i>b</i>]indoles with high enantioselectivity (up to 96% <i>ee</i>). The process combines an enantioselective organocatalytic Michael addition and a highly efficient double Friedel–Crafts reaction sequence in one pot with good yields and stereoselectivity. The structures and absolute configurations of the products were confirmed by X-ray analysis

Combined Administration of Escitalopram Oxalate and Nivolumab Exhibits Synergistic Growth-Inhibitory Effects on Liver Cancer Cells through Inducing Apoptosis

Liver cancer is one of the most lethal malignant cancers worldwide. However, the therapeutic options for advanced liver cancers are limited and reveal scant efficacy. The current study investigated the effects of nivolumab (Niv) and escitalopram oxalate (Esc) in combination on proliferation of liver cancer cells both in vitro and in vivo. Significantly decreased viability of HepG2 cells that were treated with Esc or Niv was observed in a dose-dependent manner at 24 h, 48 h, and 72 h. Administration of Esc (50 μM) + Niv (20 μM), Esc (75 μM) + Niv (5 μM), and Esc (75 μM) + Niv (20 μM) over 24 h exhibited synergistic effects, inhibiting the survival of HepG2 cells. Additionally, treatment with Esc (50 μM) + Niv (1 μM), Esc (50 μM) + Niv (20 μM), and Esc (75 μM) + Niv (20 μM) over 48 h exhibited synergistic effects, inhibiting the survival of HepG2 cells. Finally, treatment with Esc (50 μM) + Niv (1 μM), Esc (50 μM) + Niv (20 μM), and Esc (75 μM) + Niv (20 μM) for 72 h exhibited synergistic effects, inhibiting HepG2 survival. Com-pared with controls, HepG2 cells treated with Esc (50 μM) + Niv (20 μM) exhibited significantly increased sub-G1 portion and annexin-V signals. In a xenograft animal study, Niv (6.66 mg/kg) + Esc (2.5 mg/kg) significantly suppressed the growth of xenograft HepG2 tumors in nude mice. This study reports for the first time the synergistic effects of combined administration of Niv and Esc for inhibiting HepG2 cell proliferation, which may provide an alternative option for liver cancer treatment