Potential Mechanism and Involvement of P120-Catenin in the Malignant Biology of Glioma.

Objective: This study analyzed the influence of p120-catenin (CTNND1) on the malignant characteristics of glioma and elucidated the potential underlying mechanism. Methods: The p120 expression level was assessed in the brain tissues of 42 glioma patients and 10 patients with epilepsy by using the immunohistochemical method. Meanwhile, quantitative PCR technology was employed to assess the expression of P120 in the brain tissues of 71 glioma patients and 13 epilepsy patients. LN229, U251, and U87 glioma cells were used for in vitro analysis and categorized into four treatment groups: siRNA-BC group (no RNA sequence was transfected), siRNA-NC group (transfected control RNA sequences with no effect), and siRNA-1 and siRNA-2 groups (two p120-specific interfering RNA transfection). p120 expression in these treatment groups was quantified by western blotting assay. The migratory and invasive capabilities of glioma cells were studied by wound healing assay and Transwell invasion assay, respectively, under different treatment conditions. MTT assay and cell cycle and apoptosis assay were used to determine glioma cell proliferation and apoptosis, respectively. Enzyme-labeled assay was performed to measure intracellular calcium ion concentration. Immunofluorescence assay was performed for determining microtubule formation and glioma cell distribution. Results: Brain tissues of the glioma group exhibited a remarkable increase in the p120 expression level as compared to brain tissues of the nontumor group (P < 0.05). Furthermore, a strong positive correlation was noted between the malignancy degree in glioma brain tissues and p120 expression in Western blotting (r = 0.906, P = 0.00) and QT-PCR (F=830.6, P＜0.01). Compared to the BC and NC groups, the siRNA transfection groups showed a significant suppression in p120 expression in glioma cells (P < 0.05), with a marked attenuation in the invasive, migratory, and proliferative capabilities of glioma cells as well as an increase in apoptotic potential (P < 0.05). Enzyme-labeled assay showed a remarkable increase in calcium concentration in glioma cells after siRNA treatment. Immunofluorescence assay revealed that the microtubule formation ability of glioma cells reduced after siRNA treatment. Conclusion: p120 has a pivotal involvement in facilitating glioma cell invasion and proliferation by potentially modulating these processes through its involvement in microtubule formation and regulation of intracellular calcium ion levels.

Reduced Tripartite Motif-Containing Protein 29 Deteriorates the Severity of Severe Acute Pancreatitis.

OBJECTIVES: Severe acute pancreatitis (SAP) is the most serious subtype of acute pancreatitis, manifested as multiple-organ failure resulting in high morbidity and mortality. Based on the role of tripartite motif-containing protein 29 (TRIM29) in immune responses, we aimed to explore its effect on SAP. METHODS: Peripheral blood monocyte cells from the SAP or non-SAP patients, as well as bone marrow-derived macrophages from wild-type, TRIM29 -/- , or stimulator of interferon genes (STING) -/- mice after injecting 50 mg/kg of cerulein to induce SAP, were isolated to analyze the role of TRIM29 and STING in the SAP. RESULTS: Tripartite motif-containing protein 29 was significantly reduced in SAP patients. Compared with wild-type mice, TRIM29 deficiency mice displayed more severe symptom of acute pancreatitis after cerulein injection, which were lost in TRIM29 -/- STING -/- mice. Moreover, interferon and its related genes, as well as STING degradation, were decreased in TRIM29 -/- mice. CONCLUSIONS: Our study demonstrated that TRIM29 negatively regulated the severity of SAP by degrading STING at its downstream, suggesting that TRIM29 and STING might serve as therapeutic targets for SAP.

Quercetin Inhibits Glioblastoma Growth and Prolongs Survival Rate through Inhibiting Glycolytic Metabolism.

INTRODUCTION: Quercetin has been reported to have antitumor activity of a wide range of cancers, including breast, lung, colon, prostate. Here, we investigated the protective role of quercetin in glioblastoma (GBM), which causes a higher risk of morbidity and mortality, and explored the antitumor effects of quercetin on GBM using the U87MG and T98G cells and GBM mouse models. METHODS: Cell viability and colony formation assays were performed by CCK-8 and clone-formation assays. GBM xenograft mouse model was established to evaluate the tumor burden of mice treated with or without quercetin. To investigate spontaneous locomotor activity and survival rate of mice, orthotopic transplantation was performed through brain stereotaxic injection of U87 cells. Seahorse and Western blot were performed to examine the alteration of glycolytic metabolism GBM. RESULTS: We found that quercetin administration inhibited GBM cell proliferation and promoted cell apoptosis in vitro. Quercetin suppressed GBM growth, restored spontaneous locomotor activity, and improved survival rate without toxicity to peripheral organs in vivo. Moreover, quercetin inhibited glycolytic metabolism in tumor tissue. DISCUSSION/CONCLUSION: Mechanistically, quercetin inhibited proliferation and angiogenesis, promoted cancer cell apoptosis, and finally improved locomotor activity and survival by inhibiting the glycolytic metabolism in GBM tissues, suggesting that quercetin is a potential drug for the treatment of GBM.

ALKBH5 Promotes the Proliferation of Glioma Cells via Enhancing the mRNA Stability of G6PD.

This study aims to investigate the biological role of 6-methyladenine (m6A) methylation in inducing the carcinogenesis of glioma and its proliferation. Relative levels of ALKBH5 and glucose-6-phosphate dehydrogenase (G6PD) in glioma tissues and cell lines were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Gain-of-function and loss-of-function approaches were used to investigate the role of ALKBH5 in mediating proliferation and energy metabolism of glioma cells. The regulatory effect of ALKBH5 on G6PD was analyzed using m6A-qRT-PCR. Our results showed that ALKBH5 was upregulated in glioma, which stimulated glioma cells to proliferate. Serving as a m6A eraser, ALKBH5 demethylated the target transcript G6PD and enhanced its mRNA stability, thereby promoting G6PD translation and activating the pentose phosphate pathway (PPP). Collectively, ALKBH5 stimulates glioma cells to proliferate through erasing the m6A methylation of G6PD, which can be utilized as a potential therapeutic target for glioma.

µ-Opioid receptor signalling via PI3K/Akt pathway ameliorates lipopolysaccharide-induced acute respiratory distress syndrome.

NEW FINDINGS: What is the central question of this study? The aim was to investigate the role of µ-opioid receptors in acute respiratory distress syndrome and whether their protective effect is mediated via the PI3K/Akt signalling pathway. What is the main finding and its importance? Our findings show that activation of µ-opioid receptors ameliorates lung injury, and the effects are reversed by the PI3K inhibitor, wortmannin. ABSTRACT: The main pathology of acute respiratory distress syndrome (ARDS) is the accumulation of inflammatory cells in the lung and increased permeability of vascular endothelial cells. The µ-opioid receptor (MOR) is a G-protein-coupled receptor, which stimulates angiogenesis and vascular endothelial cell proliferation. In addition, the MOR inhibits cell apoptosis via the PI3K/Akt signalling pathway. In this study, we aimed to explore the contribution of the MOR in ARDS and whether its effects are mediated via PI3K/Akt signalling. An ARDS model was established by intratracheal instillation of 5 mg kg-1 lipopolysaccharide (LPS). Lung injury was confirmed by Haematoxylin and Eosin staining, lung wet/dry weight ratio, bronchoalveolar lavage fluid protein concentrations, myeloperoxidase activity and vascular cell adhesion molecule 1 expression. Lung inflammation was determined by assessment of interleukin-1ß and tumour necrosis factor-α concentrations. The protein level of p-Akt was detected by western blot. Endomorphin-1-activated MORs attenuated LPS-induced lung injury, lung wet/dry weight ratio, bronchoalveolar lavage fluid protein concentrations, myeloperoxidase activity, interleukin-1ß and tumour necrosis factor-α levels and vascular cell adhesion molecule 1 expression, and elevated LPS-induced decreased p-Akt expression. However, the protective effect of MOR activation on lung injury was reversed by the PI3K inhibitor, wortmannin. In conclusion, MOR involvement in LPS-induced ARDS is via the PI3K/Akt pathway.

Inhibition of Ubc9-Induced CRMP2 SUMOylation Disrupts Glioblastoma Cell Proliferation.

Glioblastoma (GBM) is the most aggressive astrocytoma. Despite maximum treatment, the GBM usually recurs and the patient survival is poor. Thus, understanding the molecular mechanism of GBM progression will be meaningful to ameliorate this situation. In this study, collapsin response mediator protein 2 (CRMP2) and Ubc9 protein levels were evaluated in three GBM cell lines. Sumoylated CRMP2 were enriched and immunoprecipitated using SUMO1 and IgG antibodies. CRMP2-K374A mutant was generated by site-direct mutagenesis. All indicated constructs were transfected into GL15 cells, and the corresponding proliferation-promoting effect was assessed through cell proliferation ratio. The t-CSM peptide was used to disturb Ubc9-CRMP2 interaction. CRMP2 is expressed in all tested GBM cell lines. The Ubc9 protein levels are positively correlated with CRMP2 level, and both can promote GBM cell proliferation. Blocking CRMP2 SUMOylation through SUMOylation-incompetent mutant or small peptide suppresses CRMP2-induced GBM cell proliferation. This study demonstrates that the CRMP2 SUMOylation exists widely in GBM cells and drives glioblastoma proliferation. CRMP2 SUMOylation inhibition can significantly suppress GBM proliferation in vitro.

Serum Human Beta-Defensin-2 Is a Possible Biomarker for Monitoring Response to JAK Inhibitor in Psoriasis Patients.

AIMS: To analyse the correlation between serum human beta-defensin-2 (hBD-2) levels and response to JAK inhibitor in psoriasis. METHODS: We evaluated the psoriasis area and severity index (PASI) and serum hBD-2 levels of 18 psoriasis patients randomized to receive placebo or tofacitinib 5 or 10 mg b.i.d. at baseline, week 8, and week 16. Serum hBD-2 levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The PASI achieved a dramatic reduction after tofacitinib 5 or 10 mg b.i.d. treatment for 16 weeks (p < 0.05). Serum hBD-2 levels significantly decreased in patients treated with tofacitinib 10 mg b.i.d. compared with baseline and the placebo-treated patients (p < 0.05). A significant correlation was found between hBD-2 levels and PASI (r = 0.52, p < 0.01). A serum hBD-2 level of 1,255.45 pg/mL was a cut-off between mild and moderate-to-severe psoriasis in ROC analysis. CONCLUSIONS: Serum hBD-2 level might be a possible biomarker for monitoring psoriasis treatment response and differentiating mild from moderate-to-severe psoriasis.

Efficacy and safety of fondaparinux versus enoxaparin in patients undergoing percutaneous coronary intervention treated with the glycoprotein IIb/IIIa inhibitor tirofiban.

BACKGROUND: In worldwide, the mortality rate of acute myocardial infarction (AMI) raises year by year. Although the applications of percutaneous coronary intervention (PCI) and anticoagulants effectively reduce the mortality of patients with acute coronary syndrome (ACS), but also increase the incidence of bleeding. Therefore, drugs with stable anticoagulant effects are urgently required. METHODS: We enrolled 894 patients with acute coronary syndrome who underwent percutaneous coronary intervention in Shenyang Northern Hospital from February 2010 to May 2012; 430 patients were included in the fondaparinux group (2.5 mg/d), and 464 were included in the enoxaparin group (1 mg/kg twice daily). Fondaparinux and enoxaparin were applied for 3-7 days. All patients were treated with tirofiban (10 µg/kg for 3 min initially and 0.15 µg/(kg · min) for 1 to 3 days thereafter). The primary efficacy endpoint was the incidence of a major adverse cerebrovascular or cardiovascular event. The primary safety endpoint was bleeding within 30 days and 1 year after percutaneous coronary intervention. RESULTS: One-year data were available for 422 patients in the fondaparinux group and for 453 in the enoxaparin group. The incidence of a major adverse cerebrovascular or cardiovascular event (10.9 % vs 12.6 %, P = 0.433) and cardiac mortality (0.5 % vs 1.5 %, P = 0.116) were generally lower in the fondaparinux group than in the enoxaparin group, although the differences were not significant. Compared with the enoxaparin group, the fondaparinux group had a significantly decreased rate of bleeding at 30 days (0.9 % vs 2.8 %) and 1 year (2.4 % vs 5.4 %). In addition, the rate of major bleeding events was lower in the fondaparinux group, but this difference was not significant (0.2 % vs 0.9 %, 0.2 % vs 1.1 %). CONCLUSIONS: In tirofiban-treated patients with acute coronary syndrome undergoing percutaneous coronary intervention, fondaparinux presented similar efficacy for ischemia events as enoxaparin. However, fondaparinux significantly decreased the incidence of bleeding, thus providing safer anticoagulation therapy.

Infliximab monotherapy for Chinese patients with moderate to severe plaque psoriasis: a randomized, double-blind, placebo-controlled multicenter trial.

BACKGROUND: Tumor necrosis factor-α is a key mediator in the pathogenesis of psoriasis. Infliximab is a monoclonal antibody that specifically binds to tumor necrosis factor-α. The purpose of this study was to validate the efficacy and safety of 5 mg/kg infliximab therapy in Chinese patients with moderate to severe plaque psoriasis. METHODS: In this multicenter, double-blind, placebo-controlled trial, 129 patients with moderate-to-severe psoriasis were randomized to the induction therapy (weeks 0, 2 and 6) with infliximab 5 mg/kg (n = 84) or placebo (n = 45), followed with infliximab 5 mg/kg scheduled at week 14 and week 22 in the infliximab group, and infliximab 5 mg/kg scheduled at weeks 10, 12 and 16 in the placebo group. The primary end point was the proportion of patients who achieved at least 75% improvement in Psoriasis Area and Severity Index (PASI 75 response rate) from baseline at week 10. RESULTS: At week 10, 81.0% of patients treated with infliximab (5 mg/kg) achieved a 75% or greater improvement compared with 2.2% of patients treated with placebo (P < 0.001). A significant improvement in PASI, Physician's Global Assessment (PGA) and Dermatology Life Quality Index (DLQI), was seen from week 6 through week 14 in the infliximab group compared with the placebo group. Through week 22, PASI, PGA, DLQI were well maintained. The incidence of adverse events for the infliximab treatment group was slightly higher in comparison to the placebo treatment group during the first 10 weeks without statistical significance. However, there were 3 cases of tuberculosis that developed during the 26 weeks treatment with infliximal. CONCLUSIONS: Infliximab treatment was effective as induction and maintenance treatments for Chinese patients with moderate to severe plaque psoriasis. Most drug-induced adverse events were mild to moderate, and well tolerated. Screening for tuberculosis is essential and prophylactic treatment should be given if necessary.

Paraneoplastic pemphigus associated with Castleman tumor: a commonly reported subtype of paraneoplastic pemphigus in China.

BACKGROUND: Castleman tumor, a rare lymphoproliferative disorder, is one of the associated tumors in paraneoplastic pemphigus. We analyzed the characteristics of a group of patients with Castleman tumor to clearly understand and to improve the prognosis of the disease. OBSERVATIONS: Ten cases of paraneoplastic pemphigus associated with Castleman tumor treated in the Department of Dermatology, Peking University First Hospital, Beijing, China, from May 1, 1999, to March 31, 2004, were analyzed for clinical aspects, characteristics and histologic features of the tumors, and computed tomographic findings. Literature was reviewed and data were compared with our cases. Castleman tumor was a frequently reported neoplasm in association with paraneoplastic pemphigus in China. The disease was found to be caused by an autoimmune reaction originating from the B lymphocytes in the Castleman tumor. CONCLUSIONS: Castleman tumor in association with paraneoplastic pemphigus is a commonly reported subtype of paraneoplastic pemphigus in China. Early detection and removal of the Castleman tumor are crucial for the treatment of this tumor-associated autoimmune disease.