Expression of EIF5A2 associates with poor survival of nasopharyngeal carcinoma patients treated with induction chemotherapy.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a type of head-neck cancer with a distinguishable geographic and racial distribution worldwide. Increasing evidence supports that the accumulation of additional genetic and epigenetic abnormalities is important in driving the NPC tumorigenic process. In this study, we aim to investigate the association between EIF5A2 (Eukaryotic translation initiation factor 5A2) expression status and NPC clinical outcomes. METHODS: The expression status of EIF5A2 was investigated in the NPC tissue microarray. Tissues were from 166 NPC patients staging II-IV, collected between 1999 and 2005. All patients were administered 2-3 cycles of DDP (cisplatin) + 5-Fu (5-fluorouracil) induction therapy and then treated with a uniform conventional two-dimensional radiotherapy. Cell motility assay, tumor growth assay and cytotoxicity assay were performed on the EIF5A2 overexpressed cells and control cells. siRNA was also used in the in vitro studies. RESULTS: Positive staining of EIF5A2 was observed in 85.4 % (105/123) informative tumor cases. Multivariate analyses demonstrated that EIF5A2 was an independent prognostic marker of poor overall survival (OS) (P = 0.041), failure-free survival (FFS) (P = 0.029), and distant failure-free survival (D-FFS) (P = 0.043) in patients with locoregionally advanced NPC patients treated with cisplatin + 5-Fu chemoradiotherapy. The forced expression of EIF5A2 in NPC cells enhanced the cells' motility and growth ability. Knock-down of EIF5A2 in NPC cells decreased the cell's motility and growth ability. Our results also demonstrated that EIF5A2 overexpression induced chemoresistance of NPC cells to 5-Fu. CONCLUSIONS: Our findings suggested that EIF5A2 expression, as examined by immunohistochemistry, could function as an independent prognostic factor of outcomes in NPC patients with cisplatin + 5-Fu chemoradiotherapy. EIF5A2 might be a novel therapeutic target for the inhibition of NPC progress.

Expression of Aurora-B and FOXM1 predict poor survival in patients with nasopharyngeal carcinoma.

PURPOSE: The purpose of this work was to investigate the relationship between Aurora-B, FOXM1, and clinical outcomes in patients with nasopharyngeal carcinoma (NPC) who were treated with a combination of induction chemotherapy and radiotherapy. PATIENTS AND METHODS: The expression of Aurora-B and FOXM1 were investigated by immunohistochemistry using a tissue microarray (TMA) containing samples from 166 NPC patients who were treated with cisplatin (DDP) + fluorouracil (5-FU) induction chemotherapy and radiotherapy between 1999 and 2005. The relationship of Aurora-B, FOXM1, and survival of these NPC patients was analyzed. RESULTS: Informative TMA results were obtained in 91 tumor cases for Aurora-B and 93 tumor cases for FOXM1. The 8-year failure-free survival rate (FFS) for the Aurora-B-negative and Aurora-B-positive group was 65.6 and 37.3%, respectively (p = 0.024), and the 8-year distant FFS (D-FFS) rate was 65.6 and 41.5%, respectively (p = 0.047). The 8-year overall survival (OS) in the FOXM1-negative group was moderately higher than in the FOXM1-positive group (58.4 vs 39.1%, p = 0.081). Cox regression analysis revealed that for FFS, Aurora-B expression was a significant prognostic factor (p = 0.025), while for D-FFS, Aurora-B expression was a marginally significant prognostic factor (p = 0.056). When FOXM1 expression was analyzed, the Cox regression analyses showed that FOXM1 expression was a marginally significant prognostic factor (p = 0.056) for OS. Correlation analysis showed that Aurora-B and FOXM1 expression had no significant correlation. CONCLUSION: Aurora-B and FOXM1 were both adverse prognostic markers for NPC patients treated with chemoradiotherapy. However, the two markers had no significant correlation.

Degradation of perineuronal nets in the medial prefrontal cortex promotes extinction and reduces reinstatement of methamphetamine-induced conditioned place preference in female mice.

The high rate of relapse to compulsive methamphetamine (MA)-taking and seeking behaviors after abstinence constitutes a major obstacle to the treatment of MA addiction. Perineuronal nets (PNNs), essential components of the extracellular matrix, play a critical role in synaptic function, learning, and memory. Abnormalities in PNNs have been closely linked to a series of neurological diseases, such as addiction. However, the exact role of PNNs in MA-induced related behaviors remains elusive. Here, we established a MA-induced conditioned place preference (CPP) paradigm in female mice and found that the number and average optical density of PNNs increased significantly in the medial prefrontal cortex (mPFC) of mice during the acquisition, extinction, and reinstatement stages of CPP. Notably, the removal of PNNs in the mPFC via chondroitinase ABC (ChABC) before extinction training not only facilitated the extinction of MA-induced CPP and attenuated the relapse of extinguished MA preference but also significantly reduced the activation of c-Fos in the mPFC. Similarly, the ablation of PNNs in the mPFC before reinstatement markedly lessened the reinstatement of MA-induced CPP, which was accompanied by the decreased expression of c-Fos in the mPFC. Collectively, our results provide more evidence for the implication of degradation of PNNs in facilitating extinction and preventing relapse of MA-induced CPP, which indicate that targeting PNNs may be an effective therapeutic option for MA-induced CPP memories.

Oral edaravone ameliorates behavioral deficits and pathologies in a valproic acid-induced rat model of autism spectrum disorder.

Autism spectrum disorder (ASD) is neurodevelopmental disorder with a high incidence rate, characterized by social deficits and repetitive behaviors. There is currently no effective management available to treat the core symptoms of ASD; however, oxidative stress has been implicated in its pathogenesis. Edaravone (EDA), a free-radical scavenger, is used to treat amyotrophic lateral sclerosis (ALS) and acute ischemic stroke (AIS). Here, we hypothesized that an oral formula of EDA may have therapeutic efficacy in the treatment of core ASD symptoms. A rat model of autism was established by prenatal exposure to valproic acid (VPA), and the offsprings were orally treated with EDA at low (3 mg/kg), medium (10 mg/kg), and high (30 mg/kg) doses once daily for 28 days starting from postnatal day 25 (PND25). Oral EDA administration alleviated the core symptoms in VPA rats in a dose-dependent manner, including repetitive stereotypical behaviors and impaired social interaction. Furthermore, oral administration of EDA significantly reduced oxidative stress in a dose-dependent manner, as evidenced by a reduction in oxidative stress markers and an increase in antioxidants in the blood and brain. In addition, oral EDA significantly attenuated downstream pathologies, including synaptic and mitochondrial damage in the brain. Proteomic analysis further revealed that EDA corrected the imbalance in brain oxidative reduction and mitochondrial proteins induced by prenatal VPA administration. Overall, these findings demonstrate that oral EDA has therapeutic potential for ASD by targeting the oxidative stress pathway of disease pathogenesis and paves the way towards clinical studies.

CNTN1 Aggravates Neuroinflammation and Triggers Cognitive Deficits in Male Mice by Boosting Crosstalk between Microglia and Astrocytes.

A wealth of knowledge regarding glial cell-mediated neuroinflammation, which contributes to cognitive deficits in Alzheimer's disease (AD) has emerged in recent years. Contactin 1(CNTN1), a member of the cell adhesion molecule and immunoglobulin supergene family, is centrally involved in axonal growth regulation and is also a key player in inflammation-associated disorders. However, whether CNTN1 plays a role in inflammation-related cognitive deficits and how this process is triggered and orchestrated remain to be fully elucidated. In this study, we examined postmortem brains with AD. CNTN1 immunoreactivity was markedly increased, particularly in the CA3 subregion, as compared with non-AD brains. Furthermore, by applying an adeno-associated virus-based approach to overexpress CNTN1 directly via stereotactic injection in mice, we demonstrated that hippocampal CNTN1 overexpression triggered cognitive deficits detected by novel object-recognition, novel place-recognition and social cognition tests. The mechanisms underlying these cognitive deficits could be attributed to hippocampal microglia and astrocyte activation, which led to aberrant expression of excitatory amino acid transporters (EAAT)1/EAAT2. This resulted in long-term potentiation (LTP) impairment that could be reversed by minocyline, an antibiotic and the best-known inhibitor of microglial activation. Taken together, our results identified Cntn1 as a susceptibility factor involved in regulating cognitive deficits via functional actions in the hippocampus. This factor correlated with microglial activation and triggered astrocyte activation with abnormal EAAT1/EAAT2 expression and LTP impairment. Overall, these findings may significantly advance our understanding of the pathophysiological mechanisms underlying the risk of neuroinflammation related cognitive deficits.

DAPK3 inhibits gastric cancer progression via activation of ULK1-dependent autophagy.

Dysregulation of the balance between cell proliferation and cell death is a central feature of malignances. Death-associated protein kinase 3 (DAPK3) regulates programmed cell death including apoptosis and autophagy. Our previous study showed that DAPK3 downregulation was detected in more than half of gastric cancers (GCs), which was related to tumor invasion, metastasis, and poor prognosis. However, the precise molecular mechanism underlying DAPK3-mediated tumor suppression remains unclear. Here, we showed that the tumor suppressive function of DAPK3 was dependent on autophagy process. Mass spectrometry, in vitro kinase assay, and immunoprecipitation revealed that DAPK3 increased ULK1 activity by direct ULK1 phosphorylation at Ser556. ULK1 phosphorylation by DAPK3 facilitates the ULK1 complex formation, the VPS34 complex activation, and autophagy induction upon starvation. The kinase activity of DAPK3 and ULK1 Ser556 phosphorylation were required for DAPK3-modulated tumor suppression. The coordinate expression of DAPK3 with ULK1 Ser556 phosphorylation was confirmed in clinical GC samples, and this co-expression was correlated with favorable survival outcomes in patients. Collectively, these findings indicate that the tumor-suppressor roles of DAPK3 in GC are associated with autophagy and that DAPK3 is a novel autophagy regulator, which can directly phosphorylate ULK1 and activate ULK1. Thus, DAPK3 might be a promising prognostic autophagy-associated marker.

Three new bioactive flavonoid glycosides from Viscum album.

Two new flavonoid glycosides, named viscumneoside XII (1), and viscumneoside XIII (2); a new dihydrogen flavonoid glycoside product named viscumneoside XIV (3), were isolated from the aerial part of Viscum album, along with seven known compounds (4-10). Their structures were identified by analysis of spectroscopic data. In addition, cytotoxicity assay showed that 1, 2 and 3 possessed significant inhibitory activities against C6, A549 and MDA-MB-231 (the inhibition rate arrived about 50%, 70% and 74% respectively with IC50 ≤ 60.00 µmol·L-1), while the inhibition of TF-1 and Hela was not significant.

LINC01554-Mediated Glucose Metabolism Reprogramming Suppresses Tumorigenicity in Hepatocellular Carcinoma via Downregulating PKM2 Expression and Inhibiting Akt/mTOR Signaling Pathway.

Background and Aims: Cancer cells prefer aerobic glycolysis to maintain growth advantages, but the role of long non-coding RNAs (lncRNAs) in glycometabolism still remains unclear. Here we identified one cytoplasmic lncRNA LINC01554 as a significantly downregulated lncRNA in hepatocellular carcinoma (HCC) and aimed to investigate its role in cellular glucose metabolism in the development and progression of HCC. Methods: Quantitative real-time PCR was used to determine the expression level of LINC01554. Downregulation of LINC01554 by miR-365a at transcriptional level was assessed by luciferase reporter assay. Subcellular fractionation assay and RNA fluorescence in situ hybridization were performed to detect the subcellular localization of LINC01554. RNA pull-down assay, mass spectrometry, and RNA immunoprecipitation assay were used to identify the underlying molecular mechanisms. The tumor-suppressive function of LINC01554 was determined by both in vitro assay and nude mice xenograft model. Results: LINC01554 was frequently downregulated in HCC, which was significantly associated with tumor invasion (P = 0.005), tumor size (P = 0.041), tumor staging (P = 0.023) and shorter survival (P = 0.035) of HCC patients. Luciferase reporter assay unraveled that LINC01554 was negatively regulated by miR-365a. Subcellular fractionation assay and RNA FISH revealed the cytoplasmic predominance of LINC01554 in MIHA cells and HCC clinical samples. Ectopic expression of LINC01554 inhibited HCC cell growth, colony formation in soft agar, foci formation, and tumor formation in nude mice. LINC01554 promoted the ubiquitin-mediated degradation of PKM2 and inhibited Akt/mTOR signaling pathway to abolish aerobic glycolysis in HCC cells. Further study found that LINC01554-knockout could effectively reverse the tumor-suppressive effect of LINC01554. Conclusions: Our results identify LINC01554 as a novel tumor suppressor in HCC and unravel its underlying molecular mechanism in reprogramming cellular glucose metabolism. LINC01554 could possibly serve as a novel prognostic biomarker and provide the rationale for HCC therapy.

Insight into the efficient catalytic conversion of biomass to EG and 1,2-PG over W-Ni bimetallic catalyst.

In this work, a mesoporous silica microsphere (MSM) was selected as a support to prepare a bimetallic supported catalyst (15% W-5% Ni/MSM) by a co-impregnation method that was simple and easy to conduct. We wished to improve the capability of catalytic conversion of biomass into ethylene glycol (EG) and 1,2-propylene glycol (1,2-PG). 15% W-5% Ni/MSM was examined on microcrystalline cellulose (cellulose) and corn stalks in a one-pot catalytic process, and total yields of EG and 1,2-PG reached up to 82.40 wt% and 62.60 wt%, respectively. This remarkable catalytic performance of W-Ni/MSM catalyst could be attributed to the synergistic effect between the active sites of Ni and W and the unique structure of MSM, which was suitable for mass transfer and metal loading. Based on physicochemical characterizations, the metal component was well-distributed on the surface of the MSM, and the metallic Ni, W and WO3 of the fresh catalyst were converted mainly into NiWO4 during the catalytic conversion of cellulose. To shed light on the reaction mechanism of the catalyzed hydrogenation of biomass, a possible process involving the formation of H x WO3 homogeneous catalysts, cellulose hydrolysis, C-C cleavage and hydrogenation conversion to 1,2-PG and EG was illustrated. Furthermore, the reusability of W-Ni/MSM catalyst was tested and we explored the cause of decreased diols yields. In summary, this work provides important guidance to rationally design effective catalysts for biomass conversion.

TSPAN15 interacts with BTRC to promote oesophageal squamous cell carcinoma metastasis via activating NF-κB signaling.

Beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) is crucial for the degradation of IκBα. Our previous transcriptome sequencing analysis revealed that tetraspanin 15 (TSPAN15) was significantly upregulated in clinical oesophageal squamous cell carcinoma (OSCC) tissues. Here, we show that high TSPAN15 expression in OSCC tissues is significantly associated with lymph node and distant metastasis, advanced clinical stage, and poor prognosis. Elevated TSPAN15 expression is, in part, caused by the reduction of miR-339-5p. Functional studies demonstrate that TSPAN15 promotes metastatic capabilities of OSCC cells. We further show that TSPAN15 specifically interacts with BTRC to promote the ubiquitination and proteasomal degradation of p-IκBα, and thereby triggers NF-κB nuclear translocation and subsequent activation of transcription of several metastasis-related genes, including ICAM1, VCAM1, uPA, MMP9, TNFα, and CCL2. Collectively, our findings indicate that TSPAN15 may serve as a new biomarker and/or provide a novel therapeutic target to OSCC patients.