Nuclear VCP drives colorectal cancer progression by promoting fatty acid oxidation.

Fatty acid oxidation (FAO) fuels many cancers. However, knowledge of pathways that drive FAO in cancer remains unclear. Here, we revealed that valosin-containing protein (VCP) upregulates FAO to promote colorectal cancer growth. Mechanistically, nuclear VCP binds to histone deacetylase 1 (HDAC1) and facilitates its degradation, thus promoting the transcription of FAO genes, including the rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A). FAO is an alternative fuel for cancer cells in environments exhibiting limited glucose availability. We observed that a VCP inhibitor blocked the upregulation of FAO activity and CPT1A expression triggered by metformin in colorectal cancer (CRC) cells. Combined VCP inhibitor and metformin prove more effective than either agent alone in culture and in vivo. Our study illustrates the molecular mechanism underlying the regulation of FAO by nuclear VCP and demonstrates the potential therapeutic utility of VCP inhibitor and metformin combination treatment for colorectal cancer.

IDH1 mutation impairs antiviral response and potentiates oncolytic virotherapy in glioma.

IDH1 mutations frequently occur early in human glioma. While IDH1 mutation has been shown to promote gliomagenesis via DNA and histone methylation, little is known regarding its regulation in antiviral immunity. Here, we discover that IDH1 mutation inhibits virus-induced interferon (IFN) antiviral responses in glioma cells. Mechanistically, D2HG produced by mutant IDH1 enhances the binding of DNMT1 to IRF3/7 promoters such that IRF3/7 are downregulated, leading to impaired type I IFN response in glioma cells, which enhances the susceptibility of gliomas to viral infection. Furthermore, we identify DNMT1 as a potential biomarker predicting which IDH1mut gliomas are most likely to respond to oncolytic virus. Finally, both D2HG and ectopic mutant IDH1 can potentiate the replication and oncolytic efficacy of VSVΔ51 in female mouse models. These findings reveal a pivotal role for IDH1 mutation in regulating antiviral response and demonstrate that IDH1 mutation confers sensitivity to oncolytic virotherapy.

CLC-3 and SOX2 regulate the cell cycle in DU145 cells.

Sex determining region Y-box 2 (SOX2) is a transcription factor that serves a role in numerous different types of malignant cancer. Altered expression of chloride channel proteins has been described in a variety of malignancies. However, the association between SOX2 and chloride channel proteins is not yet fully understood. The present study investigated the association between SOX2 and chloride voltage-gated channel 3 (CLC-3) in prostate cancer. Flow cytometry demonstrated that the inactivation of CLC-3 or SOX2 arrested cell cycle progression in the G0/G1 phase. Furthermore, CLC-3 was observed to bind to SOX2, and vice versa, by co-immunoprecipitation. SOX2 appears to initiate and maintain prostate cancer tumorigenesis, in part, by modulating the cell cycle. These findings indicate the potential of SOX2 and CLC-3 as targets for the development of multi-targeted therapeutics.

THRIL mediates endothelial progenitor cells autophagy via AKT pathway and FUS.

BACKGROUND: This study focused on the roles of lncRNA THRIL in coronary atherosclerotic heart disease (CAD) through regulating AKT signaling pathway and directly interacting with FUS. METHODS: QRT-PCR was conducted to detect the expression of THRIL in CAD blood samples and endothelial progenitor cells (EPCs). Cell autophagy of EPCs was examined through Cyto-ID Autophagy Detection Kit. CCK-8 assay and flow cytometry were carried out to assess cell viability and apoptosis under various interference conditions. Western blotting was conducted to detect the expression of interest proteins. The expression levels of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were measured by qRT-PCR. The direct interactions between HCG18 and FUS was confirmed through RNA electrophoretic mobility shift assay (RNA EMSA) and RNA immunoprecipitation (RIP) assay. RESULTS: THRIL was upregulated in CAD blood samples and EPCs. Knockdown of THRIL in EPCs promoted cell viability, inhibited cell autophagy and further suppressed the development of CAD. Over-expression of THRIL induced inactivation of AKT pathway, while knockdown of THRIL played reversed effects. THRIL directly interacted with FUS protein and knockdown of FUS reversed the over-expressing effect of THRIL on cell proliferation, autophagy and the status of AKT pathway. CONCLUSION: THRIL inhibits the proliferation and mediates autophagy of endothelial progenitor cells via AKT pathway and FUS.

Ultrasound Detection of Epicardial Adipose Tissue Combined With Ischemic Modified Albumin in the Diagnosis of Coronary Heart Disease.

OBJECTIVE: To evaluate the value of epicardial adipose tissue (EAT) thickness combined with serum ischemic modified albumin (IMA) concentration in the diagnosis of coronary heart disease. METHODS: A total of 180 patients with coronary heart disease from May 2017 to December 2018 were selected as the case group. After the examination of Judkins coronary angiography, they were grouped according to the results of angiography, including 60 patients in a single-vessel group, 60 patients in a double-vessel group, and 60 patients in a multi-vessel group. Sixty healthy people with physical examinations at our hospital at the same time were selected as the control group. All selected participants were tested for epicardial adipose tissue thickness by echocardiography and serum IMA concentration by albumin cobalt ion binding test. RESULTS: The EAT thickness and IMA concentration in the single-vessel disease group, double-vessel disease group, and multi-vessel disease group significantly were higher than those in the control group (P < .01). The ROC curve shows that the sensitivity is 53.33% and the specificity is 87.6%, when the EAT thickness is 6.12 mm. The sensitivity is 76.0% and the specificity is 72.3%, when the serum IMA concentration is 72 U/L. When the two were combined, the sensitivity was 40.15% and the specificity was 96.89%. In the parallel test, the sensitivity was 88.3% and the specificity was 65.44%. CONCLUSION: Ultrasound detection of EAT thickness and serum IMA concentration has certain reference value for the diagnosis of coronary heart disease. Combined diagnosis can significantly improve the diagnosis rate and accuracy of coronary heart disease.

Tetrahydropalmatine has a therapeutic effect in a lipopolysaccharide-induced disseminated intravascular coagulation model.

OBJECTIVES: The aim of this study was to determine the therapeutic effects of tetrahydropalmatine (Tet) on disseminated intravascular coagulation (DIC) by exploring the role of Tet using a lipopolysaccharide (LPS)-induced DIC model. Methods/Materials: We established a mouse DIC model by injecting LPS. Hematoxylin-eosin (HE) staining was performed to detect liver and kidney damage. Blood samples were obtained to determine liver and kidney injury indexes, coagulation indexes, and inflammatory cytokines. An in vitro cell inflammation model was also established. Tumor necrosis factor-α (TNF-α) levels and nuclear factor kappa B (NF-κB) signaling pathway activation were determined by western blot. RESULT: Tet ameliorated the damage to organ tissues, improved coagulation indexes, and reduced the inflammatory cytokine production in LPS-induced mouse DIC. Tet also inhibited TNF-α expression by suppressing NF-κB signaling pathway activation in an in vitro LPS model using RAW 264.7 macrophages. CONCLUSIONS: Tet has a mitigating and therapeutic effect on the LPS-induced DIC model via anticoagulant and anti-inflammatory effects, showing its potential as an adjunct to DIC treatment.

[Notch signaling pathway blocked by gamma-secretase inhibitor and its effect on the growth and apoptosis of SKOV3 cells].

OBJECTIVE: To determine the effect and mechanism of gamma-secretase inhibitor DAPT on the growth and apoptosis of human ovarian carcinoma SKOV3 cells. METHODS: The effect of gamma-secretase inhibitor DAPT was tested in vitro using SKOV3 cells. Its inhibition effect on cell proliferation was determined by CCK-8 assay. The cell apoptosis was detected by AO/EB double staining and flow cytometry. The expression of Notch1 mRNA and protein was detected by RT-PCR and Western blot. RESULTS: Compared with controls, 5 micromol/L, 10 micromol/L and 20 micromol/L of DAPT showed an effect of cell growth inhibition in a dose-dependent manner, with 19.87%, 28.38%, and 46.67% of 24 h inhibitory rates, respectively. Dose-dependent effect of DAPT on cell apoptosis was also evident, with (5.80 +/- 0.98)%, (12.96 +/- 4.99)%, (30.88 +/- 7.63)%, and (42.98 +/- 1.46)% apoptosis rates for the control, 5 micromol/L, 10 micromol/I, and 20 micromol/L DAPT groups, respectively. RT-PCR analysis demonstrated that the expression of Notch1 mRNA decreased significantly in the DAPT groups, with an inhibition rate of 10.23%, 20.50%, and 38.83% for the three DAPT groups, respectively. Western blot results demonstrated that the expression of Notch1 protein decreased significantly, with an inhibition rate of 12.89%, 27.47%, and 49.84% for the three DAPT groups, respectively. CONCLUSION: Gamma-secretase inhibitor DAPT can block Notch signaling pathway, inhibit proliferation, and induce apoptosis of SKOV3 cells through down-regulation of the expression of Notch1.